Download 2004-2005

Aichi Cancer Center
Research Institute
Scientific Report
2004 – 2005
Chikusa-ku, Nagoya 464-8681
Japan
(The Cover)
Looking the front entrance and east face of the
Main Building of Aichi Cancer Center
Research Institute over the drooping cherries
in bloom.
Published by
Dr. Toshitada Takahashi
Dr. Kazuo Tajima
Director
Aichi Cancer Center Research Institute
1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Telephone: 052-762-6111
Facsimile: 052-763-5233
Editorial Committee
Dr. Reiji Kannagi, Chief (Division of Molecular Pathology)
Dr. Kenji Wakai (Division of Epidemiology and Prevention)
Dr. Hirotaka Osada (Division of Molecular Medicine)
Dr. Hiroshi Kumimoto (Division of Central Laboratory & Radiation Biology)
Dr. Malcolm A. Moore, English Editor
Printed by
Nagoya University COOP
1 Furoucho, Chikusa-ku, Nagoya 464-0814, Japan
Contents
Preface
Takahashi Toshitada
1
Organization of the Aichi Cancer Center Research Institute
2
SCIENTIFIC REPORTS
Division of Epidemiology and Prevention
General summary
5
1. Descriptive epidemiologic studies on cancer incidence and mortality
Ito, H., Hirose, K., and Tajima, K.
5
2. The hospital-based epidemiologic research program at Aichi Cancer Center
(HERPACC) study
Hirose, K., Matsuo, K., Wakai, K., Ito, H., Saito, T.,Suzuki, T., Kuriki, K.,
Yang, C. X., Shinoda, M., Hatooka, S., Kanemitsu, Y., Hirai, T., Kato, T.,
Toyama, T., Iwata, H., Niwa, Y., Nakanishi, T., Morishima, Y.,
Nakamura, S., Yatabe, Y., Mitsudomi, T., Sugiura, T., and Tajima, K.
7
3. Nutritional factors and the risk of colorectal cancer: findings from the JACC
Study
Wakai, K. and the JACC Study Group
11
4. Comparative epidemiological study on increasing cancers focusing on Korea,
Japan and China (KOJACH study)
Matsuo, K., Wakai, K., Hirose, K., Kuriki, K., Huang, X-E.,
Yang, C. X., Takezaki, T., Hamajima, N., Gao, C-M., Mo, B-Q., Yoo, K-Y.,
Ahn, Y-O., Kim, J-S., Zhou, Z-Y., Cao, J., Li, C., Gao, F-C., Li, K.,
Tokudome, Y., and Tajima, K.
12
5. Ethnoepidemiologic study on virus-related cancer
Tajima, K., Matsuo, K., Sonoda, S., Chiba, H., Senoh, H., Tretli, S., and
Dobrodeeva, L.K.
12
Division of Oncological Pathology
General summary
1. High salt diets dose-dependently promote gastric chemical carcinogenesis
in Helicobacter pylori-infected Mongolian gerbils associated with a shift
in mucin production from glandular to surface mucous cells
Tatematsu, M., Tsukamoto, T., Mizoshita, T., Kato, S., Cao, X., Hirata, A.,
and Takasu, S.
2. HER2-driven constitutive activation of PI3K-AKT pathway is a new
potential molecular target of gefitinib (Iressa) in human gastric cancer
liver metastasis
Nakanishi, H., Yokoyama, H., Ikehara, Y., Kodera,Y., Ikehara, S. and
Tatematsu, M.
3. Sox2 expression in human stomach adenocarcinomas with gastric and
gastric-and-intestinal-mixed phenotype
Tsukamoto, T., Mizoshita, T., Takenaka, Y., Ogasawara, N. and
Tatematsu, M.
14
15
15
16
i
4.
5.
A carbohydrate recognition based drug delivery and controlled release
system using intraperitoneal macrophages as a cellular vehicle
Ikehara, Y., Nakanishi, H., Niwa, T., Biao, L., Ikehara, S., Ohashi, N.,
Kobayashi, T., Simizu, Y., Kojima, N. and Tatematsu, M.
Colonic and small-intestinal phenotypes in gastric cancers: relationships
with clinicopathologic findings
Mizoshita, T., Tsukamoto, T., Tanaka, H., Otsuka, T., Hirano, N., and
Tatematsu, M.
16
17
Division of Molecular Oncology
General summary
1. EGFR mutation is frequently detected in non-small cell lung cancer with
occasional genetic events of second mutation or amplification
Yokoyama, T., Kondo, M., Goto, Y., Fukui, T., Sato, N., Taniguchi, T.,
Kondo, Y., Osada, H., Yokoi, K., T. Shimokata, K., and Sekido, Y.
2. The ASH1 gene is a specific therapeutic target for lung cancers with
neuroendocrine features
Osada, H., Tatematsu, Y., Yatabe, Y., Horio, Y., and Takahashi, Ta.
3. A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung
cancers and enhances cell proliferation
Hayashita, Y., Osada, H., Tatematsu, Y., Yamada, H., Yanagisawa, K.,
Tomida, S., Yatabe, Y., Kawahara, K., Sekido, Y., and Takahashi, Ta.
4. Establishment and characterization of malignant pleural mesothelioma cell
lines from Japanese patients
Fukui, T., Taniguchi, T., Usami, N., Yokoyama, T., Hida, T., and Sekido, Y.
19
20
20
21
21
Division of Molecular Medicine
General summary
1. Anti-apoptotic function of API2-MALT1 fusion protein involved in
t(11;18)(q21;q21) MALT lymphoma
Hosokawa, Y., Suzuki, H. and Seto, M.
2. Molecular pathways leading to t(12; 21) TEL-AML1 associated leukemias
Tsuzuki, S. and Seto, M.
3. Cloning of a translocation partner of t(1;14)(p33;q32) in diffuse large B-cell
lymphoma
Suzuki, R., Nakamura, S. and Seto, M.
4. Comparison of genome profiles for identification of distinct subgroups of
diffuse large B-cell lymphoma
Tagawa, H., Suguro-Katayama, M., Tsuzuki, S., Morishima, Y. and
Seto, M.
5. Genome-wide array-based comparative genomic hybridization of natural
killer cell lymphoma/leukemia: different genomic alteration patterns of
aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma,
nasal type
Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S., Karube, K.,
Ohshima, K., Muta, K., Nawata, H., Morishima, Y., Nakamura, S. and
Seto, M.
ii
24
24
25
25
26
26
Division of Immunology
General summary
1. Identification of an epitope from the epithelial cell adhesion molecule
eliciting HLA-A*2402-restricted cytotoxic T lymphocyte responses
Tajima, Ko., Demachi-Okamura, A., Ito, Y., Nishida, K., Akatsuka, Y.,
Tsujimura, K., Kuwano, H., Mitsudomi, T., Takahashi, To. and
Kuzushima, K.
2. Three immunoproteasome-associated subunits cooperatively generate a CTL
epitope of the EBV-LMP2A by overcoming specific structures resistant
to epitope liberation
Ito, Y., Kondo, E., Demachi-Okamura, A., Akatsuka, Y., Tsujimura, K.,
Tanimoto, M., Morishima, Y., Takahashi, To. and Kuzushima, K.
3. A novel HLA-A*3303-restricted minor histocompatibility antigen encoded
by an unconventional open reading frame of the human TMSB4Y gene
Torikai, H., Akatsuka, Y., Miyazaki, M., Warren, E.H., Oba, T.,
Tsujimura, K., Motoyoshi, K., Morishima, Y., Kodera, Y., Kuzushima, K.
and Takahashi, To.
4. Combination of bortezomib and interferon-γ induces presentation of a newly
identified HLA-A24-restricted human papillomavirus type 16 E6-specific
cytotoxic T cell epitope
Morishima, S., Akatsuka, Y., Nawa, A., Kondo, E., Kiyono, T., Torikai, H.,
Nakanishi, T., Ito, Y., Tsujimura, K., Iwata, K., Ito, K., Kodera, Y.,
Morishima, Y., Kuzushima, K. and Takahashi, To.
5. Immunity against the mouse thymus-leukemia antigen (TL) protects against
development of lymphomas induced by a chemical carcinogenic agent,
N-butyl-N-nitrosourea
Tsujimura, K., Obata, Y., Matsudaira, Y., Taguchi, O., Nishida, K.,
Okanami, Y., Akatsuka, Y., Kuzushima, K. and Takahashi, To.
29
30
30
31
32
33
Division of Virology
General summary
1. Epstein-Barr virus lytic replication elicits ATM checkpoint signal
transduction while providing an S-phase-like cellular environment
Kudoh, A. and Tsurumi, T.
2. Architecture of replication compartments formed during Epstein-Barr virus
lytic replication
Daikoku, T. and Tsurumi, T.
3. Activation of ATM DNA damage checkpoint signal transduction elicited by
herpes simplex virus infection
Shirata, N. and Tsurumi, T.
4. Purification of the product of the Epstein-Barr virus BZLF1 gene
Nakasu, S. and Tsurumi, T.
5. Two Sp1/Sp3 binding sites in the major immediate-early proximal enhancer
of human cytomegalovirus genes is necessary for transcriptional activation
and viral replication
Isomura, H. and Tsurumi, T.
35
35
35
36
37
37
iii
Division of Molecular Pathology
General summary
1. Mechanism of loss of disialyl Lewis A and induction of sialyl Lewis A
expression in early stage human cancers
Miyazaki, K. Ohmori, K., Izawa, M., Koike, T. and Kannagi, R.
2. Tumor hypoxia augments sialyl Lewis X and sialyl Lewis A expression in
locally-advanced human cancers
Koike, T., Kimura, N., Miyazaki, K., Chen, G.Y., Yin, J., Kojima, T.,
Takematsu, H., and Kannagi, R.
3. Study on L-selectin ligand mediated homing of naïve T-lymphocytes
using gene-disrupted mice
Izawa, M., Kimura, N. Uchimura, K., Ohmori, K, Muramatsu, T.,
Rosen, S.D. and Kannagi, R.
4. ATRA-induced apoptosis in the human neuroblastoma cell line, SH-SY5Y,
is accompanied by alteration of ceramide species: Appearance of ceramide
containing hydroxy fatty acids
Hagiwara, K., Sobue, S., Kyogashima, M., Tamiya-Koizumi, K.,
Tadano-Aritomi, K., Hara, A., Aoyama, T., Murate, T. and Kannagi, R.
5. Rapid demonstration of diversity of sulfatide molecular species from
biological materials by MALDI-TOF MS
Kyogashima, M., Tamiya-Koizumi, K., Goto, Y., Hara, A., Aoyama, T. and
Kannagi, R.
6. Expression cloning of a cDNA encoding sialic acid cyclase, which generates
cyclic sialic acid containing glycoconjugates, and characterization of the
produced enzyme
Kanamori, A., Yamaguchi, M., Ishida, H., Kiso, M.+ and Kannagi, R.
7. Immune responses to retinal self-antigens in CD25 CD4+ regulatory T-celldepleted mice
Takeuchi, M., Keino, H., Kezuka, T., Usui, M. and Taguchi, O.
40
41
42
42
44
44
44
45
Division of Biochemistry
General summary
47
1. Formation of Plk1 and INCENP complexes required for metaphase-anaphase
transition
Goto, H., Kiyono, T., Tomono, Y., Kawajiri, A., Urano, T., Furukawa, K.,
Nigg, E.A. and Inagaki, M.
47
2. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation
during mitosis
Yamaguchi, T., Goto, H., Yokoyama, T., Silljé, H., Hanisch, A.,
Uldschmid, A., Takai, Y., Oguri, T., Nigg, E.A. and Inagaki, M.
48
3. Mitotic Chk1 phosphorylation at novel sites regulated by cyclin-dependent
kinase 1 (Cdk1)
Shiromizu, T., Goto, H., Tomono, Y., Bartek, J., Totsukawa, G., Inoko, A.,
Nakanishi, M., Matsumura, F. and Inagaki, M.
48
4. Functional analysis of the cytoskeleton
Izawa, I., Nishizawa, M. and Inagaki, M.
48
5. Characterization and functional analysis of novel keratin filament-binding
proteins, trichoplein and Fbf-1
Inoko, A., Zou, P., Sugimoto, M., Hayashi, Y., Kiyono, T., Izawa, I. and
iv
Inagaki, M.
6. Vimentin-Ser82 as a memory phosphorylation site in astrocytes
Oguri, T., Inoko, A., Shima, H., Izawa, I., Arimura, N., Yamaguchi, T.,
Inagaki, N., Kaibuchi, K., Kikuchi, K. and Inagaki, M.
49
49
Division of Central Laboratory & Radiation Biology
General summary
1. A single nucleotide polymorphism of the MDM2 gene in Japanese
esophageal and oral cancer patients
Kumimoto, H., Sugimura, T., Furue, H., Shinoda, M., Hatooka, S. and
Ishizaki, K.
2. DNA repair defects in AT cells and their hypersensitivity to low-dose-rate
radiation
Nakamura, Hid., Yasui, Y., Saito, N. and Ishizaki, K.
51
51
52
Central Service Unit
General summary
Nakamura, Hir., Terashima, M., Tokumasu, S., Nishizawa, M.,
Yamamoto, M., Hagino, M., Mizuno, M. and Nishi, Y.
Librarians
Yasuda, T., Teratani, M., Adachi, K. and Ieda, T.
55
56
Researches Supported by Special Project Programme
1. Defining second-hit genetic abnormalities involved in generation of t(12; 21)
TEL-AML1 acute lymphoblastic leukemias by array-based comparative
genomic hybridization
Tsuzuki, S., Karnan, S., Horibe, K., Matsumoto, K., Kato, K., Inukai, T.,
Goi, K., Sugita, K., Nakazawa, S., Ueda, R., and Seto, M.
57
Publications
1 Journals
2 Reviews and books
3. Abstracts for international conferences
58
80
83
Records of seminars
88
Records of symposia
90
Author index for research reports and publications
99
v
From left to right
The first row; Dr. M. Tatematsu (Associate Director, and Division chief of Oncological Pathology), Dr.
To.Takahashi (Director, and President as of April 2005), and Dr. K. Tajima (Associate Director as of
April 2005, and Division chief of Epidemiology and Prevention). The second row; Ms. E. Kaede, Ms. H.
Tamaki, and Mrs. M. Hosokawa (Adachi).
Preface
_______________________________________________________________________________________
It is my pleasure to share with you the 19th Scientific Report (2004-2005) of the Aichi Cancer
Center Research Institute. Since the establishment of the Institute in 1965, Scientific Reports have been
published biennially to document major research activities and highlight progress in and contributions to
cancer research worldwide.
As illustrated on the following page, the organization of the Research Institute was remodeled in
2000 to provide for 9 Divisions, consisting of three study groups: cancer prevention/ epidemiology;
preclinical/ experimental therapy; and carcinogenesis/ molecular biology. A total of 60 full-time staff
members, 44 researchers and 16 research assistants, as well as 12 research residents, are now conducting a
wide range of studies, together with 6 graduate school students affiliated with Nagoya University School of
Medicine, Nagoya, and approximately 30 visiting research fellows. The major areas being pursued are as
follows:
- descriptive and analytical epidemiology of cancers
- primary and secondary prevention of cancer
- molecular pathogenesis of gastrointestinal cancers
- molecular oncology of lung cancer
- molecular biology of translocation-junction genes of hemtopoietic tumors
- basic studies for cancer immunotherapy
- oncogenicity, molecular biology and immunology of DNA tumor viruses
- glycobiology of cancer cells in relation to metastasis
- molecular mechanisms of cell proliferation and movement
- involvement of repair mechanisms in carcinogenesis
More detailed descriptions of the research topics of each Division appear in the contents of the
report. It is our sincere hope that the activities of the Institute will make a major contribution to elucidation
of the mechanisms of carcinogenesis and to development of novel clinical applications in cancer diagnosis,
treatment and prevention.
Finally, I would like to express my deep appreciation to the Aichi Prefectural Government for the
continuous support received, since this Institute was founded in 1964. Granting support from the Ministry of
Education, Science, Sports, Culture and Technology, the Ministry of Health, Labor, and Welfare, the
Ministry of Economy, Trade and Industry, Japan, and other related organizations is also gratefully
acknowledged.
February, 2006
Toshitada Takahashi, M.D., D.Med.Sci.
Acting Director of the Research Institute
President of the Aichi Cancer Center
1
0)rganization ofthe Aichi Cancer
Center
Research
institute
Cheif AdministRatOr
M.Ban
tun宙l March,2005)
工Aoki
( a so f A p r i l , 2 0 0 5 )
President
R.Ohno
(un宙lMaに h,2005)
To.Takahashi
(as of Ap付:,2005)
Director
R.Ohno(un付 l DecembeL
2003)
工 Kato(aS Of January9 2004)
(Chief′Head)
―,Division of Epidemiology and Preventton(K.Taiima)
一 D i v i s ioofnO n c o l o g i cPaalt l l o l o g y ( M . T a t eum)a ほ
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J M d e t t l a rO n ∞ , o 9 y 将
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一 D i v i s oi foM no l e c u Ml ea dr i c i n e ( M . S e t O )
一 DMdon
Director
To.Takahashi
Associate Directors
M.Tatematsu
一 D i v i s i oonf l m m u n o : o g y ( K . K u z u s h i m a )
一 DMtton ofVirologytt Tsuttmり
K.千封ima
一 Division of Molecular Pathology(R.Kannagi)
(as of Ap甫12005)
―B Division of Blochemisw
(M・inagaki)
一 Central
Laboratory&Radiatton
Biclogy(ェ
ishiZaki)
_Central
Service Un忙 (HぃNakamura)
一 Animal Fadnty(M.Tatematsu)
一 Laboratory of Transiational Research
SCIENTIFIC REPORTS
From left to right
First row: Dr. H. Ito, Dr. K. Matsuo, Dr. K. Wakai, Dr. K. Tajima, Dr. K. Hirose, and Ms. T. Saito.
Second row: Ms. C. Yoshida, Ms. S. Hiraiwa, Ms. T. Sato, Ms. M. Watanabe, Ms. Y, Yamauchi, and Ms.
M. Nakano.
Third row: Dr. T. Suzuki, Dr. K. Kuriki, Ms. M. Sato, Mr. N. Ito, Ms. K. Hasegawa, Ms. K. Mizutani, Ms.
H. Achiwa, and Ms. S. Inui.
Inset: Ms. H. Fujikura, Ms. K. Fukaya, Ms. Y. Kamori, Ms. K. Tomita, Ms. T. Nishiwaki, Ms. C. Kanto,
and Ms. K. Suganuma.
4
Division
of Epidemiology and Prevention
________________________________________________________________________________
Kazuo Tajima, M.D., D.M.Sc., M.P.H. Chief
Kenji Wakai, M.D., PhD. Section Head
Kaoru Hirose, B.P., D.M.Sc. Senior Researcher
Keitaro Matsuo, M.D., PhD., S.M. Researcher
Hidemi Ito, M.D., PhD Researcher (As of April 2004)
Takeshi Suzuki, M.D. Research Resident (As of April 2005)
Toshiko Saito. Research Assistant
Visiting Trainees
Kiyonori Kuriki, B.P., D.M.Sc. Postdoctoral Fellow (Until March 2005) and Research Resident of Foundation
for Promotion of Cancer Research (As of April 2005)
Chuanxia Yang, M.D., West China University of Medical School, Chengdu, China (April 2004-March 2005)
Takeshi Suzuki, M.D. Nagoya City University Medical School (December 2004- March 2005)
Xinen Huang, M.D. Nagoya City University Medical School (Until March 2004)
Kosuke Amano, M.Ed. Showa University School of Medicine
Sanae Ikehara, Dept. of Epidemiology, Nagoya University Graduate School of Medicine
General Summary
The current research activities of the Division of Epidemiology and Prevention cover the following four subjects: 1) descriptive epidemiology of cancer incidence and mortality, with special
reference to improvement of the Aichi Prefectural Cancer Registry; 2) analytical epidemiology
based on the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC)
to determine risk and protective factors for main sites of cancer, with a particular focus on
gene-environment interactions; 3) a multi-institutional collaborative cohort study on nutritional
factors and cancer risk in Japan; 4) a Korea, Japan and China (KOJACH) collaborative study on increasing cancers for establishment of future prevention programs in each country; 5) ethnoepidemiology of tumor viruses among Mongoloids in the Asian-Pacific area.
Descriptive epidemiologic studies are necessary for nation-wide statistics like “Vital Statistics Japan”. With the new model regional cancer registry in Aichi Prefecture established in 1999, a
well organized data collection system and a risk evaluation trial of cancer in smokers and/or drinkers are now in operation. A large-scale HERPACC study was completed for more than 130,000 new
outpatients and a third version of HERPACC incorporating the Japan Multi-institutional Collaborative Cohort (J-MICC) was started in 2005 to clarify gene-environment interactions for modification
of carcinogenicity. In addition to local epidemiologic studies, international collaborative studies in
Northeast Asian countries (KOJACH Study) and the North Pole region are ongoing to obtain ethnoepidemiologic evidence of cancer risk among selected Asian populaces. Furthermore, primary
prevention trials are being conducted for control of obesity by improvement of dietary habits and
promotion of daily exercise.
Cancer prevention is the final goal of our epidemiological studies. Recently, we have been
concentrating attention on molecular epidemiology to clarify interactions between host-specific
characters and lifestyle exposure to risk factors, particularly with regard to actual functions of
metabolic and detoxifying enzymes associated with genetic polymorphisms.
1. Descriptive epidemiological studies on
cancer incidence and mortality
Ito, H., Hirose, K., and Tajima, K.
Impact of habitual smoking on cancer stage
at diagnosis based on Aichi cancer registry data:
Since 1999, information on smoking habits of cancer patients has been collected by Aichi Cancer
Registry. The purpose of this study was to examine
the risk impact of habitual smoking on cancer stage
at diagnosis by site using data registered of the Aichi Cancer Registry, Japan. The study subjects were
registered cancer cases aged 20 or over and diagnosed between 1999 and 2003. The relationship
between cancer stage at diagnosis (local, regional or
metastatic) and smoking history (never or ever) was
5
Figure 1. Smoking history and risk of metastatic and regional spread of cancer by site.
ORs of smoker group relative to non-smoker group.
assessed using a simple comparative approach. A
total of 66,400 cancer patients with smoking history
and cancer stage at diagnosis were registered up until 2004. Fifty-six percent were male and 44% were
female. The mean age was 64 years. Ever smokers
had increased risks of regional (odds ratio (OR),
1.27; 95% confidence interval (CI), 1.21 to 1.32;
p<0.001) and metastatic (OR, 1.30; 95% CI, 1.24 to
1.36; p<0.001) disease. The increase in regional
disease was most evident for oral & pharynx (OR,
1.38; 95%CI, 1.10-1.73), larynx (OR, 1.66; 95%CI,
1.01-2.73), lung (OR, 1.74; 95%CI, 1.50-2.02),
breast (OR, 1.31; 95%CI, 1.12-1.53), and uterus
(OR, 1.38; 95%CI, 1.09-1.75) cancers. Increase in
metastatic disease was most evident for the lung
(OR, 1.46; 95%CI, 1.26-1.69) and breast (OR, 1.80;
95%CI, 1.35-2.40) cancer (Figure 1). The data for
smoking status of cancer patients collected by regional cancer registration can thus be utilized to
evaluate relationships to cancer stage at diagnosis.
Ever smoking appears to be a risk factor for advanced cancers in a wide range of body sites.
Trends in cancer mortality in Japan: Cancer
mortality statistics in Japan (1950-2003) were calculated from the ‘Vital Statistics, Japan’ series.
The age-standardized death rate for all sites of cancer has been stable in males in recent years, and
gradually decreasing in females (Figure 2). The
mortality rate from stomach cancer has been decreasing in both sexes, while that from lung cancer
has been increasing, becoming stable more recently.
In 2003 the numbers of all deaths from malignant
neoplasms were 186,912 for men and 122,631 for
women. Regarding cancer causing, lung cancer is
the most common, accounting for 22.3% of all cancer deaths for males, followed by stomach cancer
with 17.2% and hepatic cancer with 12.5%, while
colorectal cancer is the most common for females
Figure 2. Time trends in age-adjusted
mortality rate for cancer in Japan, 1960-2003 (Standard
population: 1985 model population of Japan).
6
with 14.6%, followed by stomach cancer with
14.2% and lung cancers with 12.3%.
2. The hospital-based epidemiologic research program at Aichi Cancer Center
(HERPACC) study
Hirose, K., Matsuo, K., Wakai, K., Ito. H, Saito, T.,
Suzuki, T., Kuriki, K., Yang, C. X., Shinoda,
M.*1,Hatooka, S.*2, Kanemitsu, Y.*3, Hirai, T.*3, Kato,
T.*3, Toyama, T.*4, Iwata, H.*4, Niwa, Y.*5, Nakanishi,
T.*5, Morishima Y.*6, Nakamura, S.*7, Yatabe, Y.*8,
Mitsudomi, T.*9, Sugiura, T.*10, and Tajima, K.
Molecular epidemiology of folate and gastrointestinal tract cancer risk:
1) Esophageal cancer: Folate takes part in two biological pathways involved in DNA methylation and
synthesis and a potential protective influence
against carcinogenicity is now recognized in several
sites, including the esophagus. Therefore, functional
polymorphisms in encoding genes in folate metabolizing enzymes, MTHFR C677T and MTR A2756G,
might be suspected of impacting on esophageal
cancer risk. To test this hypothesis we conducted a
matched case-control study with 165 esophageal
cancer cases and 495 non-cancer controls to clarify
associations among folate intake, MTHFR C677T
and MTR A2756G polymorphisms and cancer risk.
Gene-environment interactions between the two
polymorphisms and drinking and smoking were
also evaluated. Folate consumption and MTHFR
677TT were associated with a non-significant tendency for decreased risk while MTR genotypes did
not show themselves demonstrate any significant
influence; further, when analysis was limited to
heavy drinkers, the MTHFR TT genotype signifi-
cantly decreased esophageal cancer risk (odds ratio
(OR)=0.27, 95% confidence interval (CI):
0.09-0.76). The OR for the gene-environment interaction between heavy drinking and the 677TT
genotype with a case-only design was 0.31
(0.10-0.94), indicating risk with heavy drinking to
be 69% decreased in individuals harboring the
677TT genotype. We failed to find any significant
interaction between either of the polymorphisms
and smoking.
2) Colon cancer: One-carbon metabolism, in which
folate plays an essential role, is involved in DNA
methylation and synthesis and is suspected of impacting on colorectal carcinogenesis. Alcohol is
well recognized as a risk factor for colorectal cancer
(CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members
of this pathway, MTHFR C677T and A1298C, MTR
A2756G and TS tandem repeats polymorphisms,
have attracted attention. We here conducted a
matched case-control study with 257 incident CRC
cases and 771 non-cancer controls at Aichi Cancer
Center to clarify associations among folate intake
and four polymorphisms with reference to CRC risk.
Gene-environment interactions between polymorphisms, drinking and folate consumption were also
evaluated. None of the polymorphisms was associated with any significant impact on CRC risk by
genotype alone, but when combined with alcohol
consumption, the MTHFR 677CC type showed a
significantly reduced risk (OR=0.45, 95% confidence interval (CI): 0.23-0.86) (p=0.01). MTR GG
increased risk only among drinkers (OR=3.35,
1.40-8.05) (p=0.047). The TS polymorphism did
not have a significant impact by genotype alone, but
Figure 3. Dietary factors inversely associated with the risk of (a) colon and (b) rectal cancer (Q1-Q4: quartiles 1-4) in
the HERPACC II Study.
7
interaction with drinking was evident (p=0.028),
even after stratification by daily folate consumption
and drinking habit.
Dietary factors and colorectal cancer risk (Figure 3): In Japan, the incidence rate for colon cancer
has more rapidly increased than that for rectal cancer. To compare dietary risk factors between colon
and rectal cancers, we undertook a case-control
study using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center
(HERPACC). Subjects included 507 men and
women with newly diagnosed colon (n = 265) and
rectal (n = 242) cancers, and 2,535 age- and gender-matched, cancer-free outpatients (controls). Intakes of nutrients and food groups were assessed
with a food frequency questionnaire, and multivariate-adjusted odds ratios (ORs) were estimated using
conditional logistic models. We found a decreasing
risk of colon cancer with increasing intakes of vitamin C and fruit; the ORs across quartiles of intake
were 1.00, 0.90, 0.72, and 0.72 (95% CI: 0.47-1.11;
trend p = 0.089) for vitamin C, and 1.00, 0.85, 0.67,
and 0.68 (95% CI: 0.45-1.03; trend p = 0.036) for
fruit. For rectal cancer, higher consumption of meat
and green-yellow vegetables was associated with a
reduced risk; the ORs for the highest versus lowest
quartile were 0.65 (95% CI: 0.42-1.02) and 0.62
(95% CI: 0.39-0.99), respectively. A decreased risk
associated with higher intakes of insoluble dietary
fiber was observed for colon cancer (OR for the
highest quartile: 0.57; 95% CI: 0.37-0.89) but only
suggested for rectal cancer. Carbohydrate intake
was correlated particularly with the risk of female
rectal cancer. In conclusion, differences in secular
trends and in international distributions of incidence
between the two colorectal sites may partly be attributable to variation in dietary risk factors.
Colorectal cancer risk and erythrocyte composition of fatty acids as biomarkers for dietary
habits: Fish consumption rich in n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic
acid (DHA), is suggested to reduce colorectal cancer risk through inhibiting the arachidonoic acid
(AA) cascade related to tumorigenesis and cell proliferation. High intake of saturated fatty acids
(SFAs), in contract, appears to increase the risk. To
examine associations between colorectal cancer risk
and the fatty acid composition of erythrocyte membranes, reflecting dietary intake of fish, fat and fatty
acids, we conducted a case-control study with 74
incident cases and 221 non-cancer controls
(matched by age, sex and season of data collection).
Erythrocyte fatty acids were measured by a
semi-automatic method using accelerated solvent
extraction and gas-liquid chromatography. Colorectal cancer incidence risk had no association with
dietary intake of meat, fish, fat and fatty acids.
However, the risk was inversely associated with
erythrocyte compositions of PUFAs, AA and DHA
[highest to lowest tertile, odds ratios (ORs) = 0.15,
0.42 and 0.36, 95% confidence intervals (CIs) =
0.05 to 0.46, 0.18 to 0.95 and 0.14 to 0.93, Ptrend
<0.05 to 0.005], and positively with those of SFAs,
palmitic acid and the ratio of SFAs/PUFAs (ORs =
8.20, 6.46, and 9.45, 95% CIs = 2.86 to 23.52, 2.41
to 17.26, and 2.84 to 31.43, Ptrend <0.005 to 0.0001,
Figure 4). We thus demonstrated colorectal cancer
risk to be clearly related to fatty acid composition in
erythrocyte membranes, but further studies are required to clarify the apparent discrepancy that a
high erythrocyte composition of AA may also reduce risk.
Protective and risk factors for hormone related
cancer in women:
1) Soybean products and reduction of breast cancer
risk: Components of the Japanese diet which might
contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in de-
Figure 4. Decreased (left) and
increased (right) risks for colorectal cancer according to associations with fatty acid compositions in erythrocytes.
8
tail. Since soybean products are widely consumed
in Japan a case-control study taking account of the
menopausal status was conducted using data from
the hospital-based epidemiologic research program
at Aichi Cancer Center (HERPACC). In total, 167
breast cancer cases were included and 854 women
confirmed as free of cancer were recruited as the
control group. Odds ratios (OR) and 95% confidence intervals (95%CI) were determined by multiple logistic regression analysis. Reduction in risk
of breast cancer was associated with high intake of
soybean products among premenopausal women,
the adjusted OR for the top tertile intake of tofu
(soybean curd) being 0.51 (95%CI, 0.26-0.98)
compared with women in the lowest tertile. A
significant decrease in premenopausal breast cancer
risk was also observed for increasing consumption
of isoflavones (OR=0.45, 95% CI:0.23-0.89 for
highest vs. lowest tertile, p for trend=0.02). The
present study found a statistically inverse association between tofu or isoflavone intake and risk of
breast cancer in Japanese premenopausal women
while no statistically significant association was
evident with the risk among postmenopausal
women.
2) Coffee consumption and reduction of endometrial cancer risk: Coffee has become a popular
beverage worldwide and because it contains large
amounts of antioxidants, such as chlorogenic acids,
there has been increasing interest in possible beneficial health effects. Caffeine, a major ingredient
of coffee, has been proposed to modulate circulating estrogen levels and therefore may also be of
importance for cancer development. To test this,
we examined the relationship between intake of
coffee and hormone related cancer risk among
Japanese women using data from the hospital-based
epidemiologic research program at Aichi Cancer
Center (HERPACC). In total, 2,122 breast, 539
cervical, 229 endometrial and 166 ovarian cancer
cases were included, and 12,425 women, confirmed
as free of cancer, were recruited as the control
group. A statistically significant inverse association between risk of endometrial cancer and coffee
consumption was noted in our Japanese women,
with no clear associations evident for breast, cervical or ovarian cancer risk. The ORs for daily
drinking of 1-2 cups and 3 or more cups per day for
endometrial cancer were 0.64(95%CI:0.43-0.94)
and 0.41 (95%CI:0.20-0.88), respectively, and the
linear trend was also statistically significant
(p<0.01). The effect of coffee intake on risk of
endometrial cancer was most prominent among
leaner women (BMI=<22). In summary, the results of the present study suggested that coffee
consumption reduces the risk of endometrial cancer
in Japanese, especially in relatively lean women.
3) The CYP19 gene codon39 Trp/Arg polymorphism increases breast cancer risk in subsets of
premenopausal Japanese: The production of estrogen from androgen via the estrogen biosynthesis
pathway is catalyzed by aromatase P450 (CYP19).
To assess the association between breast cancer risk
and a polymorphism at codon 39 ( Trp to Arg ) of
the encoding gene, a case-control study was conducted at Aichi Cancer Center Hospital in Japan.
Subjects were 248 histologically confirmed breast
cancer patients and 603 hospital controls without
cancer. Odds ratios (ORs) and 95% confidence
intervals (95%CI) were determined by logistic regression analysis. The allele frequency among
controls was 3.8% for the C allele and the OR of the
polymorphism relative to the TT-genotype was 1.21
(95% CI:0.69-2.14) for the TC/CC-genotypes combined. There was no association between the
CYP19 gene polymorphism and breast cancer risk
in the study group as a whole but homozygous and
heterozygous carriers of the variant Arg allele
showed a significantly increased risk of breast cancer among premenopausal women with a late age at
first-full term pregnancy (OR=7.31, 95%CI:
1.88-28.5) or a high BMI (OR=2.77, 95%CI:
1.12-6.87). Additional larger studies should be
performed to confirm that the rare CYP19 variant
increases the risk of breast cancer among premenopausal Japanese women.
Hematopoietic cancer: Recent increase in the incidence of malignant lymphoma (ML) suggests
possible involvement of environmental factors in its
genesis. Medical conditions could be one potential
candidates and their identification may provide
clues for future prevention. We focused on peptic
ulcer history on ML risk and conducted a
case-control study with 645 patients histologically
diagnosed as having malignant lymphomas and
3225 non-cancer controls. Plasma H. pylori IgG
status was assessed for subgroups for which blood
samples were available (116 cases and 114 controls). An association with a history of gastric, but
not duodenal ulcers was found for gastric lymphomas [odds ratio (OR) = 5.41, 95% confidence interval (CI): 3.12 - 9.39]. On examination according
to histological subtype, the Ors were high for both
gastric mucous-associated lymphoid tissue (MALT)
lymphoma (OR = 5.54, 95% CI: 2.56 - 12.01) and
diffuse large B-cell lymphoma (DLBCL) (OR =
9
7.23, 95% CI: 2.62 - 19.90). Further, on subgroup
analysis of subjects with H. pylori infection, gastric
ulcer history, but not duodenal ulcer history was
associated with the risk of gastric lymphoma (OR =
4.15, 95% CI: 1.02 - 16.89). This observation is
quite similar to the association between gastric
cancer and peptic ulcer history, suggesting a similar
mechanism underlying effects on gastric cancer and
gastric lymphoma development.
Molecular epidemiology of lung cancer: APE1
(apurinic/apyrimidinic endonuclease 1) and XRCC1
(X-ray cross-complementing group 1) are DNA repair proteins that play important roles in the base
excision repair (BER) pathway. Polymorphisms in
their encoding genes are associated with altered
DNA repair capacity and thus may impact on cancer risk. In a case-control study with 178 Japanese
incident lung cancer cases and 449 age- and sexmatched controls, we therefore investigated
gene-environment interactions among APE1
Asp148Glu, XRCC1 Arg399Gln, and smoking habit
in lung cancer risk. The results were analyzed using
conditional logistic regression models, adjusted for
age, sex and smoking status. The adjusted odds ratio for the current smokers with APE1 148Asp/Asp,
Asp/Glu and Glu/Glu genotypes as compared with
the never smokers with the Asp/Asp genotype were
3.01 (95% CI 1.39-6.51, p= 0.005), 2.73 (1.29-5.77,
p=0.008) and 7.33 (2.93-18.3, p<0.001), respectively. The gene-environment interaction between
current smoking and APE1 148Glu/Glu genotype
was statistically significant (OR 3.59, 1.28-10.1,
p=0.015). When APE1 Asp148Glu and XRCC1
Arg399Gln polymorphisms were evaluated together,
the adjusted odds ratios for current smokers with
0-1, 2 and 3-4 of APE1 148Glu or XRCC1 399Gln
alleles as compared with never smokers with the
rare of these alleles were 2.96 (1.57-5.58, p=0.001),
3.86 (1.85-8.05, p<0.001) and 6.01 (2.25-16.1,
p<0.001), respectively. The gene-environment interaction between current smoking and 3 or more
APE1 148Glu or XRCC1 399Gln alleles was statistically significant (OR 2.44, 1.00-9.22, p=0.049).
The OR for the gene-environment interaction of the
Glu/Glu genotype of the APE1 codon 148 with
heavy smoking was 1.04 (0.38-2.90, p=0.936) and
that with light smoking was 2.67 (1.00-7.68,
p=0.049). These results suggest that APE1
Asp148Glu and XRCC1 Arg399Gln polymorphisms
might modify the risk of lung cancer attributable to
cigarette smoking exposure.
Smoking behavior modification:
1) Interleukin 8 (IL8) polymorphisms and smoking
10
behavior in Japanese: Accumulating evidence indicates that the genotype may impact on smoking
behavior and a deeper understanding of the molecular basis could lead to more effective strategies
for preventing initiation of the habit and for helping
smokers to quit. Since individual variation in airway responsiveness to cigarette smoke might have
an important influence, we have focused on association between smoking behavior and polymorphisms affecting the inflammatory cytokine, IL-8.
In the present study, 453 Japanese non-cancer outpatients (191 males and 262 females) who visited
Aichi Cancer Center Hospital were genotyped for
the IL8 -251T/A polymorphism and age- and sexadjusted odds ratios (aORs) for smoking were estimated by a logistic regression model. The aORs for
IL8 251-TA and AA combined, genotypes associated
with high production of IL-8, were 0.52 (95% CI
0.33-0.82, p=0.004) for being an ever smoker and
0.55 (0.55, 0.33-0.92, p=0.023) for being a current
smoker. Our results suggest that the inflammatory-prone genotype of IL8 may act to deter initiation or characteristics of the smoking habit.
2) Smoking cessation inducement by providing information on the L-myc genotype: To evaluate
whether feedback of genetic information regarding
an L-myc polymorphism, identified as impacting on
tobacco-related cancer risk, has an influence on
smoking cessation, an intervention study was conducted. We recruited smokers from first-visit outpatients at Aichi Cancer Center Hospital. Six hundred
and seventeen participated and were allocated into
two groups: the biomarker-feedback group (BF) and
the follow-up smoking-status group (FS). The subjects were asked for their smoking status at enrolment and after 3- and 9-months follow-up. BF subjects were notified about their L-myc genotype. The
smoking cessation rate at 9-months follow-up was
essentially the same for both BF and FS cases, at
18.8% and 17.0%, respectively (p=0.798). However,
a difference in the rate was evident with non-cancer
subjects (12.7% and 8.4%, respectively, p=0.237),
especially in females (15.0% and 4.2%, respectively,
p=0.024). The non-cancer subjects informed of
their genotype were more likely to quit smoking
than the FS patients; particularly in those having a
risky genotype this was significant (odds ratio: 2.87,
p=0.003). Again it was most prominent in females.
In conclusion, feedback regarding an L-myc polymorphism did not impact on smoking cessation
overall, but appeared to benefit smokers without
cancer. In addition, gender could affect the response
to the feedback.
Introduction of the J-MICC Study: The Japan
Multi-Institutional Collaborative Cohort (J-MICC)
Study is a new multi-center approach to elucidate
environmental and genetic risk factors for cancer
and other lifestyle-related diseases. In this project,
three types of studies are planned: 1) follow-up to
clarify associations between development of disease
and lifestyle factors, genotypes, and other biomarkers, or their combinations; 2) search for biomarkers useful for early detection of disease particularly of cancer; and 3) cross-sectional studies
relating to lifestyle, genotypes, and biomarkers.
Men and women aged 35 to 69 years are to be recruited for the study by about ten institutions
throughout Japan from the general population, examinees of health check-ups, or hospital patients,
with a targeted number of 100,000. The subjects are
being requested to complete a questionnaire on lifestyle and medical factors and also to donate blood
samples including buffy coat, plasma, and serum.
They will be followed up for death and cancer incidence by review of death certificates or medical records, linkage with cancer registries, mail surveys,
etc., until March 2025. After hot discussion on the
protocol, especially on its ethical issues, the study
was launched in October 2005. We, the Division of
Epidmiology and Prevention, are taking part in the
J-MICC Study as a study center and have been recruiting participants of the study together with those
of the HERPACC at the Aichi Cancer Center Hospital since November 2005.
*1
*2
*3
*4
*5
*6
*7
*8
*9
*10
Department of Rehabilitation, Aichi Cancer Center
Hospital
Department of Thoracic Surgery, Aichi Cancer Center Hospital
Department of Gastroenterological Surgery, Aichi
Cancer Center Hospital
Department of Breast Oncology, Aichi Cancer Center
Hospital
Department of Gynecologic Oncology, Aichi Cancer
Center Hospital
Department of Hematology and Cell Therapy, Aichi
Cancer Center Hospital
Department of Pathology, Graduate School of Medical Sciences, Nagoya City University
Department of Pathology and Molecular Diagnostics,
Aichi Cancer Center Hospital
Department of Thoracic Surgery, Aichi Cancer Center Hospital
Department of Thoracic Oncology, Aichi Cancer
Center Hospital
3. Nutritional factors and the risk of colorectal cancer: findings from the JACC
Study
Wakai, K. and the JACC Study Group
The Japan Collaborative Cohort (JACC) Study
is a large-scale prospective study conducted in 45
areas throughout Japan. The cohort was established
from 1988 to 1990, when 110,792 inhabitants aged
40 to 79 years completed a questionnaire on lifestyle and medical history. About 35% of the participants donated blood samples. To elucidate the
role of nutritional factors in the etiology of colorectal cancer, we analyzed data from the study. Major
findings of the analyses are as follows. (a) The association of serum carotenoid levels with colorectal
cancer risk may be modified by sex. In a
nested-case control study, a higher level of serum
total carotenoids was associated with a decreased
risk in men (the odds ratio [OR] for the highest
versus the lowest tertile: 0.34; 95% CI: 0.11-1.00;
trend P over tertiles: 0.040), whereas its higher
level was related to a somewhat increased risk in
women (the corresponding OR: 2.47 [95% CI:
0.73-8.34]; trend P: 0.064). (b) Male ex- or current
drinkers demonstrated a twofold risk for colon cancer compared with nondrinkers: the incidence rate
ratio (IRR) was 2.01 (95% CI: 1.09-3.68) for
ex-drinkers and 1.97 (95% CI: 1.28-3.03) for current drinkers. (c) An inverse correlation was observed between intake of dietary fiber and the risk
of colon cancer; the IRRs across quartiles were 1.00,
1.18, 0.50, and 0.68 (95% CI: 0.38-1.21; trend P:
0.049) in men and 1.00, 0.69, 0.67, and 0.59 (95%
CI: 0.34-1.01; trend P: 0.061) in women. (d) Intake
of fat, particularly that of animal or saturated fat,
was associated with an increased risk of colon cancer. In men, the IRRs over quartiles were 1.00, 1.25,
1.86, and 1.81 (95% CI: 1.05-3.11) for total fat
(trend P: 0.015), 1.00, 1.41, 1.75, and 2.06 (95%
CI: 1.24-3.41) for animal fat (trend P: 0.003), and
1.00, 1.98, 2.83, and 2.38 (95% CI: 1.35-4.20) for
saturated fat (trend P: 0.001). Although we found
no significant dose-response relationship for total or
saturated fat in women, an increasing trend in colon
cancer risk was detected with an increasing intake
of animal fat. The IRRs across quartiles of intake
were 1.00, 1.08, 1.33, and 1.65 (95% CI: 1.02-2.67;
trend P: 0.035).
11
4. Comparative epidemiological study on
increasing colorectal and breast cancers focusing on Korea, Japan and
China (KOJACH study)
5. Ethnoepidemiologic study on virus-related cancer in Mongoloids
Matsuo, K., Wakai, K., Hirose, K., Kuriki, K., Huang,
X-E., Yang, C. X., Takezaki T., Hamajima N., Gao
C-M.*1, Yoo K-Y.*2, Ahn Y-O.*2, Cao J.*3, Pan I-M.*4
Li K.*5, Tokudome Y.*6, and Tajima, K.
Human T-cell leukemia virus type 1 (HTLV-1),
the main cause of adult T-cell leukemia/lymphoma,
is found throughout the world but with microgeographical clusters of hyperendemicity. Epidemiologic studies among Mongoloids showed that
HTLV-1 is highly endemic in South Japan (one
million carriers) and in the Andes district of South
America. In contrast, HTLV-II (also a risk factor
for adult T-cell leukemia/lymphoma) is broadly
distributed in all of South America, except the Andes line. After sero-epidemiologic studies on
HTLV-I antibodies among Tibetan people in China
and Sahme people in North Norway in 2001 and
2003 respectively, we conducted field work in the
Nenets Autonomous District of the Arkhangelsk
Region in northwestern Russia. In total, 105 blood
samples from Nenets people of Krasnoe were collected in collaboration with Institute of Physiology
of Adaptations to Environment, the Ural Branch of
the Russian Academy of Sciences. No individuals
positive for anti-HTLV-I were detected in the indigenous Nenets people, in line with the HTLV-I/II
clusters among Mongoloids in other areas of the
Asian Pacific.
To establish a basis for cancer prevention in the
Asian Pacific region, we started a case-referent
study on increasing cancers since 2000, based on a
standardized epidemiological approach, in Korea
(Seoul), Japan (Nagoya) and China (Nanjing,
Chongqing, Benxi and Shantou), the so called
KOJACH Study. In Korea they developed their own
SQFFQ and we established semi-quantitative food
frequency questionnaires (SQFFQs) in the four cities in China. The validity and reproducibility of all
SQFFQs established in Korea and China were
evaluated for further epidemiologic studies. We
have collected lifestyle data by standardized
SQFFQs and blood samples for plasma and DNA
after obtaining informed consent from more than
1,600 colorectal cancer cases in each area in Korea,
Japan and China. The same number of referents
matched by age and sex were recruited from hospital patients in Korea and Japan and from the general
population in China. A detailed analysis is now
ongoing to clarify risk and protective factors for
colorectal cancer in each of the three countries and
areas of China using data for lifestyle, genetic
polymorphisms and interactions. Furthermore, other
case-referent studies on breast cancer were also initiated in June 2005.
*1
*2
*3
*4
*5
*6
12
Division of Epidemiology, Cancer Institute of Jiangsu Province, Nanjing, China
Department of Preventive Medicine, College of
Medicine, Seoul National University, Seoul, Korea
Laboratory of Molecular Toxicology, Third Military
Medical University, Chongqing, China
Bengan General Hospital, Benxi, China
Department of Epidemiology, Shantou University,
Shantou, Chian
Life Science, Nagoya Bunri College
Tajima, K., Matsuo, K., Sonoda, S.*1, Chiba, H.*2, Senoh,
H.*3, Tretli, S.*4 , and Dobrodeeva, L.K. *5
*1
*2
*3
*4
*5
Department of Virology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan
Department of Laboratory Medicine, Hokkaido
University School of Medicine, Sapporo, Japan
Department of Anatomy, Akita University School of
Medicine, Akita, Japan,
Institute of Population-based Cancer Research, Oslo,
Norway
Department of Ecological Immunology, Institute of
Physiology of Adaptations to Environment, the Ural
Branch of the Russian Academy of Sciences, Arkhangelsk, Russia
From left to right
First row: Dr. T. Mizoshita, Dr. T. Tsukamoto, Dr. M. Tatematsu, Dr. H. Nakanishi and Dr. Y. Ikehara
Second row: Mrs. C. Ikedo, Dr. N. Hirano, Dr. Y. Takenaka, Mr. H. Tanaka, Mr. H. Asahara, Mrs. H.
Ban
13
Division
of Oncological Pathology
________________________________________________________________________________
Tatematsu Masae, M.D. Chief
Hayao Nakanishi, M.D. Section Head
Tetsuya Tsukamoto, M.D. Section Head
Yuzuru Ikehara, M.D. Senior Researcher (until Mar, 2006)
Tsutomu Mizoshita, M.D. Researcher
Harunari Tanaka, B.P., Research Assistant
Hisayo Ban, Semi-regular Employee
Mikako Asai Semi-regular Employee (until Nov, 2005)
Visiting Scientists
Malcolm A. Moore, Ph.D. Asian Pacific Organization for Cancer Prevention
Kato Kazuo, M.D., Fujita Health University School of Medicine
Visiting Trainees
Xueyuan Cao, M.D., Dept. of Gastrointestinal Surgery, The University of Tokyo
Yoshiharu Takenaka, M.D., Dept. of Gastrointestinal Surgery, The University of Tokyo
Takasuke Yamachika, M.D., Kita Hospital
Akihiro Hirata, D.V.M. Dept. of Veterinary Pathology, Gifu University
Shinji Takasu, D.V.M. Dept. of Veterinary Pathology, Gifu University
Yoshiyuki Yokoyama, M.D. Dept. of Surgery II, Nagoya University School of Medicine
Norifumi Ohashi, M.D. Dept. of Surgery II, Nagoya University School of Medicine
Kenji Tsuboi, M.D. Dept. of Surgery II, Nagoya University School of Medicine
Yuichi Ito M.D. Dept. of Surgery II, Nagoya University School of Medicine
Sanae Ikehara, Dept. ofEpidemiology, Nagoya University Graduate School of Medicine
Toru Niwa, M.D., Dept. of Internal medicine II, Wakayama Medical College
Takafumi Otsuka, M.D., Dept. of Internal medicine I, Toho University School of Medicine
Naoki Hirano M.D., Dept. of Internal medicine I, Toho University School of Medicine
Sousuke Katoh, M.D., Dept. of Internal medicine III, Hokkaido Univesity School of Medicine
Naotaka Ogasawara, M.D., Dept. of Internal Medicine and Bioregulation, Nagoya City University of Medicine.
Yoshikazu Hirata M.D., Dept. of Internal Medicine and Bioregulation, Nagoya City University of Medicine.
Masayasu Hara, M.D., Dept. of Gastroenterological Surgery, Nagoya City University of Medicine.
Mistuo Gotoh, D.D.S., School of Dentistry, Aichi-Gakuin University
Yasushi Seki, D.D.S., School of Dentistry, Aichi-Gakuin University
Fumi Ono, D.D.S., School of Dentistry, Aichi-Gakuin University
Atsutaka Kinoshita, D.D.S., School of Dentistry, Aichi-Gakuin University
Shinya Satoh, M.D., Aichi Cancer Center Hospital
Chihiro Aoki, College of Bioscience and Biotechnology, Chubu University
Hisayoshi Asahara, College of Bioscience and Biotechnology, Chubu University
General Summary
The responsibility of the Division of Oncological Pathology includes autopsy and research
activities. From the establishment of this laboratory in 1965 to the end of 2005, the number of autopsy cases amounted to 2568. Postmortem examinations are a source of valuable information on
the behavior of neoplasms and their response to therapy. Autopsy findings also supply the basis
for total evaluation of the course of disease, including the accuracy of clinical diagnosis, effectiveness or failure of drugs, irradiation and surgery, and the appearance of complications such as opportunistic infection and hemorrhage during treatment.
Main theme of this laboratory is the carcinogenesis and the progression of gastrointestinal
malignancies. During 2004-2005, the research activities are divided into the following four main
areas. The first deals with the molecular basis and detection of chemical carcinogenesis and initiation and promotion activities. In vivo five-week initiation assay model revealed heterocyclic amines,
food-derived carcinogen, revealed interference each other. The second concerns gastric cancers and
14
their precancerous lesions along with the mechanisms regulating differentiation of stomach epithelium in humans as well as rodent models. High salt diet and younger acquisition of Helicobacter
pylori (Hp) exacerbate inflammation and incidence of stomach adenocarcinomas. On the other hand,
earlier eradication well suppressed stomach carcinogenesis. Molecular mechanism of intestinal
metaplasia, major complication of Hp infection, includes alteration of gastric and intestinal transcription factors. The third research area involves basic research on tumor progression and metastasis, especially micrometastasis and its clinical application for prevention of recurrent disease after
surgery. A new potential molecular therapy targeting to HER2 overexpression using gefitinib in
gastric cancer liver metastasis is currently ongoing. In line with this therapeutic strategy, the fourth
issue includes the development of a novel drug-delivery system using the carbohydrate-coated liposomes which are selectively accumulated at a milky spot, a preferential site for intraperitoneal
metastasis of gastric cancer.
1. High salt diets dose-dependently promote gastric chemical carcinogenesis
in Helicobacter pylori-infected Mongolian gerbils associated with a shift in
mucin production from glandular to
surface mucous cells
Tatematsu, M., Tsukamoto, T., Mizoshita, T., Kato, S.*1,
Cao, X., Hirata, A.*2, and Takasu, S.*2
Intake of salt and salty food is known as a risk
factor for gastric carcinogenesis. To examine the
dose-dependence and the mechanisms underlying
enhancing effects, Mongolian gerbils were treated
with N-methyl-N-nitrosourea (MNU), Helicobacter
pylori (H. pylori), and food containing various
concentrations of salt and sacrificed after 50 weeks.
Among gerbils treated with MNU and H. pylori, the
incidences of glandular stomach cancers were 15%
in the normal diet group and 33%, 36%, and 63% in
the 2.5%, 5%, and 10% NaCl diet groups, showing
dose-dependent increase (P<0.01). Intermittent
intragastric injection of saturated NaCl solution, in
contrast, did not promote gastric carcinogenesis.
In gerbils infected with H. pylori, a high salt diet
was associated with elevation of anti-H. pylori antibody titers, serum gastrin levels, and inflammatory cell infiltration in a dose-dependent fashion.
Ten percent NaCl diet upregulated the amount of
surface mucous cell mucin (P<0.05), suitable for H.
pylori colonization, despite no increment of
MUC5AC mRNA, while H. pylori infection itself
had an opposing effect, stimulating transcription of
MUC6 and increasing the amount of gland mucous
cell mucin.
High salt diet, in turn, decreased the
amount of gland mucous cell mucin, which acts
against H. pylori infection. In conclusion, the
present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori-infected Mongolian gerbils associated with alteration of the mucous microenvi-
ronment. Reduction of salt intake could thus be
one of the most important chemopreventive methods for human gastric carcinogenesis.
*1 Dept. of Gastroenterology, Hokkaido University
Graduate School of Medicine, Sapporo, Japan
*2 Dept. of Veterinary Pathology, Gifu University, Gifu,
Japan
2. HER2-driven constitutive activation of
PI3K-AKT pathway is a new potential
molecular target of gefitinib (Iressa) in
human gastric cancer liver metastasis
Nakanishi, H., Yokoyama, H. *1, Ikehara, Y., Kodera,
Y.*1, Ikehara, S. and Tatematsu, M.
HER2 overexpressing gastric cancer is
known to lead to a poor patient outcome, but
there is virtually no efficient therapeutic modality. The purpose of the present study is to
investigate the possibility of molecular therapy
targeting to HER2 overexpression in the gastric
cancer patients. We found that gastric cancers
metastasized to the liver overexpressed HER2
at significantly higher incidence than primary
gastric cancers. We developed three new HER2
overexpressing gastric cancer cell lines
(GLM-1, GLM-2, GLM-4) without EGFR mutations derived from such liver metastasis, two
of which had HER2 gene amplification. Interestingly, all these GLM series were highly sensitive to gefitinib, a specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine
kinase (ZD1839, “Iressa”) with IC50 less than
0.1 µM, but not Herceptin, whereas most of
HER2-negative
counterparts
were
not
(IC50>10 µM). Gefitinib induced strong apoptosis depending on caspase 3 and exhibited
anti-tumor
activity
against
these
HER2-overexpressing cancer cell lines both in
15
vitro and in vivo. In GLM-1, GLM-2 and
GLM-4 cells, Akt, but not ERK1/2, was constitutively phosphorylated without loss of
PTEN expression, and gefitinib efficiently inhibited this HER2-driven Akt phosphorylation.
However, gefitinib failed to inhibit constitutive
phosphorylation of Akt in HER2-negative gastric cancer cell lines. On the other hand, gefitinib-resistant cells (GLM-1R), exhibited increased EGFR expression, followed by constitutive activation of MAPK pathway. These results suggest that the anti-tumor effect of gefitinib is due to the effective inhibition of
HER2-driven constitutive activation of
PI3K/Akt pathway and that the acquired resistance to gefitinib is due to the constitutive activation of Ras/MAPK pathway in compensation
for PI3K/Akt pathway. Gastric cancer liver
metastasis with HER2-overexpression would
be a potential molecular target for gefitinib.
*1 Department of Surgery II, Nagoya University School
of Medicine, Tsuruma, Shouwa-ku, Nagoya, Japan
3. Sox2 expression in human stomach
adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes
Tsukamoto. T., Mizoshita, T.,
Ogasawara, N.*2 and Tatematsu, M.
Takenaka,
Y.*1,
Aims: Other than ectopic expression of intestinal transcription factors, Cdx1 and Cdx2 , molecular
mechanisms underlying gastric and intestinal phenotypes of human stomach adenocarcinomas have
yet to be clarified in detail. We have reported that
Sox2, an HMG-box gastric transcription factor, is
expressed in normal gastric mucosa and
down-regulated in intestinal metaplasia.
Methods and Results: We analyzed mRNA levels of Sox2 and other differentiation markers in fifty
surgically resected stomach adenocarcinomas, immunohistochemically classified into gastric (G),
gastric-and-intestinal (GI)-mixed, solely intestinal
(I), and null (N) types. Sox2 was found to be
transcribed in G and GI-mixed type adenocarcinomas in accordance with MUC5AC and MUC6 expression, while Cdx1 and Cdx2 were up-regulated
in GI-mixed and I types along with the expression
of MUC2 and villin. In the N type, both gastric
and intestinal transcription factors were suppressed.
Immunohistochemistry confirmed expression of
Sox2 in MUC5AC positive lesions and Cdx2 localization together with MUC2. A stomach adeno-
16
carcinoma cell line, KATOIII, demonstrated both
MUC5AC and Sox2, although MUC5AC mRNA
was not detected in the Sox2-positive AGS cell line.
Conclusions: Sox2 may play an important role
in maintaining a gastric phenotype in stomach cancers as well as in normal tissue, in cooperation with
other cofactor(s).
*1 Dept. of Gastrointestinal Surgery, The University of
Tokyo, Tokyo, Japan
*2 Dept. of Internal Medicine and Bioregulation, Nagoya City University of Medicine, Nagoya, Japan.
4. A carbohydrate recognition based drug
delivery and controlled release system
using intraperitoneal macrophages as a
cellular vehicle
Ikehara, Y., Nakanishi, H., Niwa, T.*1, Biao, L.*2,
Ikehara, S., Ohashi, N.*3, Kobayashi, T. *1, Simizu, Y.*1,
Kojima, N. and Tatematsu, M.
We developed a new technology using the carbohydrate recognition by macrophages that are applied to use as a cellular vehicle in a drug delivery
system. The lymphoid tissue in the omentum, called
for milky spots, is known as an initial place for disseminated cancer cells to develop into solid tumours. Intraperitoneal macrophages significantly
took up Oligomannose-coated liposomes (OML)
that were injected into peritoneal cavity, and then
gradually accumulated in the omentum and the
other lymphoid tissues within 24 h of intraperitoneal injection of OMLs. When 5-fluorouracil
(5-FU) was encapsulated in the OMLs, more than
60% of administered 5-FU accumulated in the
omentum. Treatment of macrophages at 39 °C for
30 min led to the release of 5-FU from the macrophages, suggesting that controlled release from
macrophages could be achieved by mild hyperthermia. We encased magnetic nanoparticles, which are
known to convert electromagnetic energy to heat, in
the OMLs to achieve in vivo hyperthermia at the
site. Using this system in a mouse intraperitoneal
metastasis model, we successfully controlled tumour development by co-administration of
OML-encased 5-FU and OML-encased magnetic
nanoparticles, followed by treatment with an alternating magnetic field. No apparent reduction was
seen in tumour growth with the administration of
OML-encased
magnetic
nanoparticles
or
OML-encased 5-FU alone. Thus, we have established the use of intraperitoneal macrophages as a
novel drug-delivery system for the control of cancer
metastatic to milky spots.
*1 Department of Applied Biochemistry and The Institute of Glycotechnology, Tokai University, 1117 Kitakaname, Hiratsuka-shi, Kanagawa, 259-1292 Japan
2
* EP,
*3 Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University
5. Colonic and small-intestinal phenotypes in gastric cancers: relationships
with clinicopathologic findings
Mizoshita, T., Tsukamoto, T., Tanaka, H., Otsuka, T,*1.
Hirano, N.*1, and Tatematsu, M.
The clinicopathologic significance of colonic
and small-intestinal phenotypes has hitherto remained unclear in gastric cancers. In the present
study, we therefore examined 86 gastric carcinomas
histologically and phenotypically using several
phenotypic markers, including colon specific carbonic anhydrase 1 (CA1) and sucrase as small in-
testine specific. Of 86 gastric cancers, sucrase and
CA1 expression was observed in 12 (14.0%) and
only 2 (2.3%) cases, respectively, associated with
other intestinal markers such as villin and MUC2.
In the sucrase cases, expression appeared independent of the stage. However, CA1 expression
was observed only in two advanced cases. No association was observed between colonic and
small-intestinal phenotypes and lymph node metastasis and postoperative survival in the advanced
gastric cancer cases with intestinal phenotypic expression. Cdx2 appeared linked to upregulation of
both CA1 and sucrase. In conclusion, our data
suggest that colonic phenotype occur rarely in gastric carcinogenesis. Colonic and small intestinal
phenotypes appear with expression of several intestinal phenotypic markers under the control of Cdx2
and presumably other related transcription factors.
*1 Dept. of Internal Medicine I, Toho University School
of Medicine, Tokyo, Japan.
17
From left to right
Front row: Dr. Y. Kondo, Dr. Y. Sekido, Dr. H. Osada, and Dr. T. Fukui,
Second row: Dr. T. Yokoyama, Dr. N. Sato, Dr. T Taniguchi, and Mr. Y. Tatematsu,
Inset: Dr. Y. Goto.
18
Division
of Molecular Oncology
________________________________________________________________________________
Takashi Takahashi, M.D., Ph.D., Chief (until June 2004)
Yoshitaka Sekido M.D., Ph.D., Chief (as of April 2005)
Hirotaka Osada, M.D., Ph.D., Section Head
Kiyoshi Yanagisawa, M.D., Ph.D., Senior Researcher (until June 2004)
Yutaka Kondo, M.D., Ph.D., Senior Researcher (as of July 2005)
Shuta Tomida, Ph.D., Researcher (until March 2005)
Yoshio Tatematsu, B.S., Research Assistant
Tomoko Harano, B.S., Research Assistant (until March 2004)
Postdoctoral Fellows
Toshiyuki Takeuchi, Ph.D. (until June 2004)
Research Resident
Yoji Hayashita, M.D., (until March 2005)
Visiting Trainees
Hidemasa Nagai, M.D., Nagoya University School of Medicine (until June 2004)
Yoko Karube, M.D., Dokkyou University School of Medicine (until June 2004)
Junichi Takamizawa, M.D., Nagoya University School of Medicine (until June 2004)
Ken Maeno, M.D., Nagoya City University School of Medicine (until June 2004)
Hideki Yamada, M.D., Nagoya University School of Medicine (until June 2004)
Hisaaki Tanaka, M.D., Okayama University School of Medicine (until June 2004)
Nobuyoshi Sugito, M.D., Nagoya City University School of Medicine (until Sep. 2004)
Hiromichi Ebi, M.D., Nagoya City University School of Medicine (until March 2005)
Takayuki Fukui, M.D., Nagoya University School of Medicine (as of April 2005)
Toshihiko Yokoyama, M.D., Nagoya University School of Medicine (as of April 2005)
Naohito Sato, M.D., Nagoya University School of Medicine (as of April 2005)
Tetsuo Taniguchi, M.D., Nagoya University School of Medicine (as of May 2005)
Yasuhiro Goto, M.D., Nagoya University School of Medicine (as of Aug. 2005)
General Summary
Our goal is to determine the genetic lesions giving rise to human solid cancers and use this
information for prevention, diagnosis, and treatment of these diseases. Currently, we are focusing
on lung cancer, malignant mesothelioma, colon cancer, and hepatomas. Our studies also provide
opportunities to dissect biochemical and pathological pathways of malignant phenotypes, related to
dysregulated cell growth, differentiation, invasion, and metastasis. Human cancers arise because of
genetic mutations in protooncogenes and tumor suppressor genes, and our approach is to focus on
candidate genes, systematically analyses of molecular biochemical pathways, and apply microarray
analysis of global gene expression and comparative genomic hybridization technique for identification of chromosomal abnormalities. Epigenetic changes due to DNA methylation and histone modification are also important mechanisms of inactivation of tumor suppressor genes. We also functionally analyze candidate genes by transfecting wild type copies into human cancer cells and testing for their ability to suppress malignancy in vitro and in vivo as well as characterizing their protein products biochemically. Alternatively, we inactivate their expression using RNA interference
(RNAi) in either tumor or normal cells and then study their phenotype. Understanding the functions of genes which are mutated and the signaling pathways disrupted is necessary to provide a
firm foundation for a translational research approach to human malignancies, from bench to bedside.
19
1. EGFR mutation is frequently detected in
non-small cell lung cancer with occasional genetic events of second mutation or amplification
Yokoyama, T., Kondo, M.*1, Goto, Y., Fukui, T., Sato,
N., Taniguchi, T., Kondo, Y., Osada, H., Yokoi, K. *2, T.
Shimokata, K.*1, and Sekido, Y.
Non-small cell lung cancer (NSCLC) is one of
the leading causes of death from neoplasia in Japan
and western countries. As chemotherapy can only
marginally prolong survival among patients with
advanced disease, molecular target therapy appears
the most promising clinical option. The epidermal
growth factor receptor (EGFR), one of the ERBB
family of receptors, is a particularly promising target, because of its frequent overexpression (range,
40-80%) in NSCLCs and relation to a poor prognosis. Small molecule tyrosine kinase inhibitors
(TKIs) of EGFR such as gefitinib and erlotinib have
been shown to have anti-tumor activity and several
clinical studies have revealed that Japanese, female,
never-smoking patients with adenocarcinoma have
a high response rate to gefitinib. We have analyzed
mutation and/or amplification of EGFR, HER2, and
KRAS, which are involved in EGFR signaling cascades, among resected primary NSCLCs from
Japanese patients and determined whether there is a
correlation with clinicopathological factors.
EGFR mutations were found in 102 (29%) of a total
of 349 tumors, and 7 tumors had two missense mutations. Reverse transcriptase-polymerase chain
reaction of EGFR and subsequent subcloning
analyses idemonstrated the double mutations in the
same allele, since we found both mutations in most
mutation-positive cDNA clones. Furthermore, in
202 NSCLCs analyzed by Southern blotting, 11
(5.4%) exhibited amplification of EGFR, with 8
tumors containing an EGFR mutation. Sequence
analysis detected only weak or no signals of the
wild-type allele in the 8 tumors, strongly suggesting
the mutated allele to be selectively amplified.
These findings indicate that a dual genetic change
of EGFR can occur in the same allele either with a
possible second-hit mutation or amplification,
which may imply a more selective growth advantage in cancer cells. At the same time, HER2 mutation and amplification were found in 6 (1.7%) of
349 tumors and 3 (1.5%) of 202 tumors, respectively, and KRAS mutations in 21 (6%) of 349 tumors. Mutations of the EGFR and HER2 genes
were more frequently found in female, never or
light smoking patients with adenocarcinomas, and
20
there were no tumors that had two or more EGFR,
HER2, and KRAS mutations. Our study further
demonstrated that a double genetic event of EGFR
can occasionally occur in lung cancer, thus providing new clues to the understanding of the involvement of EGFR signaling cascades in the pathogenesis of NSCLCs.
*1 Department of Respiratory Medicine, Nagoya University Graduate School of Medicine
*2 Division of General Thoracic Surgery, Nagoya University Graduate School of Medicine
2. The ASH1 gene is a specific therapeutic
target for lung cancers with neuroendocrine features
Osada, H., Tatematsu, Y., Yatabe, Y.*1, Horio, Y.*2, and
Takahashi, Ta.*3
Lung cancers with neuroendocrine (NE) features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined.
The basic-helix-loop-helix protein,
achaete-scute
complex-like
1
(ASCL1)/
achaete-scute homolog 1 (ASH1), is expressed in
normal fetal pulmonary NE cells and lung cancers
with NE elements, and is suggested to be involved
in lung carcinogenesis. We have shown inhibition
of ASH1 expression by plasmid-based RNAi to
significantly suppress growth of lung cancer cells
with ASH1 expression through G2/M-cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7.
However, lung cancer cell lines without ASH1 expression and an immortalized normal BEAS-2B
bronchial epithelial cells were not affected. The
RNAi-resistant mutant ASH1 clearly induced rescue from G2/M-arrest, suggesting a target-specific
effect of RNAi. An ASH1-RNAi adenovirus was
also established, and shown to significantly inhibit
not only in vitro cell proliferation but also in vivo
xenograft growth of ASH1-positive NCI-H460 cells.
Elevated levels of apoptosis were also observed in
NCI-H460
xenografts
with
the
ASH1-RNAi-adenovirus.
Our present studies
therefore suggest that ASH1 plays a crucial role in
lung cancer development and may be an effective
therapeutic target in lung cancers with NE features.
*1 Department of Pathology and Molecular Diagnostics,
*2
Aichi Cancer Center Hospital
Department of Thoracic Oncology, Aichi Cancer
Center Hospital
*3
Division of Molecular Carcinogenesis, Center for
Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine.
sive form, SCLC, and that the C13orf25 gene may
well be serving as a vehicle in this regard.
*1
3. A polycistronic miRNA cluster, miR-1792, is overexpressed in human lung
cancers and enhances cell proliferation
Hayashita, Y.*1, Osada, H., Tatematsu, Y., Yamada, H.*2,
Yanagisawa, K.*2, Tomida, S.*2, Yatabe, Y.*3, Kawahara,
K.*1, Sekido, Y., and Takahashi Ta.*2.
MicroRNAs (miRNAs) are small, non-coding
RNAs, thought to be involved in physiological and
developmental processes by negatively regulating
expression of target genes. We have previously
reported frequent down-regulation of the let-7
miRNA family in lung cancers and in the present
study assessed alteration in a panel of 19 lung cancer cell lines. Using Northern blot and quantitative RT-PCR analyses, we found for the first time
that the miR-17-92 cluster, which comprises six
miRNAs (miR-17, miR-18a, miR-19a, miR-20a,
miR-19b-1, miR-92-1) and resides in intron 3 of the
C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially examples with
small cell lung cancer (SCLC) histology. The
paralogous clusters, miR-106a-92 (Xq26.2) or
miR-106b-25 (7q22), did not
show significant alteration of
their expression in lung cancers. Southern blot analysis
revealed the presence of increased gene copy numbers
of the miRNA cluster in a
fraction of lung cancer cell
lines with overexpression.
In addition, we were able to
show predominant localization of C13orf25 transcripts
within the nuclei, introduction of the expression construct of the miR-17-92 cluster, but not the putative open
reading frame of C13orf25,
enhancing lung cancer cell
growth.
These findings
clearly suggest that marked
overexpression
of
the
miR-17-92 cluster with occasional gene amplification
may play a role in the development of lung cancers, especially in their most aggres-
*2
*3
Department of Oncological Science (Surgery II),
Oita University Faculty of Medicine
Division of Molecular Carcinogenesis, Center for
Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine,
Department of Pathology and Molecular Diagnostics,
Aichi Cancer Center Hospital.
4. Establishment and characterization of
malignant pleural mesothelioma cell
lines from Japanese patients
Fukui, T., Taniguchi, T., Usami, N.*1, Yokoyama, T.,
Hida, T.*2, and Sekido, Y.
Malignant mesothelioma (MM) is an aggressive
neoplasm arising from mesothelial cells, most often
occurring in the pleural cavity as malignant pleural
mesothelioma (MPM). Owing to the long latency
period and the widespread use of asbestos fibers for
many years, the incidence of MPM is projected to
rise sharply worldwide in the next two decades. In
Japan, 500 patients with MM died in 1995, and the
number increased to approximately 900 patients in
2003. MM has been demonstrated to be resistant
21
to all of conventional therapy regimens including
chemotherapy, radiotherapy and surgery, and the
prognosis of patients remains very poor. However,
the discrepancy between the rising incidence of
MM and the lack of success of new more effective
therapeutic strategies seems to be related at least in
part to inadequate knowledge of the biological
properties of this tumor. It is hoped that a better
understanding of MM biology may provide the rationale for new therapeutic strategies. In this regard, the development of tumor cell lines has been
an important tool in setting up suitable in vitro
models for studying the biological properties of
many tumors and to assess tumor sensitivity to
various drugs or biological response modifiers.
However, as opposed to lung cancer for example,
where several hundred cell lines have been established, only a relatively small number of MPM cell
lines are available. Furthermore, only a few cell
lines have been established from Japanese patients
with MPM.
We therefore have established four MPM cell
lines, ACC-MESO-1, ACC-MESO-4, Y-MESO-8A,
and Y-MESO-8D from Japanese patients, with the
latter two from the same patient with biphasic-like
22
characteristics of MPM, showing epithelial and
sarcomatous phenotypes in cell culture. Mutation
and expression analyses demonstrated that the tumor suppressor gene of NF2, which is known to be
one of the most frequently mutated in MPMs, is
mutated in ACC-MESO-1. We detected homozygous deletion of p16 INK4A / p14 ARF in all four
MPM cell lines. We also analyzed genetic alterations of six other MPM cell lines and confirmed
frequent mutations of NF2 and p16 INK4A / p14 ARF.
To characterize biological differences between
Y-MESO-8A and -8D, we performed cDNA microarray analysis and detected genes that are differentially expressed in these two cell lines. Thus,
our new MPM cell lines seem to be useful as models for studying various aspects of the biology of
human MPM as well as materials for development
of future therapy.
*1 Division of General Thoracic Surgery, Nagoya University School of Medicine
2
* Department of Thoracic Oncology, Aichi Cancer
Center Hospital
First row (from left to right): Dr. Y. Hosokawa, Ms. Y. Kasugai, Dr. M. Sato, Ms. H. Suzuki, Dr. S. Tsuzuki.
Second row (from left to right): Dr. Y. Kameoka, Dr. N. Hukuhara, Dr. Y. Nakashima, Dr. A. Oshiro.
Third row (from left to right): Dr. H. Tagawa, Dr. R. Suzuki, Dr. M. Nakagawa, Ms. S. Sato, Mr. S. Karnan.
Insets (from left to right): Dr. X. Zhang, Dr. K. Mayama, Dr. M. Suguro-Katayama.
23
Division
of Molecular Medicine
________________________________________________________________________________
Masao Seto, MD., PhD. Chief
Yoshitaka Hosokawa, M.D., Ph.D. Section Chief (Until March, 2006)
Shinobu Tsuzuki, M.D., Ph.D. Section Chief
Ritsuro Suzuki, M.D., Ph.D. Senior Researcher (Until December, 2005)
Hiroyuki Tagawa, M.D., Ph.D. Senior Researcher
Hiroko Suzuki, B.P. Senior Research Assistant
Yumiko Kasugai, B.S. Research Assistant
Visiting Trainees
Karnan Sivasundaram, Graduate School of Medical Sciences, Nagoya City University
Miyuki Suguro-Katayama, MD. The Second Department of Internal Medicine, Mie University School of Medicine (Until August, 2004)
Koh Mayama, MD. The Third Department of Internal Medicine, Hirosaki University School of Medicine (Until
September, 2004)
Yoshihiro Kameoka, MD. The Third Department of Internal Medicine, Akita University School of Medicine
(Until August, 2005)
Masao Nakagawa, MD. The Third Department of Internal Medicine, Hokkaido University School of Medicine
(Until September, 2005)
Xiaohua Zhang, M.D. Department of Pathology, Yan’an University School of Medicine (Until January, 2004)
Yasuhiro Nakashima, MD. Department of Medicine and Bioregulatory Science, Graduate School of Medical
Sciences, Kyushu University
Aya Oshiro, MD. Second Department of Internal Medicine, University Hospital, University of the Ryukyus
Noriko Fukuhara, MD. Department of Rheumatology and Hematology, Tohoku University School of Medicine
General Summary
Research in this laboratory is aimed at generating a better understanding of the genetic and
molecular bases of human cancer, with eventual application of the acquired knowledge in the field
of medical oncology. Our work has been mainly focused on hematologic malignancies, in cooperation with physicians of the Department of Hematology and Cell Therapy Aichi Cancer Center Hospital (Chief, Dr. Yasuo Morishima). Research on hematologic malignancies have several advantages
for exploration of the molecular bases of neoplasia. Chromosomal abnormalities have been analyzed by a large number of researchers and the observed strong association between specific chromosome changes and specific hematopoietic tumors provides direct evidence that the resultant gene
alterations play a pivotal role in the disease development. Over the last two years, we have concentrated attention on the following issues.
The function of API2-MALT1 linked to mucosa-associated lymphoid tissue lymphomas is
now being studied to identify target genes. An array-CGH (comparative genomic hybridization) that
contains 2300 BAC clones on a slide glass that can scan the whole genome every 1.4 MB in average was applied to various kinds of hematopoietic malignancy. Differences in the genome profiles
between NK cell leukemias and T/NK cell lymphomas were thereby clarified. Target genes in the
6p21 region amplicon were found to be either CCND3 or BYSL or both. TEL-AML1 leukemias
were also analyzed by the array CGH approach and found to also have a characteristic genome profile. In vivo oncogenic function of the TEL-AML1 chimeric gene in combination with new oncogenes is being analyzed in a bone marrow transplantation system.
1. Anti-apoptotic action of the API2MALT1 fusion protein involved in
t(11;18)(q21;q21) MALT lymphomas
Hosokawa, Y., Suzuki, H. and Seto, M.
t(11;18)(q21;q21) is a characteristic chromoso-
24
mal translocation in the mucosa-associated lymphoid tissue (MALT) type lymphoma, which results
in fusion transcripts of APoptosis Inhibitor 2 (API2),
also known as c-IAP2, and Mucosa-Associated
Lymphoid Tissue translocation gene 1 (MALT1).
Although API2-MALT1 has been shown to enforce
activation of NF-κB signaling, the transcriptional
target genes of this fusion protein remain to be
identified.
Our analyses of API2-MALT transfectants have
suggested that one target gene may be the apoptotic
inhibitor API2 gene. Luciferase reporter assays
with deletion and mutational constructs of the API2
promoter and electrophoretic mobility shift assays
(EMSA) established that API2-MALT1 induces
transcriptional activation of the API2 gene through
two NF-κB binding elements. Moreover, supershift experiments indicated that these elements are
recognized by the NF-κB p50/p65 heterodimer.
Taken together, our results strongly indicate that
API2-MALT1 possesses a novel mechanism of
self-activation by up-regulating its own expression
in t(11;18)(q21;q21)-carrying MALT lymphomas,
highlighting a positive feedback-loop pathway resulting in sustained NF-κB activation.
We also demonstrated that API2-MALT1 possesses an anti-apoptotic effect, in part through direct
interactions with apoptotic regulators.
These
findings therefore have led us to hypothesize that
the anti-apoptotic effect of API2-MALT1 may be
mediated by its interaction with apoptotic regulators
on the one hand as well as by NF-κB-mediated
upregulation of apoptotic inhibitor genes on the
other. We have also established that BCL10 and
MALT1 shuttle between the nucleus and cytoplasm,
and that MALT1 can regulate the subcellular location of BCL10.
It is hoped that further studies will facilitate development of therapeutic drugs that specifically inhibit the antigen receptor signaling pathway.
CARMA1 and MALT1 represent promising molecular targets, because knock-out mice for these
molecules exhibit defects that are exclusively restricted to this pathway. Recent studies also indicated that self-oligomerization of API2-MALT1 fusion proteins results in deregulated ubiquitin ligase
activity of MALT1, thereby leading to NF-κB activation. Thus, the development of specific inhibitors of API2-MALT1 ubiquitin ligase would be also
beneficial for the treatment of MALT lymphoma.
Such drugs would be expected to inhibit, with controllable side-effects, inappropriate growth and expansion of lymphoma clones.
2. Molecular pathways leading to t(12; 21)
TEL-AML1 associated leukemias
Tsuzuki, S. and Seto, M.
The t(12; 21) translocation which generates the
TEL-AML1 (ETV6-RUNX1) fusion gene is the
commonest structural chromosome change in
childhood cancer and is exclusively associated with
the common, B cell progenitor subset of acute
lymphoblastic leukemias (ALLs). Evidence suggests that the translocation usually occurs in utero
during foetal haematopoiesis and most probably
constitutes an initiating or “first hit” mutation
which is necessary but itself insufficient for the development of overt, clinical leukemia.
In our search for additional “second hit” mutations that could be linked to leukemia development,
we applied a genome-wide array-CGH technique to
24 TEL-AML1 leukemia samples and two cell lines
and found that at least three chromosomal imbalances were involved in all samples. The results
suggest that, in addition to TEL previously reported
as lacking, genes involved in cell cycle regulation
(p16INK4a/ARF, BTG1), p53 pathways and apoptosis are also often deleted.
To delineate the roles of deregulated cell cycle/p53/apoptosis pathways in leukemia development, we have developed retroviral vectors to express TEL-AML1 along with a second gene or
siRNAs. We are currently investigating the cooperative roles of the “first” and “second” hits for
leukemia development in mice.
3. Cloning of a translocation partner of
t(1;14)(p33;q32) in diffuse large B-cell
lymphoma
Suzuki, R., Nakamura, S. *1 and Seto, M.
Several oncogenes, such as cyclin D1, BCL2,
BCL6, and c-Myc, are activated by the immunoglobulin heavy chain (IgH) gene in B-cell lymphomas. We have therefore focused on the translocation partner of the IgH gene in t(1;14)(p33;q32)
identified as a novel translocation in diffuse large
B-cell lymphoma. High molecular weight DNA was
extracted from a frozen sample, and long distance
inverse PCR technique was employed for cloning.
The cloned genomic sequence matched the chromosome 1p34 sequence on database search. No
known gene existed around the breakpoint on 1p34,
but the expression of one EST was highly activated
in the tumor sample. Performance of 5’- and
3’-RACE allowed a non-coding RNA spanning
more than 20kb to be cloned as the partner. The
presence of micro RNA was further investigated,
but we could not identify any known or novel micro
RNA. Although the mechanism and the significance
of expression of non-coding RNA have yet to be
25
fully
elucidated,
lymphomagenesis
by
t(1;14)(p33;q32) apparently features a novel and
previously unrecognized mechanism, which warrants further investigation.
*1
Department of Pathology and Molecular Diagnostics,
Aichi Cancer Center Hospital, Aichi, Japan
4. Comparison of genome profiles for
identification of distinct subgroups of
diffuse large B-cell lymphoma
Tagawa, H., Suguro-Katayama, M., Tsuzuki, S.,
Morishima, Y. *1 and Seto, M.
Diffuse large B-cell lymphoma (DLBCL) comprise distinct molecularly subgroups such as activated B-cell-like (ABC) and germinal center
B-cell-like (GCB) forms. We previously reported
that CD5+ and CD5-CD10+ DLBCL constitute
clinically relevant subgroups. To determine whether
these two subgroups are related to ABC and GCB
DLBCL, we analyzed the genomic imbalance of 99
cases (36 CD5+, 19 CD5-CD10+ and 44
CD5-CD10-) using array-CGH. Some 46 of these
cases (22 CD5+, 7 CD5-CD10+ and 17 CD5-CD10-)
were subsequently subjected to gene expression
profiling, resulting in their division into 28 ABC
(19 CD5+ and 9 CD5-CD10-) and 18 GCB (3 CD5+,
7 CD5-CD10+ and 8 CD5-CD10-) types. A comparison of genome profiles of distinct subgroups of
DLBCL demonstrated that: i) the ABC DLBCL is
characterized by gain of 3q, 18q and 19q and loss of
6q and 9p21, and the GCB DLBCL by gain of 1q,
2p, 7q and 12q; ii) the genomic imbalances characteristic of the CD5+ and CD5-CD10+ groups are
similar to those of the ABC and GCB types, respectively. These findings suggest that CD5+ and
CD5-CD10+ subgroups are included, respectively,
in the ABC and GCB types. Finally, on searching
for genomic imbalances that affect patients’ prognosis, we found that 9p21 loss (p16INK4a locus)
marks the most aggressive type of DLBCL.
*1
Department of Hematology and Cell Therapy, Aichi
Cancer Center Hospital, Nagoya, Aichi.
5.
Genome-wide array-based comparative
genomic hybridization of natural killer
cell lymphoma/leukemia: different genomic alteration patterns of aggressive
26
NK-cell leukemia and extranodal
NK/T-cell lymphoma, nasal type
Nakashima, Y., Tagawa, H., Suzuki, R., Karnan, S.,
Karube, K.*1, Ohshima, K. *1, Muta, K. *2, Nawata, H. *2,
Morishima, Y. *3, Nakamura, S. *4 and Seto, M.
Natural killer (NK) cell lymphomas/leukemias
are highly aggressive lymphoid malignancies, but
little is known about their genomic alterations, and
thus there is an urgent need for identification and
analysis of NK cell lymphomas/leukemias. Recently, we developed our own array-based comparative genomic hybridization (array CGH) with
an average resolution of 1.3 Mb. We performed an
array CGH analysis for 27 NK-cell lymphoma/leukemia cases that were classified into two
disease groups based on the World Health Organization Classification (10 aggressive NK-cell leukemia cases and 17 extranodal NK/T-cell [NK/T]
lymphomas, nasal type). We identified the differences in the genomic alteration patterns of the two
groups. The recurrent regions characteristic of the
aggressive NK-cell leukemia group compared with
those of the extranodal NK/T lymphoma, nasal type
group, were gain of 1q and loss of 7p15.1-p22.3 and
17p13.1. In particular, gain of 1q23.1-q24.2 (P=
0.041) and 1q31.3-q44 (P= 0.003-0.047), and loss
of 7p15.1-p22.3 (P= 0.012 - 0.041) and 17p13.1 (P=
0.012) occurred significantly more frequently in the
former than in the latter group. Recurrent regions
characteristic of the extranodal NK/T lymphoma,
nasal-type group, compared with those of the other
group were gain of 2q, and loss of 6q16.1-q27,
11q22.3-q23.3, 5p14.1-p14.3, 5q34-q35.3, 1p36.23p36.33, 2p16.1-p16.3, 4q12, and 4q31.3-q32.1. Our
results can be expected to provide further insights
into the genetic basis of lymphomagenesis and the
clinicopathologic features of NK-cell lymphomas/leukemias.
*1
Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan
*2
Department of Medicine and Bioregulatory Science,
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
*3
Department of Hematology and Chemotherapy, Aichi
Cancer Center Hospital, Aichi, Japan
*4
Department of Pathology and Molecular Diagnostics,
Aichi Cancer Center Hospital, Aichi, Japan
The 11th Aichi Cancer Center International Symposium “Forefront of Cancer
Prevention Strategy in Asia,” held on February 5, 2005.
27
From left to right
First row: Dr. Y. Akatsuka, Dr. K. Kuzushima, Dr. K. Tsujimura, Ms. Y. Matsudaira
Second row: Ms. T. Tsuboi, Dr. H. Torikai, Ms. F. Ando, Dr. Demachi-Okamura, Ms. K. Nishida, Dr. Y.
Ito, Dr. T. Kawase, Ms. Y. Nakao, Dr. S. Morishima
Insets: Dr. R. Ohta, Dr. M. Miyazaki, Dr. Y. Okanami, Dr. H. Miyauchi, Ms. K. Watanabe, Dr. S. Shimato, Ms. M. Nakayama
28
Division
of Immunology
________________________________________________________________________________
Kiyotaka Kuzushima, M.D. Chief
Yoshiki Akatsuka, M.D. Section Head
Kunio Tsujimura, M.D. Section Head
Yoshinori Ito, M.D. Senior Researcher
Ayako Demachi-Okamura, Ph.D. Research Resident
Rieko Ohta, Ph.D. Research Resident (as of August 2004, until June 2005)
Yasue Matsudaira, B.S. Senior Research Assistant
Keiko Nishida, B.P. Senior Research Assistant
Tomiko Tsuboi, Semi-regular Employee
Yumi Nakao, Semi-regular Employee
Fumiyo Ando, Semi-regular Employee (as of August 2004)
Michiyo Nakayama, Semi-regular Employee (as of February 2004)
Visiting Scientists
Yuichi Obata, Ph.D. Department of Biological Systems, RIKEN BioResource Center
Kazuhiro Yoshikawa, B.M.T., M.D. Second Department of Pathology, Aichi Medical University
Visiting Trainees
Mikinori Miyazaki, M.D. Department of Internal Medicine and Molecular Science, Nagoya City University
Graduate School of Medical Sciences
Hiroki Torikai, M.D. Third Department of Internal Medicine, National Defense Medical College
Yuko Okanami, M.D. First Department of Surgery, Mie University School of Medicine (until March 2005)
Satoko Morishima, M.D. Cancer Genetics, Nagoya University Graduate School of Medicine
Takakazu Kawase, M.D. Cancer Genetics, Nagoya University Graduate School of Medicine
Hidemasa Miyauchi, M.D. Blood Purification Center, JISHOKAI Health System, Inc.
Kazue Watanabe, M.S. Medical & Biological Laboratories Co., Ltd. (as of June 2005)
Shinji Shimato, M.D. Department of Neurosurgery, Nagoya University Graduate School of Medicine (as of
September 2005)
General Summary
The object of our research is to characterize and understand T lymphocyte responses to antigens expressed on cancer and virus-infected cells. The major projects undertaken over the past two
years are summarized below.
In the field of human immunology, four projects are continuing with the focus on epitope
identification and fine characterization of processing of the epitopes recognized by cancer- and virus-targeting cytotoxic T lymphocyte (CTLs). Firstly, an HLA-A*2402-restricted CTL epitope was
determined in the epithelial cell adhesion molecule, which is expressed in almost all carcinomas.
Secondly, precise roles of interferon (IFN)-γ inducible immunoproteasome-associated molecules in
generation of a CTL epitope derived from Epstein-Barr virus latent membrane protein 2A were elucidated. Unequivocal involvement of the immunoproteasome subunit low molecular weight protein
7 and 2 and the proteasome activator 28 α subunit was confirmed by means of RNA interference
gene silencing. Thirdly, a novel HLA-A*3303-restricted male-specific minor histocompatibility antigen encoded by an unconventional open reading frame of human TMSB4Y gene was identified.
Fourthly, an HLA-A*2402-restricted epitope recognized by CTL targeting the HPV-16 protein was
characterized. Interestingly, combined treatment with proteasome inhibitors like bortezomib and
IFN-γ dramatically augmented CTL-mediated lysis of SiHa cells carrying HPV. Thus, this may
provide a novel approach for CTL-based immunotherapy in cervical cancer patients.
To understand the roles of specific immunity to tumor progression in vivo, we have been
conducting animal experiments employing the mouse thymus-leukemia antigen (TL) as a model.
Both cellular and humoral immune responses to chemical carcinogen-induced lymphomas expressing the TL were extensively studied using T3b-TL transgenic and parental (B6 and C3H) strains.
29
1. Identification of an epitope from the
epithelial cell adhesion molecule eliciting HLA-A*2402-restricted cytotoxic T
lymphocyte responses
Tajima, Ko.*1, Demachi-Okamura, A., Ito, Y., Nishida,
K., Akatsuka, Y., Tsujimura, K., Kuwano, H.*1,
Mitsudomi, T.*2, Takahashi, To.*3 and Kuzushima, K.
Since the epithelial cell adhesion molecule
(Ep-CAM) is expressed in almost all carcinomas
and human leukocyte antigen (HLA)-A*2402 is the
most common allele in many ethnic groups, including Japanese, identification of peptide sequences
which elicit HLA-A*2402-restricted Ep-CAMspecific CTL responses should facilitate specific
immunotherapy for various histological types of
carcinomas. We have focused on identifying an
epitope through the following steps: (a) computer-based epitope prediction from the amino acid
sequence of Ep-CAM; (b) MHC stabilization assays
to determine the affinity of predicted peptides with
HLA-A*2402 molecules; (c) stimulation of CD8+ T
cells with peptide-pulsed dendritic cells; (d) testing
CTL specificity by enzyme-linked immunospot
(ELISPOT) assays, CTL assays and MHC/peptidetetramer staining (Fig. 1). Peripheral CD8+ T cells
of 4 of 5 healthy donors after 3 rounds of stimulation with the peptide Ep-CAM173-181 (RYQLDPKFI)
were found to secrete IFN-γ in ELISPOT assays. A
CTL clone specific for one peptide efficiently lysed
Ep-CAM-expressing cancer cell lines in an
HLA-A*2402-restricted fashion and endogenous
processing and presentation of the peptide in a lung
cancer cell line could be confirmed by cold target
inhibition assays. The CTL clone was also lytic to
normal bronchial epithelial cells but to a lesser extent at low effector : target ratios. All these data
suggest that peptide-specific CTL responses may
play roles in both anti-cancer and autoimmune reactions. Our peptide should prove useful to study
anti-Ep-CAM CTL responses among populations
possessing HLA-A*2402.
*1 Department of Surgery I, Gunma University Faculty
of Medicine
2
* Department of Pulmonary Medicine, Aichi Cancer
Center Hospital
*3 President, Aichi Cancer Center
2. Three immunoproteasome-associated
subunits cooperatively generate a CTL
epitope of the EBV-LMP2A by overcoming specific structures resistant to
epitope liberation
Ito, Y., Kondo, E.*1, Demachi-Okamura, A., Akatsuka,
Y., Tsujimura, K., Tanimoto, M.*1, Morishima, Y.*2,
Takahashi, To.*3 and Kuzushima, K.
Precise roles of interferon-γ inducible immunoproteasome-associated molecules in generation of
cytotoxic T lymphocyte (CTL) epitopes have yet to
be fully elucidated. We describe here a unique
epitope derived from the Epstein-Barr virus (EBV)
latent membrane protein 2A (LMP2A) presented by
Fig. 1. Tetramer staining of Ep-CAM peptide-specific poly- and monoclonal CTLs.
A, Polyclonal CD8+ T cells after stimulation 4
times with an Ep-CAM derived peptide
RYQLDPKFI (Ep173), were stained with
FITC-labeled anti-CD8 antibodies and
PE-labeled HLA-A24-tetramers incorporating
Ep173 or a control peptide RYLRDQQLL
(ENV584), derived from HIV envelope protein.
Percentages of tetramer-positive cells
among total CD8+ T cells are shown at the
upper right in each case. B, An
Ep173-specific CTL clone was stained as described above. The percentages of
tetramer-positive cells among total CD8+ T
cells are shown at the upper right in each
case.
30
HLA-A*2402 molecules. Generation of the epitope,
designated LMP2A222-230, from the full length protein requires the immunoproteasome subunit low
molecular weight protein 7 (ip-LMP7) and the proteasome activator 28 α subunit, and is accelerated
by ip-LMP2, as revealed by gene expression experiments using an LMP2A222-230-specific CTL
clone as a responder in enzyme-linked immunospot
assays. Unequivocal involvement of all three components was confirmed by means of RNA interference gene silencing.
Interestingly, the
LMP2A222-230 epitope could be efficiently generated
from incomplete EBV-LMP2A fragments produced
by puromycin treatment, or gene-engineered shortened EBV-LMP2A lacking some of its hydrophobic
domains. In addition, epitope generation was increased by a single amino acid substitution from
leucine to alanine immediately flanking the
C-terminus, this being predicted by a
web-accessible program to increase the cleavage
strength. Taken together, the data indicate that generation of LMP2A222-230 is not only influenced by
extrinsic influences such as immunoproteasomes,
but also by intrinsic factors such as the length of the
EBV-LMP2A protein and proteasomal cleavage
strength at specific positions in the source antigen.
*1 Department of Internal Medicine II, Okayama University Graduate School of Medicine and Dentistry
2
* Department of Hematology and Cell Therapy, Aichi
Cancer Center Hospital
*3 President, Aichi Cancer Center
3. A novel HLA-A*3303-restricted minor
histocompatibility antigen encoded by
an unconventional open reading frame
of the human TMSB4Y gene
Torikai, H.*1, Akatsuka, Y., Miyazaki, M.*2, Warren,
E.H.*3, Oba, T.*4, Tsujimura, K., Motoyoshi, K.*1,
Morishima, Y.*5, Kodera, Y.*4, Kuzushima, K. and
Takahashi, To.*6
Minor histocompatibility (H) antigens are MHC
(HLA in human)-associated peptides originating
mainly from polymorphisms in the genome that
trigger T cell responses between MHC identical allogeneic individuals. Graft-versus-host disease and
graft-versus-leukemia/lymphoma (GVL) effects in
hematopoietic stem cell transplant recipients are
initiated by donor T cell recognition of minor H antigens on recipient cells. In the setting of female-to-male hemopoietic stem cell transplantation
(HSCT), T cell responses against male-specific mi-
nor H (H-Y) antigens encoded by the Y chromosome are elicited frequently. All previously identified H-Y antigens have been found to be encoded
by conventional open reading frames.
We here isolated an HLA-A*3303-restricted
CD8+ CTL clone termed 1B6 from a male patient
after HSCT from his HLA-identical sister. By examining the lytic patterns of EBV-transformed cell
lines carrying various Y chromosome terminal deletions by clone 1B6, a narrow region containing 5
candidate genes was localized. Further correlation
studies between the lytic patterns of the cell lines by
1B6 and mRNA expression levels from genes of the
mapped region in these cell lines successfully identified a gene encoding the minor H antigen,
TMSB4Y. Minigene transfection and epitope reconstitution assays allowed determination of an 11-mer
peptide,
EVLLRPGLHFR,
designated
TMSB4Y/A33. Surprisingly, its first amino acid
was located 405 bp upstream of the TMSB4Y initiation codon (Fig. 2A). Analysis of the precursor
frequency of CTL specific for recipient minor H
antigens in post-HSCT peripheral blood T cells using limiting dilution methods revealed that a significant fraction of the total donor CTL response in
this patient was directed against the TMSB4Y epitope (30% and 10% at days 50 and 146 post-HCT,
respectively, Fig. 2B and C). Tetramer analysis
continued to detect TMSB4Y/A33-specific CD8+ T
cells at least up to 700 days post-HSCT, indicating
the TMSB4Y/A33 epitope to indeed be immunogenic. This finding underscores the in vivo immunological relevance of minor H antigen derived
from unconventional open reading frame products.
Because 1B6 preferentially lysed target cells of
hematopoiesis origin, despite relatively ubiquitous
expression of TMSB4Y in various tissues, this minor H antigen might be involved in GVL rather than
GVHD.
*1 Third Department of Internal Medicine, National Defense Medical College
*2 Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of
Medical Sciences
3
* Division of Immunology, Fred Hutchinson Cancer
Research Center
*4 Department of Hematology, Japanese Red Cross Nagoya First Hospital
5
* Department of Hematology and Cell Therapy, Aichi
Cancer Center Hospital
*6 President, Aichi Cancer Center
31
Fig. 2. A, Genomic organization of TMSB4Y and the relationship with its mRNA. E1 and E2 indicate exons
1 and 2, respectively. The conventional ORF is indicated below the mRNA as cORF and the location of
identified epitope is shown below the 5'UTR of TMSB4Y cDNA. B and C, The proportions of CTL precursors specific for the identified TMSB4Y peptide among total CTLp against the recipient minor H antigens
was quantitated using a standard limiting dilution assay. The CTLp frequencies against recipient PHA
blasts (open circles) or donor PHA blasts pulsed with TMSB4Y peptide (closed triangles) or unpulsed
(open triangles) were calculated with L-Calc software.
4. Combination of bortezomib and interferon-γ induces presentation of a newly
identified HLA-A24-restricted human
papillomavirus type 16 E6-specific cytotoxic T cell epitope
Morishima, S.*1, Akatsuka, Y., Nawa, A.*2, Kondo, E.*3,
Kiyono, T.*4, Torikai, H.*5, Nakanishi, T.*2, Ito, Y.,
Tsujimura, K., Iwata, K.*6, Ito, K.*7, Kodera, Y.*8,
Morishima, Y.*9, Kuzushima, K. and Takahashi, To.*10
Around 50% of cervical cancers are associated
with human papillomavirus type 16 (HPV-16) and
since the HPV-16 E6 and E7 oncoproteins are constitutively expressed in tumor cells, they are attractive targets for cytotoxic T lymphocyte
(CTL)-mediated immunotherapy. Nevertheless,
only a limited number of HPV-16 E6 epitopes have
so far been identified. Using reverse immunological
methods, we have generated a CTL clone against
the HPV-16 E649-57 epitope restricted by
HLA-A*2402, which is the most common allele in
Japan and worldwide. The CTL clone was found
able to lyse 293T cells transduced with
32
HLA-A*2402 and HPV-16 E6, but could not recognize the SiHa cervical cancer cell line positive for
HPV-16 and HLA-A*2402. However, SiHa cells
transduced with the E6-E7 genes did become susceptible to lysis, suggesting insufficient generation
of antigenic peptides in the cell line. Interestingly,
combined treatment with proteasome inhibitors,
bortezomib or epoxomicin, and interferon (IFN)-γ,
fully restored CTL-mediated lysis of SiHa cells.
Furthermore, pretreatment of three of four other
cervical cancer cell lines expressing HPV-16 E6
and HLA-A*2402 with bortezomib and IFN-γ induced cytokine production by specific CTLs. Unexpectedly, HPV-16 E6 levels were found to be decreased with the combined treatment. These data
suggest that impaired presentation of the E649-57
epitope is most likely due to peptide destruction by
proteasomes. Thus, combined treatment with a proteasome inhibitor and IFN-γ may further provide a
novel approach for CTL-based immunotherapy in
cervical cancer patients.
*1 Cancer Genetics, Nagoya University Graduate School
of Medicine
*2 Department of Gynecology and Oncology, Aichi
Cancer Center Hospital
*3 Department of Internal Medicine II, Okayama University Graduate School of Medicine and Dentistry
*4 Virology Division, National Cancer Center Research
Institute
*5 Third Department of Internal Medicine, National Defense Medical College
*6 Iwata Hospital
*7 Sakae Obstetrics and Gynecology Clinic
*8 Department of Hematology, Japanese Red Cross Nagoya First Hospital
*9 Department of Hematology and Cell Therapy, Aichi
Cancer Center Hospital
*10 President, Aichi Cancer Center
5. Immunity against the mouse thymus-leukemia antigen (TL) protects
against development of lymphomas induced by a chemical carcinogenic
agent, N-butyl-N-nitrosourea
Tsujimura, K., Obata, Y.*1, Matsudaira, Y., Taguchi,
O.*2, Nishida, K., Okanami, Y.*3, Akatsuka, Y.,
Kuzushima, K. and Takahashi, To.*4
Mouse thymus-leukemia antigens (TL) are
aberrantly expressed on T lymphomas in C57BL/6
(B6) and C3H/He (C3H) mice, but not on normal T
lymphocytes
in
these
strains.
When
N-butyl-N-nitrosourea (NBU), a chemical carcinogen, was administered orally to B6 and C3H strains,
lymphoma development was slower than in T3b-TL
gene-transduced counterpart strains expressing TL
ubiquitously as self-antigens, suggesting that
anti-TL immunity may play a protective role. In
addition, the development of lymphomas was
slightly slower in C3H than in B6, in accordance
with the results of skin graft experiments indicating
both cellular and humoral immunities against TL to
be stronger in the C3H strain. The interesting finding that B lymphomas derived from a T3b-TL
transgenic strain (C3H background) expressing a
very high level of TL were rejected in C3H, but not
in H-2Kb transgenic mice (C3H background), raises
the possibility that TL-specific effector T cell
populations are eliminated and/or anergized to a
certain extent by interacting with H-2Kb molecules.
*1 Department of Biological Systems, RIKEN BioResource Center
*2 Division of Molecular Pathology, Aichi Cancer Center
Research Institute
*3 First Department of Surgery, Mie University School
of Medicine
*4 President, Aichi Cancer Center
33
From left to right
First row: Dr. N. Shitara, Dr. S. Iwahori, Mr. K. Ohtake, and Dr. T. Tsurumi.
Second row: Mr. J. Ohtsuka, Dr. A. Kudoh, Mr. L. Zhang, Dr. T. Daikoku, Dr. H. Isomura, Dr. S. Nakasu,
and Mr. Y. Nishikawa.
34
Division of Virology
__________________________________________________________________
Tatsuya Tsurumi, M.D. Chief
Shou Nakasu, PhD. Senior Researcher
Hiroki Isomura, M.D. Senior Researcher
Tohru Daikoku, Ph.D. Senior Researcher (until March 2006)
Yutaka Sugaya, PhD. Research Resident (until March 2005)
Noriko Shirata, PhD. Research Resident (until March 2006)
Satoko Iwahori, PhD. Research Resident (as of April 2005)
Yasuhiro Nishikawa. Research Assistant
Ayumi Kudoh, Ph.D. Research Fellow of the Japanese Society for the Promotion of Science
Visiting Trainees
Zhan lumen. M.S. Department of Virology, Nagoya University Graduate School of Medicine
General Summary
Approximately 15% of all human cancers have a viral etiology, but only six viruses have actually been implicated in their development. Among these the Epstein-Barr virus (EBV) is the object of our own studies. EBV is a ubiquitous gamma
herpesvirus associated with several malignant diseases, including Burkitt’s lymphoma,
nasopharyngeal lymphoma, a subset of Hodgkin’s lymphomas, some gastric cancers,
and B cell lymphomas in immunosuppressed patients. Our research aims are to elucidate the molecular mechanisms of viral proliferation and oncogenesis of EBV as part
of the world-wide effort to combat virus-infected cancers. During the period 2004-2005,
our research interest was concentrated on the following issues: 1) Architecture of EBV
replication compartments; 2) EBNA1 binding to oriP during EBV latent and lytic replications; 3)Activation of DNA damage checkpoint signal transduction elicited by EBV
genome replication; 4)Interaction between p53 and EBV-encoded immediate-early protein BZLF1; 5) Analysis of the human cytomegalovirus major immediate-early enhancer and promoter.
1. Epstein-Barr virus lytic replication elicits ATM checkpoint signal transduction
while providing an S-phase-like cellular
environment
Kudoh, A. and Tsurumi, T.
When exposed to genotoxic stress, eukaryotic
cells demonstrate a DNA damage response with
delay or arrest of cell-cycle progression, providing
time for DNA repair. We have established that induction of the Epstein-Barr virus (EBV) lytic program elicits a cellular DNA damage response, with
activation of the ataxia telangiectasia-mutated
(ATM) signal transduction pathway. Activation of
the ATM-Rad3-related (ATR) replication checkpoint pathway, in contrast, is minimal. The DNA
damage sensor Mre11-Rad50-Nbs1 (MRN) complex and phosphorylated ATM are recruited and retained in viral replication compartments, recognizing newly synthesized viral DNAs as abnormal
DNA structures. Phosphorylated p53 also becomes
concentrated in replication compartments where it
physically interacts with viral BZLF1 protein. Despite the activation of ATM checkpoint signaling,
we found p53-downstream signaling to be blocked,
with rather high S-phase CDK activity associated
with progression of lytic infection. Therefore, although host cells activate ATM checkpoint signaling with response to the lytic viral DNA synthesis,
we conclude that the virus can skillfully evade this
host checkpoint security system and actively promote an S-phase-like environment advantageous for
viral lytic replication.
2. Dynamics of Epstein-Barr virus EBNA1
protein binding to the viral genome and
the architecture of replication compartments formed during lytic replication
Daikoku, T. and Tsurumi, T.
Epstein-Barr virus (EBV), a lymphotropic hu-
35
man herpesvirus, possesses two life styles; latent
and lytic infections. During latent infection, EBV
genomes are maintained as double-stranded DNA
episomes, and replicated once per cell cycle during
the S phase, following the rules of chromosome
replication. The viral latent gene product, EBNA1,
binds directly to the latent replication origin, oriP,
as a homodimer but lacks any activity predicted to
be required for replication initiation. Lytic replication differs from the latent amplification state in
that multiple rounds of replication are initiated
within the lytic replication origin, oriLyt, and the
replication process has a greater dependence on
seven EBV-encoded lytic replication proteins. A
low level of EBNA1 transcripts is still produced
during the viral productive cycle. Understanding
protein-DNA interactions in vivo at origins of DNA
replication throughout the cell cycle and lytic replication may shed further insight on EBNA1 functions on replication control.
Our focus has therefore been on EBNA1 binding to the EBV genome-wide mapping through latent and lytic replication by ChIP assay. We thereby
found that EBNA1 binds to the oriP region of the
EBV genome throughout the cell cycle. Even after
induction of lytic replication EBNA1 still continues
to bind to oriP. From confocal microscopy analyses,
lytic DNA replication occurs at discrete sites in nuclei, called replication compartments, where viral
replication proteins are clustered. During lytic replication, no chromosomal DNA replication occurs.
In latent infection EBNA1 could be shown to be
distributed broadly in nuclei as fine punctate dots
with weak, diffuse stainig. After induction of lytic
replication, EBNA1 was redistributed and clustered
to replication compartments with bright granular
spots. However, the spots of EBNA1 did not appear
to completely coincide with BrdU staining or viral
replication proteins, but rather were located side by
side with the viral replication proteins and viral
progeny DNA.
In our study we also performed comprehensive
analyses of the architecture of the replication compartments were EBV productive DNA replication
occurs. The BZLF1 oriLyt binding proteins showed
a fine, diffuse pattern of distribution throughout the
nuclei at immediate-early stages of induction and
then became associated with the replicating EBV
genome in the replication compartments during
lytic infection. The BMRF1 polymerase (Pol) processivity factor showed a homogenous, not dot-like,
distribution in the replication compartments, which
completely coincided with the newly synthesized
36
viral DNA. Inhibition of viral DNA replication with
phosphonoacetic acid, a viral DNA Pol inhibitor,
eliminated the DNA-bound form of the BMRF1
protein, although the protein was sufficiently expressed in the cells. These observations together
with the finding that almost all abundantly expressed BMRF1 proteins exist in the DNA-bound
form suggest that BMRF1 proteins not only act at
viral replication forks as Pol processive factors but
also are widely distribute on newly replicated EBV
genomic DNA. In contrast, the BALF5 Pol catalytic
protein, the BALF2 single-stranded-DNA binding
protein, and the BBLF2/3 protein, a component of
the helicase-primase complex, were colocalized as
distinct dots distributed within replication compartments, representing viral replication factories.
Whereas cellular replication factories are constructed based on nonchromatin nuclear structures
and nuclear matrix, Such viral replication factories
could be easily solubilized by DNase I treatment.
Thus, compared with cellular DNA replication,
EBV lytic DNA replication factories appear simpler
so that construction of the replication domain is facilitated.
3. Activation of ATM DNA damage checkpoint signal transduction elicited by
herpes simplex virus infection
Shirata,N. and Tsurumi, T.
Eukaryotic cells are equipped with machinery to
monitor and repair damaged DNA. Herpes simplex
virus (HSV) DNA replication occurs at discrete
sites in nuclei, considering a replication compartment, where viral replication proteins cluster and
synthesize large amounts of viral DNA. In our recent studies, HSV infection was found to elicit a
cellular DNA damage response, with activation of
the ATM signal transduction pathway, as observed
by autophosphorylation of ATM and phosphorylation of multiple downstream targets including Nbs1,
Chk2, and p53, while infection with a
UV-inactivated virus or with a replication-defective
virus did not. Activated ATM and the DNA damage
sensor MRN complex composed of Mre11, Rad50,
and Nbs1 were recruited and retained at sites of viral DNA replication, probably due to recognition of
newly synthesized viral DNAs as abnormal DNA
structures. These events were not observed in
ATM-deficient
cells,
indicating
an
ATM-dependence for the underlying processes. In
Nbs1-deficient cells, HSV infection induced an
ATM DNA damage response which was delayed,
suggesting a functional MRN complex requirement
for efficient ATM activation. However, ATM silencing had no effect on viral replication in 293T
cells. Our data open up the interesting question of
how the virus is able to complete its replication,
despite host cells activation of ATM checkpoint
signaling in response to the HSV infection.
4. Purification of the product of the Epstein-Barr virus BZLF1 gene
Nakasu, S. and Tsurumi, T.
The product of the BZLF1 gene (pBZLF1) of
the Epstein-Barr virus (EBV) is a nuclear protein
which is an activator of the lytic cycle in cells latently infected with EBV. pBZLF1 has been suggested to play the role as a DNA binding protein
specific for the viral lytic origin of DNA replication
(ori lyt).
In order to understand the contribution of
pBZLF1 to induction of the lytic cycle, we focused
on purification of the protein and characterization
of its biochemical features. We first tried to purify
pBZLF1 from insect cells infected with baculoviruses which overproduced pBZLF1. But the partially purified protein tended to form aggregates and
was eluted with a wide range of salt concentrations
from ion exchange chromatography columns. The
results suggested an abnormal conformation of the
pBZLF1 produced in the insect cells so that we next
focused on pBZLF1 from B95-8 cells, a cell line
latently infected with EBV in which the lytic cycle
can be infected. The pBZLF1 could be extracted
from the induced cells with high salt buffer (0.6 to 1
M NaCl) and purified more than 100 fold by hydrophobic, DEAE sephacel, phospho (P) cellulose
and hydroxyapatite chromatographies.
Most
pBZLF1 appeared to be complexed with other proteins in low salt buffer (< 0.12 M NaCl) and was
eluted from columns with high salt buffer (1.5 M
NaCl). The pBZLF1 was further purified with gel
filtration and sucrose gradient centrifugation under
high salt conditions (1.5 M NaCl) in which it behaved as a monomer. Though a pBZLF1 sample
bound to P cellulose in 0.12 M NaCl buffer was applied to gel filtration and sucrose gradient centrifugation, some proportion flowed through P cellulose
equilibrated with 0.12 M NaCl buffer after these
procedures (FT fraction). The pBZLF1 in the FT
fraction bound to DEAE sephacel stronger than before gel filtration and sucrose gradient centrifugation. In addition to these changes in ion exchange
chromatographies, the pBZLF1 in the FT fraction
sedimented at a monomer position with sucrose
gradient centrifugation under low salt conditions
(0.1 M NaCl), indicating existence as a free protein.
Starting from 2 l culture, the protein composition of
the final fraction (0.2 ml) proved hardly visible by
CBB staining of SDS page separation. Therefore a
larger scale purification procedure will be required
for the further purification.
5. Two Sp1/Sp3 binding sites in the major
immediate-early proximal enhancer of
human cytomegalovirus genes are
necessary for transcriptional activation
and viral replication
Isomura, H. and Tsurumi, T.
HCMV is reactivated under immunosuppressive
conditions as with other herpesviruses and progress
of medical intensive care has made this virus an
important pathogen that causes pneumonitis, hepatitis, retinitis, and gastrointestinal diseases in immunocompromized individuals. The molecular
mechanisms of HCMV replication, especially in
vivo, remain unclear. But it is clear that the major
immediate early (IE) genes, IE1 and IE2, are expressed without de novo protein synthesis like other
auxiliary IE genes. Furthermore, IE2 is essential.
Thus, the cis-elements of the MIE genes are thought
to regulate the efficiency for viral replication.
We previously reported that replication of recombinant HCMV was less efficient when the enhancer was replaced by murine components, even
though the human and murine enhancers are positional homologues. Since both have similar effects on the promoter in transient transfection assays, the results of transfection experiments clearly
do not always coincide with expectation of the viral
genome.
In the present study our goal was to assess the
effect of the enhancer and the roles of its individual
repeat elements on IE transcription and viral replication in the context of HCMV infection.
HCMV has a genome over 200 kbp in length
and therefore it is very difficult to make recombinant viruses on which specific target genes are mutated. However, we recently have developed new
genetic engineering in bacteria using homologous
recombination. The HCMV genome was cloned
into the bacterial artificial chromosome (BAC) in
1999. This has allowed us to construct recombinant infectious human CMV DNA containing BAC
in vivo in E.coli., whereby mutagenesis can be manipulated. using double-stranded linear fragments
37
amplified by PCR. This is possible because the
bacteriophage-encoded recombination proteins exo,
beta, and gam efficiently recombine sequences with
homologies as short as 35 to 40 bases in the absence of the E.coli RecA protein. We have constructed recombinant HCMVs featuring either entire or partial deletion of the enhancer using this
new rapid and reliable technology, and compared
the growth of recombinant and parental viruses.
As a result, we found that different from the
murine CMV case, the HCMV enhancer is essential
for viral replication, and a minimal requirement for
viral growth is the SpI binding site in the proximal
enhancer between –39 and –67 relative to the transcription start site of +1, newly discovered by
EMSA and supershift assay with SpI antibodies in
the present study. Moreover, infection of NF-kB
dominant negative cells with the recombinant viruses revealed that two NF-kB and one CREB or
ATF binding sites between –-39 and –173 facilitate
transcription from the MIE promoter.
Figure
Left panel; Accumulation of DNA damage checkpoint proteins such as ATM and MNR complex at sites of
viral replication during EBV lytic infection. Right panel; Model for DNA damage signaling induced by
EBV lytic replication.
38
From left to right
First row: Dr. Keiko Tamiya-Koizumi, Dr. Osamu Taguchi, Dr. Reiji Kannagi, Dr. Akiko Kanamori and
Ms. Yoshiko Goto.
Second row: Ms. Naoko Kimura, Ms. Keiko Miyazaki, Dr. Lim Keh-Ti, Ms. Sasako Eguchi, Ms. Mineko
Izawa, Ms. Akiko Nishioka, Mr. Hirokazu Yagi, Ms. Sachiko Kondo, Dr. Guo-Yun Chen, Mr. Jun
Yin and Dr. Mamoru Kyogashima.
39
Division of Molecular Pathology
__________________________________________________________________
Reiji Kannagi, M.D., D.M.Sc., Chief
Osamu Taguchi, D.M.Sc., Section Head
Mamoru Kyogashima, M.D., D.M.Sc., Senior Researcher (as of April, 2004)
Akiko Kanamori, Ph.D., Researcher (until March, 2005), Senior Researcher (as of April 2005)
Takaaki Yaomura, M.D., Research Resident (until March, 2005)
Masaru Ueda, M.D., Research Resident (until March, 2005)
Mineko Izawa, B.A., Research Assistant
Yoshiko Goto, D.V.M.S., Research Assistant
Sasako Eguchi, Semi-regular Employee
Akiko Nishioka, M.T., Semi-regular Employee
Visiting Scientists
Hiroshi Ikeda, M.D., D.M.Sc., Aichi Medical University
Guo-Yun Chen, M.D., D.M.Sc., Japan Science and Technology Agency
Keiko Miyazaki, M.T., Japan Science and Technology Agency
Lim Keh-Ti, Ph.D., National Institute of Biomedical Innovation
Ayako Hashimoto, B.A., Japan Science and Technology Agency (until October, 2005)
Fathy Mohamed Mohamed El-Fasakhany, M.D., D.M.Sc., JSPS (until September, 2005)
Takashi Murate, M.D., D.M.Sc., Nagoya University School of Health Sciences (as of April, 2004)
Keiko Tamiya-Koizumi, Ph.D., Nagoya University School of Health Sciences (as of April, 2004)
Visiting Trainees
Naoko Kimura, B.P., Nagoya City University
Jun Yin, M.T. Nagoya University School of Bioagricultural Sciences
Tetsufumi Koike, M.D., Fukushima University School of Medicine
Atsushi Akutagawa, M.D., Nagoya University School of Medicine (as of April 2004)
Kazumi Hagiwara, M.T., Nagoya University School of Health Sciences (as of April 2004)
Sayaka Sobue, M.T., Nagoya University School of Health Sciences (as of April 2005)
Hirokazu Yagi, M.P. Nagoya City University (as of April 2005)
Sachiko Kondo, M.E. Nagoya City University (as of April 2005)
Masaru Ueda, M.D., Kyoto Prefectural University of Medicine (as of April 2005)
Akinari Watanabe, M.D., Fukushima University School of Medicine (until March, 2005)
Takaaki Hattori, M.D., Tokyo Medical University (until March, 2004)
General Summary
Cell adhesion molecules called selectins and their specific carbohydrate ligands,
namely sialyl Lewis X and sialyl Lewis A, are involved in hematogenous metastasis of
cancers. Expression of sialyl Lewis X and sialyl Lewis A is markedly enhanced on
cancer cells compared to normal epithelial cells. During the period 2004-2005, we
have succeeded in elucidating the mechanism involved in the cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression in human cancers. We found that
normal epithelial cells express carbohydrate determinants that are more complex than
the parent ligands. Good examples of such complex determinants are sialyl 6-sulfo
Lewis X or disialyl Lewis A, which have additional modifications to sialyl Lewis X or
sialyl Lewis A, respectively. Upon malignant transformation, intracellular synthesis
of such complex carbohydrate determinants become partially impaired because of
transcriptional suppression of some of the genes involved (we call this as "incomplete
synthesis"), which results in accumulation of sialyl Lewis X and sialyl Lewis A with
relatively simple structures in tumors at early stages. In tumor nests within locally
advanced tumors, hypoxia-resistant cancer cells are clonally selected because of the
hypoxic environment. Such cancer cells have a strong and sustained expression of a
40
transcription factor, hypoxia inducible factor-1α (HIF-1α), which induces expression of
various genes which enable cancer cells to cope with or adapt to hypoxia. Included
are several genes involved in sialyl Lewis X or sialyl Lewis A synthesis, and our studies have indicated that this further enhances expression of these carbohydrate determinants in hypoxia-resistant cancer cells, which selectively grow in advanced stages of
cancers undergoing distant hematogenous metastasis. Selectin-mediated cell adhesion mediates homing of lymphocytes in healthy individuals, and during the period
2004-2005, we have clarified, using knock out mice, that the sialyl 6-sulfo Lewis X determinant contributes as a specific ligand for L-selectin in this normal homing. In
these two years we have also concentrated attention on the role of regulatory T-cells in
immune responses against self-antigens.
1. Mechanism of loss of disialyl Lewis A
and induction of sialyl Lewis A expression in early stage human cancers.
gesting that histone deacetylation and/or DNA methylation may be involved in the silencing of the
gene in cancers.
Miyazaki, K. Ohmori, K.*1, Izawa, M., Koike, T. and
Kannagi, R.
*1
Expression of sialyl Lewis A, a ligand for
E-selectin which mediates hematogenous metastasis,
is known to be increased in cancers of digestive organs. In contrast, disialyl Lewis A, which has an
extra sialic acid attached at the C6-position of the
penultimate GlcNAc in sialyl Lewis A, is expressed
preferentially on the surface of nonmalignant colonic epithelial cells, and is significantly
down-regulated on malignant transformation. Introduction of the gene for a 2-6 sialyltransferase
responsible for disialyl Lewis A synthesis into colon cancer cells in our laboratory resulted in a
marked increase in disialyl Lewis A expression and
corresponding decrease in sialyl Lewis A expression. This was accompanied by complete loss of
E-selectin binding of the cells. In contrast, transfected cells acquired significant binding activity to
Siglec-7/p75/AIRM-1, an inhibitory receptor expressed on lymphoid cells (Fig. 1). These findings
indicate that the shift in carbohydrate determinants
from a disialyl Lewis A-dominant status to a sialyl
Lewis A-dominant status on malignant transformation has a dual functional consequence: loss of
normal cell-cell recognition between mucosal
epithelial cells and lymphoid cells on the one hand
and gain of E-selectin binding activity on the other.
The transcription of a gene encoding the 2-6 sialyltransferase was found to be markedly
down-regulated in cancer cells compared with
nonmalignant epithelial cells, in line with the decreased expression of disialyl Lewis A and increased expression of sialyl Lewis A. Treatment
of cancer cells with butyrate or 5-azacytidine
strongly induced disialyl Lewis A expression, sug-
Department of Laboratory Medicine, Kyoto University, School of Medicine.
Fig. 1. Confocal microscopic analyses of epithelial
cells expressing disialyl Lewis A and leukocytes
expressing Siglec-7 in human colonic mucosa.
The distribution of Siglec-7, as detected by
polyclonal anti-Siglec-7 antibody, is shown in
green, and that of the disialyl Lewis A determinant in red. Left panel, low magnification of
nonmalignant colonic mucosa, indicating adhesion of Siglec-7-expressing lymphoid cells to
colonic epithelial cells (arrows). Right panels,
higher magnification micrographs showing adhesion of Siglec-7-expressing lymphoid cells
(green) to nonmalignant colonic epithelial cells
expressing the disialyl Lewis A determinant
(red) through pseudopodia-like extensions (arrowheads). Bars, 10 µm. (Cancer Res., 64:
4498-4505, 2004)
41
2. Tumor hypoxia augments sialyl Lewis X
and sialyl Lewis A expression in locally-advanced human cancers.
Koike, T., Kimura, N., Miyazaki, K., Chen, G. Y., Yin, J.,
Kojima, T.*1, Takematsu, H.*2, and Kannagi, R.
Cancer cells undergo distinct metabolic changes
to cope with their hypoxic environment, at least
partly through the action of transcriptional factors
called hypoxia-inducible factor-α and related
molecules (HIFs). We have investigated gene expression in human colon cancer cells cultured under
hypoxic conditions with special reference to
cell-adhesion molecules and carbohydrate determinants having cell-adhesive activity using
DNA-microarray and RT-PCR techniques. Hypoxic culture of colon cancer cells induced a
marked increase in expression of selectin ligands,
the sialyl Lewis X and sialyl Lewis A determinants
at the cell surface, which led to a definite increase
in cancer cell adhesion to endothelial E-selectin.
The transcription of genes for fucosyltransferase
VII (FUT7), sialyltransferase ST3Gal-I (ST3O), and
UDP-galactose transporter-1 (UGT1), which are all
known to be involved in the synthesis of the carbohydrate ligands for E-selectin, was significantly induced in cancer cells by hypoxic culture. In addition, remarkable induction was detected for the
genes encoding syndecan-4 (SDC4) and α5-integrin
(ITGA5) (Fig. 2), cell-adhesion molecules involved
in enhanced adhesion of cancer cells to fibronectin.
Transcriptional induction by hypoxia was reproduced in luciferase-reporter assays for these genes,
which
were
significantly
suppressed
by
co-transfection of a dominant-negative form of HIF.
These results indicate that the metabolic shifts of
cancer cells partly mediated by HIFs significantly
enhance their adhesion to vascular endothelial cells,
through both selectin- and integrin-mediated pathways, and suggest that this enhancement further facilitates hematogenous metastasis and tumor angiogenesis.
*1
*2
Department of Medical Technology, Nagoya University School of Health Sciences.
Supra-Biomolecular System Research Group, RIKEN
Frontier Research System.
3. Study on L-selectin ligand mediated
homing of naïve T-lymphocytes using
gene-disrupted mice.
Izawa, M., Kimura, N. Uchimura, K.*1, Ohmori, K*2,
Muramatsu, T.*3, Rosen, S.D.*1 and Kannagi, R.
Fig. 2. Hypoxia-induced syndecan-4 and α5integrin expression. Signals including
syndecan-4 (left panel) and α5-integrin
(right panel) in the DNA microarray are
shown (white arrows).
Cy3-dUTP
(normoxia, red) or Cy5-dUTP (hypoxia,
1% O2 for 24 h: green) was incorporated
into cDNA prepared from a human colon
cancer cell line, SW480. (Proc. Natl.
Acad. Sci. U.S.A., 101: 8132-8137, 2004)
42
Selectin-mediated cell adhesion is involved in
the routine homing of lymphocytes. Two kinds of
carbohydrate ligands for selectin have so far been
noted in humans, one is conventional sialyl Lewis
X, and the other is sulfated sialyl Lewis X as represented by sialyl 6-sulfo Lewis X. Conventional
sialyl Lewis X is preferentially involved in the recruitment of leukocytes in inflammation, while sialyl 6-sulfo Lewis X primarily mediates routine
homing of leukocytes. The sialyl 6-sulfo Lewis X
determinant is expressed on the high endothelial
venules (HEVs) of peripheral lymph nodes and
Peyer's
patches,
where
it
mediates
L-selectin-dependent homing of lymphocytes, and
is synthesized through the sequential action of
6-O-sulfotransferase and fucosyltransferase. Two
6-O-sulfotransferase isoenzymes are proposed to be
involved in the synthesis of sialyl 6-sulfo Lewis X
in HEV, GlcNAc6ST-1 and -2. Mice with disrupted genes for GlcNAc6ST-1 or -2 are known to
have impaired lymphocyte homing, indicating both
enzymes to be involved in the synthesis of sialyl
6-sulfo Lewis X. Expression of sialyl 6-sulfo
Lewis X in HEV of Peyer's patches and mesenteric
lymph nodes is decreased in GlcNAc6ST-1 KO
mice, while its expression in peripheral lymph node
is decreased with GlcNAc6ST-2 KO. In line with
this, lymphocyte homing to Peyer's patches is partially impaired in the GlcNAc6ST-1 KO case, and
that to peripheral lymph node is partially reduced in
GlcNAc6ST-2 KO mice. In double-KO mice for
both GlcNAc6ST-1 and -2, expression of sialyl
6-sulfo Lewis X in HEV of all lymphoid tissues,
including Peyer's patches, peripheral and mesenteric lymph nodes, is almost completely abrogated
(Fig. 3), and marked reduction of lymphocyte
homing is observed. These results confirmed our
previous finding in humans that sialyl 6-sulfo Lewis
X is the major ligand for L-selectin in lymphocyte
homing, and indicate that both GlcNAc6ST-1 and
-2 are involved in its synthesis.
*1
*2
*3
Department of Anatomy, Program in Immunology,
Cardiovascular Research Institute, University of California.
Department of Laboratory Medicine, Kyoto University, School of Medicine.
Department of Biochemistry, Nagoya University
Graduate School of Medicine.
4. ATRA-induced apoptosis in the human
neuroblastoma cell line, SH-SY5Y, is
accompanied by alteration of ceramide
species: Appearance of ceramide containing hydroxy fatty acids.
Hagiwara, K., Sobue, S., Kyogashima, M.,
Tamiya-Koizumi, K., Tadano-Aritomi, K.*1, Hara, A.*2,
Aoyama, T.*2, Murate, T. and Kannagi, R.
All-trans retinoic acid (ATRA) and its related
compounds are regarded as promising reagents for
neuroblastoma treatment, but mechanisms of action
remain to be clarified. The purpose of our present
study was to elucidate the molecular background to
Fig. 3. Sialyl 6-sulfo Lewis X expression in HEVs of wild-type and GlcNAc6ST-deficient lymphoid organs. Cryostat-cut sections of peripheral lymph nodes, mesenteric lymph nodes and Peyers' patches from wild-type and
GlcNAc6ST-deficient mice were preincubated with sialidase. Sections were then stained with monoclonal
antibody AG223, which recognizes 6-sulfo Lewis X. Arrows indicate HEVs lacking sialyl 6-sulfo Lewis X
expression. Methyl green was used to counterstain the sections. Bars, 40µm. (Nat. Immunol., 6:
1105-1113, 2005)
43
ATRA-induced cell death in the human neuroblastoma cell line, SH-SY5Y. ATRA rapidly caused
cell death in fetal calf serum-depleted culture, as
confirmed to be apoptosis by identification of DNA
ladder formation and inhibitory effects of a caspase-3 inhibitor. We focused our attention on
sphingolipid metabolism as a signaling pathway of
apoptosis. Metabolic labeling of sphingolipids
with [14C]-serine revealed that ATRA increased radioactivity in the ceramide fraction and decreased
that of sphingomyelin. When we measured in vitro activities of sphingomyelinase, ceramidase, serine palmitoyltransferase, and synthases of sphingomyelin, ceramide and glycolipid, which may be
responsible for the increased of radioactive ceramide, none of the enzymes examined showed distinct ATRA-dependent changes. However, analysis of the molecular species of radioactive ceramide
by thin-layer chromatography detected ceramide
containing
hydroxy
fatty
acid
in
an
ATRA-dependent manner. These results suggest
that hydroxy fatty acid in ceramide may play a role
in ATRA-induced apoptosis. Further detailed
analysis of ceramide species unique to
ATRA-induced apoptosis is now in progress using
mass spectrometry.
*1
*2
Department of Biochemistry, Teikyo University
School of Medicine.
Department of Metabolic Regulation, Institute on
Aging and Adaptation, Shinshu University Graduate
School of Medicine.
5. Rapid demonstration of diversity of
sulfatide molecular species from biological materials by MALDI-TOF MS
Kyogashima, M., Tamiya-Koizumi, K., Goto, Y., Hara,
A.*1, Aoyama, T.*1 and Kannagi, R.
By combining the partition method for enrichment of sulfatides without any chromatographic
procedures and a preparation method for lysosulfatides, we have succeeded in analyzing sulfated glycosphingolipids from biological materials by
MALDI-TOF MS within a single day. We found
SM4s (galactosylsulfatide) to be composed of different species. While the exact composition depended on the source material, SM4s always contained hydroxy fatty acids to various degrees. In
addition to the common sphingoid 4-sphingenine
(d18:1), uncommon/unusual sphingoids phytosphingosine (t18:0), 4-eicosasphinganine (d20:0),
4-eicosasphingenine (d20:1), and sphingadienine
44
(d18:2) were readily detected. Finally, in addition
to SM4s, sulfatide SM3 (sulfated lactosylceramide)
and SM2 (sulfated gangliotriaosylceramide) were
clearly present in renal tubule cells. The major
SM4s was composed of ceramides possessing d18:1
with C22 hydroxy fatty acids (C22:0h), C23:0h, and
C24:0h, whereas the major SM3/SM2 forms were
composed of ceramides possessing t18:0 with C22
normal fatty acids (C22:0), C23:0, C24:0. Namely,
in these two series of sulfatides, either fatty acids or
sphingoids were hydroxylated, and chain lengths of
these components were exactly the same, consequently resulting in a similar polarity of ceramide
moieties. These results demonstrate diversity of
sulfatide molecular species, not only with respect to
sugar- but also to ceramide moieties, which is
probably important for specific effective functions
in particular microenvironments, such as lipid
membrane microdomains.
*1
Department of Metabolic Regulation, Institute on
Aging and Adaptation, Shinshu University Graduate
School of Medicine.
6. Expression cloning of a cDNA encoding
sialic acid cyclase, which generates cyclic sialic acid containing glycoconjugates, and characterization of the produced enzyme.
Kanamori, A., Yamaguchi, M.*1, Ishida, H.*1, Kiso, M.*1
and Kannagi, R.
Recently we have identified a metabolic pathway leading to modification of sialic acid so that a
novel ring form named "cyclic sialic acid", lacking
its carboxyl group, is generated. By the expression cloning method, we focused on isolating a
cDNA encoding a "sialic acid cyclase", which could
catalyse this process. For this purpose, HEK-293T
cells stably expressing sialyl 6-sulfo Lewis X were
used as the recipient cells. Using the G159 monoclonal antibody recognizing cyclic sialyl 6-sulfo
Lewis X antigen as a probe, a cDNA clone (indicated as clone A) causing expression of a G159 antigen was isolated. Interestingly, in order for the
G159 antigen to be produced in recipient cells, another two cDNA clones needed to be co-transfected,
whose encoded proteins appeared to contribute to
the intracellular localization of the clone A product.
On the other hand, expression of clone A protein in
a HUT-102 derived mutant cell line lacking G159
antigen caused the expression of the latter. The
expression levels of sialyl 6-sulfo Lewis X antigen
found to be in inverse proportion to those of cyclic
sialyl 6-sulfo Lewis X detected as the G159 antigen.
Sialic acid cyclase activity of the recombinant clone
A protein could be assayed by an ELISA method
and analysis of the effects of elements which influence its level is now in progress. Our conclusion
is that the enzyme protein encoded by clone A indeed possesses sialic acid cyclase activity.
*1
Department of Applied Bioorganic Chemistry, Gifu
University, School of Agriculture.
7. Immune responses to retinal self-antigens in CD25+CD4+ regulatory T-celldepleted mice.
Takeuchi, M.*1, Keino, H.*1, Kezuka, T.*1, Usui, M.*1 and
Taguchi, O.
Prior work has shown that autoimmune uveoretinitis develops spontaneously in CD25(+)CD4(+)
regulatory T-cell-depleted mice (Tr-depleted mice).
In our recent studies, the generation of autoantibodies and autoreactive T-cells specific to retinal
antigens was examined in Tr-depleted mice with
uveoretinitis, and the pathogenic and immunogenic
abilities of the autoreactive T cells were evaluated.
Tr-depletion was achieved in (C57BL/6 x A/J)
F1 (B6A) mice by thymectomy on day 3 of life followed by intraperitoneal injection of an anti-CD25
monoclonal antibody.
At 6 months of age,
autoantibodies to the retina were evaluated by indirect immunofluorescence, and total IgG2a levels in
sera were assessed by ELISA. The pathogenic abilities of the splenic T cells were examined after
adoptive transfer to syngeneic nu/nu mice, and the
proliferation responses and the secretion of granulocyte-macrophage
colony-stimulating
factor
(GM-CSF), IFN-gamma, and IL-10 on stimulation
by retinal self-antigens were also determined.
Autoantibodies to the retinal photoreceptor cell
layer were detected in Tr-depleted mice, and the
titers correlated well with the grades of inflammatory lesions.
Splenic CD4(+) T cells of
Tr-depleted mice induced uveoretinitis in the recipients by adoptive transfer and exhibited proliferative responses and secretion of IFN-gamma, but
not IL-10, by in vitro stimulation with S-Ag and interphotoreceptor retinoid-binding protein (IRBP).
Moreover, the total IgG2a level in serum was
markedly and significantly augmented in
Tr-depleted mice. The results suggest that in
Tr-depleted mice in which uveoretinitis develops,
S-Ag and IRBP-specific T cells are spontaneously
sensitized and shifted to a Th1-phenotype. These
sensitized T cells may account for the development
of autoimmune uveoretinitis.
*1
Department of Ophthalmology, Tokyo Medical University, Tokyo.
45
From left to right
First row: Ms. Y. Takada, Dr. A. Kawajiri, Ms. T. Yuhara, Ms. Y. Hayashi.
Second row: Mr. T. Oguri, Dr. P. Zou, Mr. T. Siromizu, Ms. N. Saito, Ms. M. Nishizawa.
Third row: Dr. M. Inagaki, Dr. A. Inoko, Dr. H. Goto, Mr. T. Yamaguchi, Dr. I. Izawa.
Insets: Dr. K. Nagata, Dr. M. Sugimoto, Dr. T. Yokoyama, Dr. N. Hanai, Mr. M. Inoue.
46
Division of Biochemistry
__________________________________________________________________
Masaki Inagaki, M.D. Chief
Koh-ichi Nagata, M.D. Section Head (until March, 2004)
Ichiro Izawa, M.D. Senior Researcher
Hidemasa Goto, M.D. Senior Researcher (as of April, 2004)
Akihito Inoko, M.D. Researcher
Miwako Nishizawa, B.P. Senior Research Assistant (until March, 2004)
Yuko Hayashi, Ph.D. Research Assistant (as of April, 2004)
Noriko Saito, B.M.T. Research Assistant (until March, 2004)
Tomoya Yokoyama, M.D. Research Resident (until June, 2005)
Zou Peng, M.D. Research Resident (as of April, 2005)
Postdoctoral Fellows
Nariko Arimura, Ph.D. (as of April, 2004, until August, 2005)
Visiting Trainees
Aie Kawajiri, Ph.D. Department of Pathology, Nagoya University School of Medicine (until April, 2004, as of
September, 2005)
Nobuhiro Hanai, M.D. Department of Otorhinolaryngology, Nagoya City University School of Medicine (until
March, 2004)
Masahiko Sugimoto, M.D. Department of Ophthalmology, Mie University School of Medicine (until June,
2005)
Takashi Oguri, M.S. Department of Cancer Genetics, Nagoya University School of Medicine
Takashi Siromizu, M.S. Department of Cancer Genetics, Nagoya University School of Medicine
Tomoya Yamaguchi, M.S. Department of Cancer Genetics, Nagoya University School of Medicine (as of
April, 2004)
Masaki Inoue, Nagoya University School (as of April, 2003, until March, 2004)
General Summary
Abnormalities in the cell cycle control and tissue architecture are considered to
lead to uncontrolled proliferation, genetic instability, and cell invasion (metastasis),
which are the characteristics of cancers. However, the precise processes of carcinogenesis remain largely unknown.
Our research aim is to elucidate the mechanisms by which cell cycle (including
cell cycle checkpoint) and tissue architecture (including intracellular cytoskeletal network) are controlled. Our attention is focused on 2 specific areas. (1) Identification and
functional analysis of protein kinases involved in cell cycle control and checkpoint; (2)
Regulation of the cytoskeletal protein (especially intermediate filaments) and its associated protein in the cell adhesion.
1. Complex Formation of Plk1 and INCENP
Required for Metaphase-Anaphase
Transition
Goto, H., Kiyono, T.*1, Tomono, Y.*2, Kawajiri, A.,
Urano, T.*3, Furukawa, K.*3, Nigg, E.A.*4 and Inagaki,
M.
Mitotic chromosomal dynamics is regulated by
the coordinated activities of many mitotic kinases,
such as cyclin-dependent kinase 1 (Cdk1),
Aurora-B or Polo-like kinase 1 (Plk1). The abnormalities in these protein kinases can lead to genetic
instability, but its precise regulation remains un-
known. Here we found that Cdk1 phosphorylates
Thr59 and Thr388 on inner centromere protein
(INCENP), which regulates localization and kinase
activity of Aurora-B, from prophase to metaphase.
INCENP depletion disrupts Plk1 localization specifically at the kinetochore. This phenotype is rescued by the exogenous expression of INCENP wild
type (WT) and INCENP mutated at Thr59 to Ala
(T59A), but not at Thr388 to Ala (T388A). The replacement of endogenous INCENP with T388A resulted in the delay of progression from metaphase
to anaphase. These results suggested that INCENP
phosphorylation by Cdk1 is necessary for the re-
47
cruitment of Plk1 to the kinetochore, and the complex formation of Plk1 and Aurora-B on INCENP
may play critical roles in the regulation of chromosomal dynamics.
*1 Virology Division, National Cancer Center Research
Institute
*2 Division of Molecular and Cell Biology, Shigei
Medical Research Institute
*3 Department of Biochemistry II, Nagoya University
Graduate School of Medicine
*4 Department of Cell Biology, Max-Planck Institute for
Biochemistry, Germany.
2. Phosphorylation by Cdk1 induces
Plk1-mediated vimentin phosphorylation during mitosis
Yamaguchi, T., Goto, H., Yokoyama, T., Silljé, H.*1,
Hanisch, A.*1, Uldschmid, A. *1, Takai, Y.*2, Oguri, T.,
Nigg, E.A.*1 and Inagaki, M.
Several kinases phosphorylate vimentin, the most
common intermediate filament protein, in mitosis.
Aurora-B and Rho-kinase regulate vimentin filament separation through the cleavage furrow-specific vimentin phosphorylation. Cdk1 also
phosphorylates vimentin from prometaphase to
metaphase, but its significance has remained unknown. Here we demonstrated a direct interaction
between Plk1 and vimentin-Ser55 phosphorylated
by Cdk1, an event that led to Plk1 activation and
further vimentin phosphorylation. Plk1 phosphorylated vimentin at ~ 1 mol phosphate/mol substrate,
which partly inhibited its filament forming ability,
in vitro. Plk1 induced the phosphorylation of
vimentin-Ser82, which was elevated from metaphase and maintained until the end of mitosis. This
elevation
followed
the
Cdk1-induced
vimentin-Ser55 phosphorylation, and was impaired
by Plk1 depletion. Mutational analyses revealed
that Plk1-induced vimentin-Ser82 phosphorylation
plays an important role in vimentin filaments segregation, coordinately with Rho-kinase and
Aurora-B. Taken together, these results indicated a
novel mechanism that Cdk1 regulated mitotic
vimentin phosphorylation via not only a direct enzyme reaction but also Plk1 recruitment to
vimentin.
*1
*2
48
Department of Cell Biology, Max-Planck Institute for
Biochemistry, Germany.
Department of Obstetrics and Gynecology, Saitama
Medical Center.
3. Mitotic Chk1 Phosphorylation at Novel
Sites Regulated by Cyclin-dependent
kinase 1 (Cdk1)
Shiromizu, T., Goto, H., Tomono, Y.*1, Bartek, J.*2,
Totsukawa, G.*3, Inoko, A., Nakanishi, M.*4, Matsumura,
F.*3 and Inagaki, M.
Chk1 is phosphorylated at Ser317 and Ser345 by
ATR in response to stalled replication and
genotoxic stresses. This Chk1 activation is thought
to play critical roles in the prevention of premature
mitosis. However, the behavior of Chk1 in mitosis
remains largely unknown. Here we reported that
Chk1 was phosphorylated in mitosis. The reduction
of this phosphorylation was observed at the metaphase-anaphase transition. Two-dimensional phosphopeptide mapping revealed that Chk1 phosphorylation sites in vivo were completely overlapped with the in vitro sites by cyclin-dependent
protein kinase (Cdk) 1 or by p38 MAP kinase.
Ser286 and Ser301 were identified as novel phosphorylation sites on Chk1. Treatment with Cdk inhibitor butyrolactone I induced the reduction of
Chk1-S301 phosphorylation, although treatment
with p38-specific inhibitor SB203580 or siRNA did
not. In addition, ionizing radiation (IR) or ultraviolet (UV) light did not induce Chk1 phosphorylation
at Ser317 and Ser345 in nocodazole-arrested mitotic cells. These observations implied the regulation of mitotic Chk1 function through Chk1 phosphorylation at novel sites by Cdk1.
*1
*2
*3
*4
Division of Molecular and Cell Biology, Shigei
Medical Research Institute.
Danish Cancer Society, Institute of Cancer Biology,
Department of Cell Cycle and Cancer, Denmark.
Department of Molecular Biology and Biochemistry,
Rutgers University, USA.
Biochemistry, Nagoya City University Medical
School.
4. Functional analysis of cytoskeleton
Izawa, I., Nishizawa, M. and Inagaki, M.
Intermediate filaments (IF) form the structural
framework of cytoskeleton. Although the histopathological detection of IF proteins are utilized for
examining cancer specimens as reliable markers,
the molecular mechanisms how IFs are involved in
the biology of cancer cells are still unclear. We set
out to search for the binding partners with simple
epithelial keratin 8/18, and have thus far identified
Mrj, TNF receptor type 1-associated death domain
protein (TRADD) and trichoplein. Mrj, a DnaJ/Heat
shock protein 40 (Hsp40) family protein, directly
binds to keratin 18. Mrj may play an important role
in the regulation of the keratin 8/18 filament organization as a keratin 18-specific co-chaperone to
work together with Hsp/c70. We found a direct association of keratin 18 with TRADD, an indispensable adaptor molecule for TNF receptor type 1
(TNFR1) signaling. Thus, keratin 18 may sequester
TRADD to attenuate the interaction of TRADD
with activated TNFR1, leading to diminution of
TNF-induced apoptosis. These results suggest that
simple epithelial keratins may play a role in modulating the response to some apoptotic signals.
Trichoplein has a domain that shows a low degree
of sequence similarity between trichohyalin and
plectin, designated as trichohyalin/plectin homology domain (TPHD). Trichoplein may be involved
in the organization of the keratin filament network,
possibly affecting cell polarity in simple epithelial
cells. The identifications of IF-binding proteins and
lessons from transgenic mouse models and human
diseases have indicated that IF may affect cell
growth, cell death and cell polarity through the interactions with a variety of non-structural proteins,
including kinases and adaptors for cell signaling. It
is hence plausible that IF may play profound roles
in cancer development, invasion and metastasis.
5. Characterization and functional analysis of novel keratin filament-binding
proteins, trichoplein and Fbf-1
Inoko, A., Zou, P., Sugimoto, M., Hayashi, Y., Kiyono,
T.*1, Izawa, I. and Inagaki, M.
As described above, we searched for the binding
partners with keratin 8/18 to reveal the function of
cytoskeleton especially in the epithelial cells. And,
we identified a novel protein of trichoplein and
Fbf-1 as keratin filament-binding proteins.
Concerned about trichoplein, we newly found that
trichoplein localized not only on keratin filament
but also at desmosome. This means that the
trichoplein of keratin filament-binding protein has
potential to participate in the organization of
cell-cell contact. Next, to elucidate the function of
trichoplein, we executed RNA interfere experiments.
The results suggested that the decrease of
trichoplein causes morphological changes of cultured cells. So, now we are investigating the molecular mechanism of this alteration.
Fbf-1 was previously reported as a Fas-binding
protein. But, we newly characterized this protein as
a keratin filament-binding protein which mainly
concentrated at cell-cell border, and we found that
the amino acid sequence of Fbf-1 has similarity to
trichoplein because both have TPHD. Subsequently,
we are going to clarify the function of Fbf-1 with
RNA interfere experiments.
*1
Virology Division, National Cancer Center Research
Institute
6. Vimentin-Ser82 as a phosphorylation
site that memorizes the activity of
CaMKII in astrocytes
Oguri, T., Inoko, A., Shima, H.*1*2, Izawa, I., Arimura,
N., Yamaguchi, T., Inagaki, N.*3, Kaibuchi, K.*4,
Kikuchi, K.*1 and Inagaki, M.
In astrocytes, the PGF2α or ionomycin treatment induces the phosphorylation at Ser38 and
Ser82 of vimentin, a type III intermediate filament,
by Ca2+/calmodulin-dependent protein kinase II
(CaMKII). We found here that vimentin phospho-Ser82 was dephosphorylated much slower than
phospho-Ser38. Vimentin phospho-Ser38 was
dephosphorylated quickly by purified PP1 catalytic
subunit (PP1c) in vitro, whereas phospho-Ser82
was insensitive to PP1c. Because PP1c directly
bound to vimentin through a VxF motif
(Val83-Asp84-Phe85), the PP1c active site appeared to be unable to approach phospho-Ser82,
leading to the prolongation of the phosphorylation
at Ser-82. In astrocytes, PP1cαwas in vivo associated with vimentin filaments. The repetitive treatment by ionomycin at a short interval resulted in the
sustained elevation of Ser82 phosphorylation, leading to the marked disassembly of vimentin filaments. Taken together, these results suggest that
phosphorylation state of vimentin is regulated by
PP1c in astrocytes, and vimentin-Ser82 may act as a
phosphorylation site that memorizes the activity of
CaMKII.
*1
*2
*3
*4
Division of Biochemical Oncology and Immunology,
Institute for Genetic Medicine, Hokkaido University
Division of Cancer Chemotherapy, Miyagi Cancer
Center Research Institute
Division of Signal Transduction, Graduate School of
Biological Science, Nara Institute of Science and
Technology
Department of Cell Pharmacology, Graduate School
of Medicine, Nagoya University
49
From left to right
First row: Dr. H. Furue, Dr. Hid. Nakamura, Ms. N. Saito and Dr. K. Ijichi,
Second row: Ms. S. Matsumoto, Dr. K. Ishizaki, Dr. Y. Yasui and Dr. H. Kumimoto
50
Division of Central Laboratory & Radiation Biology
__________________________________________________________________
Kanji Ishizaki, Ph.D. Chief
Hiroshi Kumimoto, Ph.D. Researcher
Yoshihiro Yamane, Ph.D. Research Resident (until March 2004)
Hideaki Nakamura, Ph.D. Research Resident (as of April 2004)
Hiroki Furue, D.D.S. Research Resident (as of April 2005)
Yuko Hayashi, Ph.D. Research Assistant (until March 2004)
Yoshihiro Yasui, Ph.D. Research Assistant
Noriko Saito, Research Assistant (as of April 2004)
Visiting Trainees
Kei Ijichi, M.D. School of Medicine, Nagoya City University (as of April 2004)
Tomotaka Sugimura, D.D.S. School of Medicine, Nagoya University (until March 2005)
Makoto Adachi, D.D.S. Asahi University School of Dentistry
General Summary
One of our main research projects is molecular genetic analysis of human esophageal and
oral tumors. We are studying interactions between genetic polymorphisms and life-style factors in
development of these tumors to find clues for effective prevention. So far, we have analyzed polymorphisms in the L-myc, CHK2, CYP1A1, CYP1B1, CYP2E1, XPA, XPC, XPD, XPF, OGG1,
XRCC1, ERCC1, STK15, and MDM2 genes and found that specific alleles of the L-myc and
STK15 genes are associated with induction of esophageal tumors by smoking and drinking. Polymorphisms of the CYP2E1, XPA, and ERCCI genes were also shown to be related to oral cancers.
Another research project is the study of genetic effects of low-dose-rate radiation on human cells. For this purpose we have established immortal cell lines derived from normal individuals
and patients with ataxia telangiectasia (AT), a radiation sensitive genetic disease, by introducing the
human telomerase gene. These cell lines are immortal but without any changes in the p53 and other
genes that are involved in cellular signal transduction. Using these cell lines we have revealed that
cytotoxic effects and mutation induction by low-dose rate radiation in normal cells is much lower
than those by high-dose-rate radiation but that AT cell lines exhibit similar radiation sensitivity independent of the dose-rate. Using phosphorylated H2AX foci as indicators of DNA double strand
breaks (DSBs), we have demonstrated that AT cells exhibit a partial defect in the repair of DSBs.
1. A single nucleotide polymorphism of
the MDM2 gene in Japanese esophageal
and oral cancer patients
Kumimoto, H., Sugimura, T.*1, Furue, H.*1, Shinoda,
M.*2, Hatooka, S.*2, and Ishizaki, K.
The human homologue of mouse double minute 2 (MDM2) is a key negative regulator of p53.
A single nucleotide polymorphism (SNP309) has
been identified in the first intron of the MDM2 gene
with functional consequences, since the G allele
shows higher promoter activity than the T allele.
Thus the SNP309 can influence p53 tumor suppressorion through its expression level. The G allele of the SNP309 showed an increased expression
level of the MDM2. And the GG genotype was
reported to be associated with high cancer susceptibility and an early onset of soft tissue sarcoma development (G.L. Bond et al., Cell 119 (2004)
591-602).
Since mutations of the p53 gene which is a
target of the MDM2 protein, and amplification of
the MDM2 gene are frequently observed in esophageal cancer, and since oral cancer is developed
in the same upper digestive tract area, risks with
SNP309 for these cancers were analyzed by the polymerase chain reaction-based restriction fragment
length polymorphism (PCR-RFLP) approach.
Total of 330 Japanese non-cancer outpatients and
165 patients with esophageal cancer at Aichi Cancer Center Hospital were the subjects. And also
PCR-RFLP analysis was performed 122 patients
with oral cancer. The genotype distribution fitted
with the Hardy-Weinberg equilibrium among
non-cancer subjects; 106 with the GG genotype,
165 with the GT genotype and 61 with the TT
genotype. While the T allele is dominant in the
United States, the G allele was found to be most
51
OR
1.4
1.2
1
0.4
standard
0.6
standard
0.8
0.2
0
GG GT TT
GG GT TT
esophageal cancer oral cancer
Fig. 1. Age-sex-adjusted ORs for esophageal or
oral cancer according to the genotype of the
MDM2 gene. ORs for the GG and GT genotypes
in esophageal cancer were significantly low compared with the TT genotype. However, no significant differences risks were found for oral cancers.
prevalent, with significance (p<0.001), suggesting
that the genotype distribution of the SNP309 may
be different among each ethnic group. The risks
of esophageal cancer in the GG and TG genotypes
compared with the TT genotype were significantly
low (OR=0.53 95%CI 0.32-0.88, and OR=0.48
95%CI 0.30-0.77, respectively), which is opposite
age
60
40
20
0
GG GT TT
GG GT TT
esophageal cancer oral cancer
Fig. 2. The average ages of onset of esophageal
and oral cancers with each genotype of the MDM2
gene. The average ages of onset of esophageal
cancer in each genotype were similar each other.
And those of oral cancer were also similar.
52
to the result in the United States, while the risk of
oral cancer did not significantly differ with the
genotype (Fig. 1). Interactions with smoking were
also analyzed. Smoking and drinking rate did impact on esophageal cancer but no genotype differences were significant. Risks of oral cancer, were
also significantly influenced by smoking or heavy
drinking but again the genotype did not appear to
play any role. The average ages of onset of esophageal cancer were similar with each genotype and
this was also the case for oral cancer (Fig. 2). In
conclusion, the genotype distribution of the MDM2
gene among Japanese differ from that among
Americans and the risks of upper alimentary tract
cancers with the GG genotype are not high compared with the TT genotype, suggesting that the
contribution of the GG genotype of the MDM2 gene
in cancer development might be, if anything, small
in Japanese.
*1
*2
Nagoya University Graduate School of Medicine, 65
Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550
Department of Thoracic Surgery, Aichi Cancer Center Hospital
2. DNA repair defect in AT cells and their
hypersensitivity to low-dose-rate radiation
Nakamura, Hid., Yasui, Y., Saito, N. and Ishizaki, K.
To investigate the effects of low-dose-rate radiation on ataxia telangiectasia (AT) cells arrested
in the G0/G1 phase, AT and normal cells immortalized with the human telomerase gene were irradiated in non-proliferative condition at high- (2
Gy/min) or low-dose-rate (0.3 mGy/min) radiation.
Figure 1 shows the survival curves obtained by
colony formation assay with AT (AT1OS/T-n,
AT2KY/T-n and AT5KY/T-n) and normal
(SuSa/T-n) cells exposed to high- or low-dose-rate
radiation. While normal cells showed a higher resistance after irradiation at a low-dose rate than a
high-dose rate, AT cells showed virtually the same
survival after low- and high-dose-rate irradiation.
Then, we used the micronucleus assay as a measure
of induction of chromosomal aberrations. Although
the frequency of micronuclei by low-dose-rate radiation showed a large reduction in normal cells, in
AT cells it did not exhibit a significant reduction
(data not shown). Since recent studies showed a
close correlation between the number of γH2AX
foci in a nucleus and the number of expected DSBs
after irradiation, we determined the number of
AT1OS/T-n HDR
AT1OS/T-n LDR
AT2KY/T-n HDR
AT2KY/T-n LDR
AT1OS/T-n HDR
AT1OS/T-n LDR
AT2KY/T-n HDR
AT2KY/T-n LDR
AT5KY/T-n HDR
AT5KY/T-n LDR
SuSa/T-n HDR
SuSa/T-n LDR
AT5KY/T-n HDR
AT5KY/T-n LDR
SuSa/T-n HDR
SuSa/T-n LDR
40
1
γH2AX foci/cells
Survival
35
0.1
30
25
20
15
10
5
0.01
0
0
1
2
3
4
5
6
Dose (Gy)
FIG. 1. Dose-dependent survival curves of AT and
normal cells exposed to high- (HDR: open symbol, 2
Gy/min) or low-dose-rate (LDR: closed symbol, 0.3
mGy/min) radiation. Bars indicate standard deviations
(n = 3).
FIG. 2. γH2AX foci in SuSa/T-n and AT2KY/T-n
cells observed after irradiation at 5 Gy of high(HDR) or low-dose rate (LDR). Quiescent cells in the
SlideFlask were irradiated at high- or low-dose rate
and stained with a specific antibody to γH2AX. Nuclei were also stained with DAPI (blue).
0
1
2
3
4
5
6
7
Dose (Gy)
FIG. 3. Dose-response curves for γH2AX focus induction in AT and normal cells after high- (HDR:
open symbol, 2 Gy/min) or low-dose-rate (LDR:
closed symbol, 0.3 mGy/min) radiation. For each
dose, more than 100 nuclei are scored, and mean
values with standard errors were shown.
DSBs and DSB repair activity by analysis of the
focus formation of the γH2AX. Figure 2 shows
representative focus formations in SuSa/T-n and
AT2KY/T-n cells after high- or low-dose-rate irradiation. The numbers of foci on each nucleus were
counted, and the mean numbers of foci induced by
each dose of radiation are shown in Fig. 3. The
number of γH2AX foci increased in proportion to
the dose in both AT and normal cells after
high-dose-rate irradiation. Although few γH2AX
focus formations were observed by low-dose-rate
radiation in normal cells, significant and
dose-dependent γH2AX foci were observed in AT
cells even after low-dose-rate irradiation, indicating
that DNA damage was not completely repaired
during low-dose-rate irradiation. These results suggest that AT cells might not be able to repair some
fraction of DNA damage and are severely affected
by low-dose-rate radiation.
53
From left to right,
First row: Dr, Hir. Nakamura and Mr. Y. Minoura
Second row: Ms. M. Mizuno, Ms. M. Nishizawa and Ms. M. Yamamoto
54
Central Service Unit
__________________________________________________________________
Hiromu Nakamura, D.M.Sc. Section Head
Morio Terashima, B.A. Senior Research Assistant (until March 2004)
Sachiko Tokumasu, B.D. Research Assistant (until March 2004)
Miwako Nishizawa, B.P. Senior Research Assistant (as of April 2004)
Masami Yamamoto, D.V.M. Research Assistant
Mikio Hagino Research Assistant (Animal care specialist)
Visiting Trainees
Yoshimi Nishi, PhD. Nagoya University School of Medicine (until March 2004)
General Summary
The Central Service Unit fulfills many functions in assisting the investigations performed by
the Institute and has responsibilities for the maintenance and operation of various instruments for
biotechnology research. These are the DNA sequencer (ABI 3100), flow-cytometer (BectonDickinson FACS Calibur), imaging analyzers (Fujix BAS-2500Mac, Amersham-Pharmacia
ImageMaster-CL and FluorImager-595), X-ray machine (Hitachi MBR-1520R3), electron
microscopes (JEOL TEM and Hitachi SEM), confocal laser microscope (Bio-Rad Radiance),
real-time PCR equipment (Roche Light Cycler), ultracentrifuges (Beckman and Hitachi), and
computer systems for image treatment (Windows and Macintosh systems).
Furthermore, we maintain and manage the radioisotope experimental facilities, SPF and
conventional animal rooms, laboratories for translational research and technical photography and
hazardous chemical storage, ultra-low temperature freezers, cold rooms, the liquid nitrogen storage
room, security systems, air-conditioning, water purifying and waste water treatment systems, as
well as the carbon dioxide gas supply, thereby contributing to many other of the Institute’s
functions. During the last two years we replaced several instruments such as an ultracentrifuge
(Beckman-Coulter Optima LE-80K), a molecular interaction analyzer (Biacore X-system), a
flow-cytometer (Becton-Dickinson FACS Calibur) and a real-time PCR (ABI 7500 Fast Real-Time
PCR System). Our activities thus provide essential background support for all the research carried
out by the Research Institute.
55
Librarians
________________________________________________________________________________
From Left to right
Librarians, Ms. K. Adachi, Ms. T. Ieda, Ms. M. Teratani, Ms. T. Yasuda, supporting
scientific and medical informations.
56
Researches
Supported by Special Project Programme
________________________________________________________________________________
1. Defining Second-Hit Genetic Abnormalities Involved in Generation of t(12; 21)
TEL-AML1 Acute Lymphoblastic Leukemias by Array-based Comparative Genomic Hybridization
Tsuzuki, S., Karnan, S., Horibe, K.*1, Matsumoto, K.*2,
Kato, K.*2, Inukai, T.*3, Goi, K.*3, Sugita, K.*3,
Nakazawa, S.*3, Ueda, R.*4, and Seto, M.
The TEL (ETV6)-AML1 (RUNX1) chimeric gene
fusion is the most common genetic abnormality in
childhood acute lymphoblastic leukemias (ALL).
Evidence suggests that chimeric gene fusion usually
occurs in utero during fetal hematopoiesis and most
probably constitutes an initiating or first-hit
mutation that is necessary but insufficient for the
development of overt, clinical leukemia. In our
search for additional secondary and postnatal
genetic events that could be linked to leukemia
development, we applied a genome- wide arrayCGH technique to 24 TEL-AML1 leukemia
samples and two cell lines (REH, KOPN41) and
found that at least three chromosomal imbalances
were involved in all patient samples and cell lines.
Recurrent regions of chromosomal imbalance
(found in > 10% of clinical samples) were gain of
chromosomes 10 (17 %) and 21q (25 %) and loss of
chromosomes 2p11 (100 %), 12p13.2 (87 %),
9p21.3 (29 %), 9p13.2 (25 %), 12q21.3, (25 %),
3p21 (21 %), 6q21 (17 %), 4q31.23 (17 %),
11q22-q23 (13 %) and 19q13.11-q13.12 (13 %).
The two cell lines showed gain of 21q22.12-qter
and loss of 2p11.2, 9p21.3, 12p13.2, and 12q21.3.
Among these, six regions of loss (2p11, 3p21,
4q31.23, 9p13.2, 12q21.3 and 19q13.12) have not
been identified previously by conventional CGH in
TEL-AML1 leukemias. Representative genes
involved in the regions of loss were Igkappa (2p11),
TEL (12p13.2), p16INK4a/ARF (9p21.3), Pax5
(9p13.2), BTG1 (12q21.3), LIMD1 (3p21), AIM1
and BLIMP1 (6q21), NR3C2 (4q31.23), ATM
(11q22-q23), and PDCD5 (19q13.11-q13.12), while
the region of gain at 21q contained RUNX1. These
findings suggest that, in addition to TEL previously
reported to be lacking, genes involved in cell cycle
regulation, p53 pathways and apoptosis are also
often deleted. Our array –CGH obtained data should
provide further insights into the molecular basis of
TEL-AML1 leukemia development.
*1
*2
*3
*4
Clinical Research Center, National Hospital
Organization Nagoya Medical Center
Division of Hematology and Oncology, Children's
Medical Center, Japanese Red Cross Nagoya First
Hospital
Department of Pediatrics, Faculty of Medicine,
University of Yamanashi
Department of Internal Medicine and Molecular
Science, Nagoya City University, Graduate School of
Medical Sciences
57
Publications
________________________________________________________________________________
Journals
J001. Abe, T., Takano, K., Suzuki, A., Shimada,
Y., Inagaki, M., Sato, N., Obinata, T. and Endo,
T.: Myocyte differentiation generates nuclear
invaginations traversed by myofibrils associating
with sarcomeric protein mRNAs. J.Cell Sci. 117:
6523-6534, 2004. (PMID: 15572409)
J002. Akazawa, T., Masuda, H., Saeki, Y.,
Matsumoto, M., Takeda, K., Tsujimura, K.,
Kuzushima, K., Takahashi, To., Azuma, I., Akira,
S., Toyoshima, K. and Seya, T.: Adjuvant-mediated
tumor regression and tumor-specific cytotoxic
response
induction
are
impaired
in
MyD88-deficient mice. Cancer Res. 64: 757-764,
2004. (PMID: 14744795)
J003. Akiyama, Y., Kuzushima, K., Tsurumi, T.
and Yamaguchi, K.: Analysis of HLA-A24restricted CMVpp65 peptide-specific CTL with
HLA-A*2402-CMVpp65 tetramer. Immunol. Lett.
95: 199-205, 2004. (PMID: 15388261)
activities of chemicals in rat liver. J Appl Toxicol,
25: 554-561, 2005. (PMID: 16208626)
J008. Azuma, T., Otsuki, T., Kuzushima, K.,
Froelich, C.J., Fujita, S. and Yasukawa, M.:
Myeloma cells are highly sensitive to the granule
exocytosis pathway mediated by WT1-specific
cytotoxic T lymphocytes. Clin. Cancer Res. 10:
7402-7412, 2004. (PMID: 15534117)
J009. Bork, S., Yokoyama, N., Ikehara, Y.,
Kumar, S., Sugimoto, C. and Igarashi, I.:
Growth-inhibitory effect of heparin on Babesia
parasites. Antimicrob. Agents Chemother. 48:
236-241, 2004. (PMID: 14693545)
J010. Cao, X., Tsukamoto, T., Nozaki, K.,
Mizoshita, T., Ogasawara, N., Tanaka, H.,
Takenaka, Y., Kaminishi, M., and Tatematsu, M.:
β-Catenin gene alteration in glandular stomach
adenocarcinomas
in
N-methyl-N-nitrosoureatreated and Helicobacter pylori-infected Mongolian
gerbils. Cancer Sci., 95: 487-490, 2004. (PMID:
15182428)
J004. Anumanthan, G., Halder, SK., Osada, H.,
Takahashi, Ta., Massion, PP., Carbone, DP., and
Datta, PK.: Restoration of TGF-β signalling
reduces tumorigenicity in human lung cancer cells.
Br. J. Cancer. 93: 1157-1167, 2005. (PMID:
16251876)
J011. Cao, X., Tsukamoto, T., Nozaki, K.,
Shimizu, N., Mizoshita, T., Kumagai, T.,
Kaminishi, M., and Tatematsu, M.: Eradication of
Helicobacter pylori induces apoptosis and inhibits
proliferation of heterotopic proliferative glands in
infected Mongolian gerbils. Cancer Sci, 95:
872-877, 2004. (PMID: 15546504)
J005. Arimura, N., Ménager, C., Kawano, Y.,
Yoshimura, T., Kawabata, S., Hattori, A., Fukata,
Y., Amano, M., Goshima, Y., Inagaki, M., Morone,
N., Usukura, J. and Kaibuchi, K.: Phosphorylation
by Rho-kinase regulates CRMP-2 activity in growth
cones. Mol. Cell. Biol. 25: 9973-9984, 2005.
(PMID: 16260611)
J012. Chiba, H., Takezaki, T., Neupani, D., Kim,
J., Yoshida, S., Mizoguchi, E., Takeuchi, J.,
Suzuki, J., Tanaka, Y., Ito, K., Kitamura, T.,
Kuriki, K., Wakai, K., Samejima, K., Sonoda, S.
and Tajima, K.: An epidemiological study of HBV,
HCV and HTLV-I in Sherpas of Nepal. Asian Pac J
Cancer Prev, 5: 370-373, 2004. (PMID: 15546239)
J006. Asano, N., Suzuki, R., Kagami, Y., Ishida,
F., Kitamura, K., Fukutani, H., Morishima, Y.,
Takeuchi, K. and Nakamura, S.: Clinicopathologic
and prognostic significance of cytotoxic molecule
expression in nodal peripheral T-cell lymphoma,
unspecified. Am. J. Surg. Pathol., 29:1284-1293,
2005. (PMID: 16160469)
J013. Chiba, H., Tretli, S., Lund, E., Wakai, K.,
Takezaki, T., Senoo, H., Sonoda, S. and Tajima,
K.: Lack of HTLV-I carriers in the Sami, an ethnic
group living in the Arctic area in Norway. Asian
Pac J Cancer Prev, 5: 50-53, 2004. (PMID:
15075005)
J007. Asaoka, Y., Sakai, H., Takahashi, N.,
Hirata, A., Tsukamoto, T., Yamamoto, M., Yanai,
T., Masegi, T., and Tatematsu, M.: Intraperitoneal
injection of D-galactosamine provides a potent cell
proliferation stimulus for the detection of initiation
58
J014. Daikoku, T., Kudoh, A., Fujita, M.,
Sugaya, Y., Isomura, H. and Tsurumi, T.: In vivo
dynamics of EBNA1-oriP interaction during latent
and lytic replication of Epstein-Barr virus. J. Biol.
Chem. 279: 54817-54825, 2004. (PMID:
15498777)
J015. Daikoku, T., Kudoh, A., Fujita, M.,
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Tokyo, p. 3-28, 2005.
R062. Tsurumi, T., Fujita, M. and Kudoh, A.:
Latent and lytic Epstein-Barr virus replication
strategies. Rev. Med. Virol. 15: 3-15, 2005. (PMID:
15386591)
R054. Tatematsu, M., Tsukamoto, T., and
Mizoshita, T.: Role of Helicobacter pylori in gastric
carcinogenesis: the origin of gastric cancers and
R063. Uchida, A., Matsuo, K. and Tanimoto, M.:
APL during gefitinib treatment for non-small-cell
lung cancer. N Engl J Med, 352: 843, 2005. (PMID:
82
15728826)
R064. Utsunomiya, H., Inada, K., Tsukamoto, T.,
and Tatematsu, M.: Inhibitory effects of
"Bainiku-ekisu", Japanese apricot extracts, on
motility and growth of Helicobacter pylori. In:
Tanaka, T., and Tsuda, H. (eds). Carcinogenesis
and Modification of Carcinogenesis, Research
Signpost, Kerala, India,2005.
R065. Wakai, K., Ando, M., Ozasa, K., Ito, Y.,
Suzuki, K., Nishino, Y., Kuriyama, S., Seki, N.,
Kondo, T., Watanabe, Y., Ohno, Y. and
Tamakoshi, A.: Updated information on risk
factors for lung cancer: findings from the JACC
Study. J Epidemiol, 15 Suppl 2: S134-139, 2005.
(PMID: 16127225)
R066. Wakai, K.: The JICA training course,
community-based cancer prevention for Asian
Pacific countries, 2004 (Epidemiological approach).
Asian Pac J Cancer Prev, 5: 231-236, 2004. (PMID:
15460556)
R067. Yokoyama, T.: Methods for the preparation
of activated kinase in the insect expression system.
In: Protocols for post-translational protein
modification (Inagaki, M. ed.), pp. 266-275, Tokyo:
Yodosha, 2005 [in Japanese].
Abstracts for international conferences
A001. Akatsuka, Y., Kuzushima, K. and
Takahashi,
To.:
Identification
of
minor
histocompatibility
antigens
involved
in
graft-versus-leukemia effect and GVHD following
allogeneic hematopoietic cell transplantation.
Abstract for US-Japan Cooperative Cancer
Research Program, 2005.
A002. Akatsuka, Y.: Identification of two novel
minor histocompatibility antigens by linkage
analysis and their clinical relevance, Abstract for
the 2004 Tandem BMT Meeting (IBMTR/ABMTR
and ASBMT), 2004.
A003. Daikoku, T., Kudoh, A. and Tsurumi, T.:
Dynamics of Epstein-Barr virus EBNA1 protein
binding to viral genome and subcellular
redistribution from latent to lytic infection. EBV
symposium 2004 The 11th Symposium of the
International Association for Research on
Epstein-Barr Virus and Associated Diseases. 04.12
Regensburg, Germany. 2004.
A004. Daikoku, T., Kudoh, A. and Tsurumi, T.:
Postreplicative mismatch repair factors are recruited
to Epstein-Barr virus replication compartments. 5th
3R symposium P47, Awaji Yumebutai, Hyogo.
2005
A005. Fujiwara, K., Fujimoto, N., Tabata, K.,
Matsuo, K., Kozuki, A., Tokuda, Y., Kiura, K.,
Nishii, K., Ueoka, H. and Tanimoto, M.:
Identification of aberrant promoter methylation in
serum DNA for early detection of lung cancer.
Proceeding of Annual Meeting 2004, American
Association of Cancer Research, 3959, 2004.
A006. Hirose, K., Tajima, K. and Tokudome, S.:
Soybean products and reduction of breast cancer
risk ： A case-control study in Japan. The 3rd
Regional Conference of Asian Pacific Organization
for Cancer Control, 26, 2005.
A007. Hotta, K., Matsuo, K., Ueoka, H., Kiura,
K., Tabata, M., Harita, S., Gemba, K., Yonei, T.,
Bessho, A. and Tanimoto, M.: Continued gefitinib
treatment after disease stabilization prolongs
survival of patients with advanced non-small-cell
lung cancer. J Clin Oncol. 23: 642S, 2005.
A008. Ikehara, Y., Kojima, N., Nakanishi, H.,
Yoshii, T., Biao, L., Niwa, T., and Tatematsu, M.:
Intra peritoneal macrophage is activated by uptake
83
of Mannose conjugated Liposome. American
Society of Glycobiology, Poster, Hawaii, USA,
2004.
A009. Ikehara, Y.,Sato, T., Niwa, T., Nakamura,
S., Goto,M. ,Ikehara, K., S., Kiyohara, K., Iwai, T.,
Hirabayashi, J., Nakanishi, H., Tatematsu, M.
and Narimatsu, H.: Apical Golgi localization of
N,N'-diacetyllactosediamine
synthase
β
4GalNAc-T3, is responsible for LacdiNAc
expression on gastric mucosa. American Society of
Glycobiology, Poster, Boston, USA,2005.
A010. Ikehara, Y.: Polymorphisms of two
fucosyltransferase genes (Lewis and Secretor
genes) involving type I Lewis antigens are
associated with the presence of anti-Helicobacter
pylori IgG antibody. The 11th Aichi Cancer Center
International Symposium, Nagoya, Japan,2005.
A011. Inagaki,
M.:
Identification
and
characterization of cleavage fullow kinases. Gordon
Research Conference on “Intermediate Filaments”.
Oxford, 2004.
A012. Inoko, A., Nishizawa, M., Izawa, I.,
Nagata, K. and Inagaki, M.: Identification and
characterization of a novel keratin binding protein,
trichoplein(trichohyalin and plectin like protein), as
a desmosomal protein. Gordon Research
Conference on “Intermediate Filaments”. Oxford,
2004.
A013. Ishizaki, K.: Effects of low-dose-rate
radiation on HTERT-immortalized human cells. 3rd
International Workshop on Space Radioration
Reserch. NewYork, USA, May 2004.
A014. Isomura , H., Stinski, M.F., Kudoh, A.,
Daikoku, T., Shirata, N. and Tsurumi, T.: Two
SP1/SP3 binding sites in the major immediate-early
proximal enhancer of human cytomegalovirus have
a significant role in viral replication. 30th
Herpesvirus Workshop. 1.42, Turku, Finland. 2005.
A015. Isomura, H., Tsurumi, T. and Stinski, M.F.:
The Role of the Proximal Enhancer in human
Cytomegalovirus Replication. 29th Herpesvirus
Workshop, 1.16, Nevada, USA. 2004.
A016. Ito, H. and Tajima, K.: Comparison of
relative risk impact of habitual smoking and
drinking for cancer by site based on regional cancer
registry data for Aichi prefecture, Japan. The 3rd
Regional Conference of Asian Pacific Organization
for Cancer Control, 14, 2005.
A017. Ito, H., Hamajima, N., Matsuo, K.,
84
Mitsudomi, T., Sugiura, T., Sato, S., Ueda, R. and
Tajima, K.: Gene-environment interaction between
smoking habit and DNA repair genes, APE1
Asp148Glu and XRCC1 Arg399Gln, in lung cancer
risk among Japanese. The 6th joint conference of
the American Association for Cancer Research and
the Japanese Cancer Association, A59, 2004.
A018. Ito, H., Masui, T. and Tajima, K.: Impact
of habitual smoking on cancer stage at diagnosis
based on regional cancer registry data for Aichi
prefecture, Japan. Final program and abstract book
of 27th annual meeting of the International
Association of Cancer Regisries, 60, 2005
A019. Ito, H., Matsuo, K., Shinoda, M., Hatooka,
S., Hirose, K., Saito, T., Wakai, K. and Tajima, K.:
Esophageal cancer and polymorphisms of APE1
Asp148Glu and XRCC1 Arg399Gln. The 2nd
APOCP General Assembly Conference, 100, 2004.
A020. Iwata, S., Sato, C., Ando, H., Kiso, M.,
Kannagi, R., and Kitajima, K.: Studies on chemical
properties of cyclic sialic acid using their synthetic
S- and O-glycosides as model compounds.
US/Japan Glyco 2004 (Joint meeting of the Society
for Glycobiology and the Japanese Society of
Carbohydarate Research, (President, M.E. Etzler)
Hawaii, November 17-20, 2004.
A021. Kakizaki, I., Kojima, K., Takagaki, K.,
Endo, M., Kannagi, R., Yasuda, T., Mita, S.,
Kimata, K., and Itano, N.: A novel inhibition
mechanism
of
hyaluronan
synthesis
by
4-methylumbelliferone. US/Japan Glyco 2004
(Joint meeting of the Society for Glycobiology and
the Japanese Society of Carbohydrate Research,
(President, M.E. Etzler) Hawaii, November 17-20,
2004.
A022. Kannagi, R.: Carbohydrate determinants
involved in cell-cell interactions: Transcriptional
regulation of their expression. Human Disease
Glycomics/Proteome Initiative (HGPI) Workshop
"Functional Glycomics in Disease", Chaired by N.
Taniguchi, Osaka, Japan, August 23-24, 2004.
A023. Kannagi, R.: Regulation of gene
expression in carbohydrate-mediated cell-cell
interactions. 2004 Glycolipid and Sphingolipid
Biology Gordon Conference, Chaired by Suzuki, A.
and Futerman, T., SPring-8, Hyogo, Japan, July
25-30, 2004.
A024. Kannagi, R.: Relationship between
enhanced selectin-mediated cell adhesion and
hypoxia-induced metabolic shift in human cancers.
Joint meeting of the Japanese and American
Consortia for Glycomics (Chaired by Paulson JC
and Taniguchi N), Hawaii, November 21, 2004.
A025. Kannagi, R.: Sialoconjugates involved in
cell-cell interactions.
Sapporo Sphingolipid
Symposium, Chaired by Igarashi, Y., Sapporo,
Japan, July 21 - 23, 2004.
A026. Kim, D. H., Ahn, Y. O., Lee, B. H., Whang,
D. Y., Kono, S., Wakai, K., Matsuo, K., Hamajima,
N. and Tajima, K.: The effect of alcohol and
aldehyde dehydrogenase polymophism on the risk
of colorectal cancer. Proceedings of 18th Asia
Pacific Cancer Conference-Cancer Research and
Treatment, 161, 2005.
A027. Kudoh, A. and Tsurumi, T.: Epstein-Barr
virus lytic replication evokes ATM checkpoint
signal transduction while preventing p53dounstream signaling. EBV symposium 2004 The
11th Symposium of the International Association
for Research on Epstein-Barr Virus and Associated
Diseases. 04.18. Regensburg, Germany. 2004.
A028. Kudoh, A., Daikoku, T., Ishimi, Y.,
Shirata, N., Iwahori, S. and Tsurumi, T.:
Phosphorylation of MCM4 at sites inactivating
DNA hericase activity of the MCM4-6-7 complex
during Epstein-Barr virus productive replication. 5th
3R symposium. P10, Awaji Yumebutai, Hyogo.
2005
A029. Kumimoto, H., and Ishizaki, K.: Frequent
somatic mutations in a D-loop region of the
mitochondria! DNA in esophageal squamous cell
carcinoma. 6th Joint Conference of the American
Association for Cancer Research and the Japanese
Cancer Association. Advances in Cancer Research.
Hawaii, USA, Jan. 2004.
A030. Kumimoto, H. and Ishizaki, K.: Novel
polymorphisms in the L-myc 5' UTR showed
different risks of smoking of drinking for
esophageal cancer. The 9th Japan - Korea Cancer
Research Wrokshop -Molecular signature of cancer
cells and its application to diagnosis and treatment,
pp 82-83, Gyeongju, Korea, Dec 2004.
A031. Kuriki, K., Matsuo, K., Ito, H., Hirose, K.,
Wakai, K., Saito, T. and Tajima, K.: Colorectal
cancer risk according to interactions between meat
consumption and genetic polymorphisms of fat
metabolism related PPARgamma and CD36 among
Japanese. The 3rd Regional Conference of Asian
Pacific Organization for Cancer Prevention
(APOCP) GI Cancer Control, 17, 2005.
A032. Kyogashima, M., Hara, A., Aoyama, T.,
Kannagi, R.: Determination of sulfatides and
complicated sulfated glycosphingolipids by
MALDI-TOF MS. US/Japan Glyco 2004, Joint
meeting of the Society for Glycobiology and the
Japanese Society of Carbohydrate Research,
(President, M.E. Etzler) Hawaii, November 17-20,
2004.
A033. Matsuo, K. Folate metabolizing gene
polymorphisms and risk of malignant lymphoma in
Japan. Proceedings U.S.-Japan Meeting on Large
Cohort Studies for Molecular Epidemiology, 19-20,
2004.
A034. Matsuo, K. and Tajima, K.: Hepatitis C
virus infection and risk of non-Hodgkin's
lymphoma: Meta-analysis. The 2nd APOCP
General Assembly Conference, 87, 2004.
A035. Matsuo, K., Hamajima, N. and Tajima, K.:
Risk of esophageal cancer by alcohol drinking is
modified by genetic polymorphisms. Proceeding of
The fourth Japan-China Joint Conference for
Cancer Research, 8-9, 2005.
A036. Matsuo, K., Hamajima, N., Mueller, N. E.,
Nakamura, S., Seto, M., Morishima, Y. and
Tajima, K.: Methylenetetrahydrofolate reductase
gene (MTHFR) polymorphisms and reduced risk of
malignant lymphoma. The 6th joint conference of
the American Association for Cancer Research and
the Japanese Cancer Association, A56,2004.
A037. Matsuo, K., Tagawa, H., Tsuzuki, S.,
Suzuki, R., Morishima, Y., Nakamura, S., Tajima,
K. and Seto, M.: Different genomic gain pattern by
MTHFR C677T genotypes in diffuse large B-cell
lymphoma. Proceeding of Annual Meeting 2005,
American Association of Cancer Research, 5793,
2005.
A038. Matsuo, K., Yang, C. X., Ito, H., Hirose,
K., Wakai, K., Kuriki, K. and Tajima, K.:
Gene-environment interaction between alcohol
drinking and MTHFR C677T polymorphism for
esophageal cancer risk. The 3rd Regional
Conference of Asian Pacific Organization for
Cancer Control, 15, 2005.
A039. Matsuo, K.: Challenging strategy of cancer
epidemiology in hospital. Aichi Cancer Center
International Symposium XI, 6-7, 2005.
A040. Miyazaki, K., Ohmori, K., Izawa, M.,
Koike, T., Yamaji, T., Hashimoto, Y., Suzuki, A.
and Kannagi, R.: Interconversion of carbohydrate
ligands for siglecs and selectins on colonic
85
epithelial cells upon malignant transformation.
Interlec 21, the 21st International Lectin Meeting,
Chaired by K. Kasai, Shonan, Kanagawa,Japan,
May 23-28, 2004.
A041. Mizoshita, T., Tsukamoto, T., Takenaka,
Y., Ogasawara, N., Joh, T., Itoh, M., Ito, S.,
Nakamura, T., Yamamura, Y., and Tatematsu, M.:
Cdx2 Correlates with Intestinal Phenotypic
Expression and Prognosis in Advanced Gastric
Cancers. 6th International Gastric Cancer Congress,
Oral 9, Yokohama, Japan,2005.
A042. Nakanishi, H., Kodera, Y., Ito, S.,
Yamamura, Y., Jun, Q., Hara, T.,Hirai, T., Kato,
T., Tatematsu, M.: Comparison of peritoneal
metastasis between gastric cancer and colorectal
cancer:Clinical and experimental studies. The 3rd
International Conference on Gastroenterological
Carcinogenesis, Oral, Sapporo, Japan,2004.
A043. Nakanishi, H., Yokoyama, Y., Ikehara, Y.,
Kodera, M., tatematsu, M.: Anti-tumor effects of
EGFR tyrosine kinase inhibitor, gefitinib, on the
HER2-overexpressing human gastric cancer cell
lines derived from liver metastasis. International
Conference on Tumor Progression and Therapeutic
Resistance. Poster, Philadelphia, USA,2004.
A044. Shirata, N. and Tsurumi, T.: Activation of
ATM DNA damage checkpoint signal transduction
elicited by herpes simplex virus infection. 5th 3R
symposium. P103, Awaji Yumebutai, Hyogo. 2005
A045. Suzuki, T., Matsuo, K., Wakai, K., Ito, H.,
Hirose, K., Sato, S., Nakamura, S., Ueda, R. and
Tajima, K.: Past history of gastric ulcer and risk of
malignant lymphoma. Proceedings of 18th Asia
Pacific Cancer Conference-Cancer Research and
Treatment, 1827, 2005.
A046. Tajima, K. Overview of cancer statistics in
Asia. Proceeding of The 3rd Asia High-Technology
Network, 44, 2005
A047. Tajima, K. UICC programs for cancer
prevention in Asia. The 2nd APOCP General
Assembly Conference, 24, 2004.
A048. Tajima, K.: A model of hospital-based
epidemiologic research program for cancer control
in Japan: case-referent studies, cohort study and
prevention trial. Proceedings U.S.-Japan Meeting
on Large Cohort Studies for Molecular
Epidemiology, 9-12, 2004.
A049. Tajima, K.: Cultural determinants for
cancer control. Proceeding of the 2nd Regional
86
APOCP Meeting, 3, 2004.
A050. Tajima, K.: Epidemic patterns and
prevention strategies for GI tract cancers in the
Asian Pacific. The 3rd Regional Conference of
Asian Pacific Organization for Cancer Control, 2,
2005.
A051. Tajima, K.: National cancer control
program. Proceedings of 18th Asia Pacific Cancer
Conference-Cancer Research and Treatment, 40-41,
2005.
A052. Tajima, K.: Virus related cancers in the
Asian Pacific with special reference to ATL.
Proceeding of the 36th international symposium of
the Princess Takamatsu Cancer Research
Foundation
Developments
in
Cancer
Epidemiology-Prospects for Cancer Control in the
Asian Pacific-Region. 42-43, 2005.
A053. Takematsu, H., Yamamoto, H., Okuno, Y.,
Kannagi, R., Suzuki, A., Kozutsumi, Y.: DNA
Microarray analysis of genes responsible for the
expression of carbohydrate epitopes. US/Japan
Glyco 2004, Joint meeting of the Society for
Glycobiology and the Japanese Society of
Carbohydarate Research, (President, M.E. Etzler)
Hawaii, November 17-20, 2004.
A054. Tatematsu, M.: Helicobacter pylori and
gastric carcinogenesis in Mongolian gerbils. 6th
International Gastric Cancer Congress, Symposium
5, Yokohama, Japan,2005.
A055. Terakura, S., Murata, M., Nishida, T.,
Emi, N., Akatsuka, Y., Riddell, S.R., Morishima,
Y., Kodera, Y. and Naoe, T.: Impact of
homozygous deletion of UGT2B17 on outcome of
allogeneic BMT. Abstract for the 46th Annual
Meeting of the American Society of Hematology,
2004. (Abstract#1837)
A056. Terakura, S., Murata, M., Nishida, T.,
Emi, N., Akatsuka, Y., Riddell, S.R., Morishima,
Y., Kodera, Y. and Naoe, T.: Increased risk for
treatment-related mortality of bone marrow
transplantation in GSTM1-positive recipients.
Abstract for the 47th Annual Meeting of the
American Society of Hematology, 2005. (Abstract#
1756)
A057. Teshima, T., Matsuo, K., Matsue, K.,
Kawano, F., Taniguchi, S., Hatanaka, K., Nakao,
S., Tanimoto, M., Hara, M., Eto, T., Wake, A., Abe,
Y., Ohno, Y., Takemoto, Y., Harada, M.,
Takahashi, S., Ishida, Y., Kanda, Y., Imamura, M.,
Kasai, M. and Takaue Y.: Impact of HLA
Mismatch on the Incidence of Acute GVHD and
Rejection after Reduced-Intensity Conditioning
Hematopoietic Stem Cell Transplantation (RICT).
Blood. 104: 2758, 2004.
A058. Tsukamoto, T., Mizoshita, T., Ito, S.,
Yamamura, Y., Nakamura, T., Ushijima, T., and
Tatematsu, M.: Alteration of gastric and intestinal
transcription factors in intestinal metaplasia and
adenocarcinomas of the human stomach. 6th
International Gastric Cancer Congress, Workshop 2,
Yokohama, Japan,2005.
A059. Tsurumi, T. and Kudoh, A.: Epstein-Barr
virus lytic replication elicits ATM checkpoint
signal transduction while providing an S-phase-like
cellular environment. The Awaji International
Forum on Infection and Immunity, Awaji
Yumebutai, Hyogo. 2004.
A060. Tsurumi, T. and Kudoh, A.: Epstein-Barr
virus lytic replication elicits ATM checkpoint
signal transduction while providing an S-phase-like
cellular environment. The XIII International
congress of Virology, P116, V-22, San Francisco,
USA. 2005.
A061. Uchida, A., Tabata, M., Matsuo, K., Ogino,
A., Fujiwara, K., Hotta, K., Shinagawa, K., Kiura,
K., Ueoka, H. and Tanimoto M.: An increase in
incidence of acute promyelocytic leukemia during
gefitinib treatment for advanced non-small cell lung
cancer. J Clin Oncol. 23: 667S, 2005.
A062. Uchimura, K., Singer, M.S, Tsay, D.,
Kadomatsu, K., Kannagi, R., Muramatsu, T., and
Rosen, S.D.: GlcNAc 6-O-sulfotransferase
(GlcNAc6ST)-1 and GlcNAc6ST-2 regulate
lymphocyte homing to lymph nodes. US/Japan
Glyco 2004, Joint meeting of the Society for
Glycobiology and the Japanese Society of
Carbohydrate Research, (President, M.E. Etzler)
Hawaii, November 17-20, 2004.
A063. Wakai, K. Japan Collaborative Cohort
Study. Aichi Cancer Center International
Symposium XI, 10-11, 2005.
A064. Wakai, K., Hirose, K., Matsuo, K., Ito, H.,
Kuriki, K. and Tajima, K.: Dietary factors and
colorectal cancer risk in Japan: comparison between
colon and rectal cancers.
The 2nd APOCP
General Assembly Conference, 88, 2004.
A065. Wakai, K., Suzuki, K., Kojima, M.,
Tamakoshi, K., Toyoshima, H., Watanabe, Y.,
Hayakawa, N., Hashimoto, S., Tokudome, S., Ito,
Y. and Tamakoshi, A. for the JACC Study Group.:
Serum carotenoids, retinol, and tocopherols and
colorectal cancer risk: a case-control study nested in
the Japan Collaborative Cohort (JACC) Study. The
6th joint conference of the American Association
for Cancer Research and the Japanese Cancer
Association, C1, 2004.
A066. Wu, P-X., Kimura, N., Kannagi, R., and
Sato, T.: Synthesis of sulfated oligosaccharides by
sulfotransferase-transfected ECV304 cells using
saccharide primer and structure analysis by
MALDI-TOF mass spectrometry. US/Japan Glyco
2004, Joint meeting of the Society for Glycobiology
and the Japanese Society of Carbohydrate Research,
(President, M.E. Etzler) Hawaii, November 17-20,
2004.
A067. Yagi, H., Takahashi, N., Yamaguchi, Y.,
Kimura, N., Kannagi, R., and Kato, K.:
Development and application of multi-dimensional
HPLC mapping of N-linked glycans. 2nd
Pharmaceutical
Sciences
World
Congress
(PSWC2004) Chaired by Sugiyama Y, Kyoto,
Japan, May 29-June 2, 2004.
A068. Yagi, H., Takahashi, N., Yamaguchi, Y.,
Kimura, N., Kannagi, R., and Kato, K.:
Development of structural analyses of sulfated
N-glycans by mass spectrometry and HPLC
mapping. US/Japan Glyco 2004, Joint meeting of
the Society for Glycobiology and the Japanese
Society of Carbohydrate Research, (President, M.E.
Etzler) Hawaii, November 17-20, 2004.
A069. Yanada, M., Emi, N., Usui, N., Takeuchi,
J., Sugiura, I., Takeuchi, M., Kobayashi, T.,
Yagasaki, F., Ohtake, S., Matsuo, K., Naoe, T. and
Ohno, R.: Combination of intensive chemotherapy
and imatinib (IDEAMOP regimen) for the
treatment of newly diagnosed BCR-ABL positive
acute lymphoblastic leukemia; excellent efficacy
without increasing toxicity. Blood, 2736, 2004.
A070. Yanada, M., Takeuchi, J., Akiyama, H.,
Usui, N., Yagasaki, F., Emi, N., Miyazaki, Y.,
Ohtake, S., Jinnai, I., Matsuo, K., Naoe, T. and
Ohno R.: High complete remission rate and
promising outcome by combination of imatinib and
chemotherapy for newly diagnosed BCR-ABLpositive acute lymphoblastic leukemia. Blood. 1827,
2005.
A071. Yang, C. X., Matsuo, K., Wang, Z. M. and
Tajima, K.: Phase I/II enzyme gene polymorphisms
and esophageal cancer risk: A Meta-analysis. The
2nd APOCP General Assembly Conference, 98,
2004.
87
Record
of Seminars
___________________________________________________________
Invited Speakers
2004
Mar. 09
Kaneko, R., Kawaguchi, K. and Yashiro K. (Life Science Division, Merk Ltd. Japan) Expression
and solubilization of proteins.
April 02
Moore, M. (APPOCP Coordination Director) A practical guide to the use of scientific English.
Jun. 22
Henderson, B. (University of Southern California) Inter-continental comparative study on breast
cancer risk among Japanese with special reference to application of a genome wide scan for
molecular epidemiology.
Jun. 30
Hanaoka, F. (Institute for Molecular and Cellular Biology, Osaka University) Function of DNA
polymerase eta as a Xeroderma pigmentosum variant responsible gene.
July 16
Kanoh H (Department of Science, Tokyo University) Application of Raman spectroscopy for cell
biology and medical science.
Oct. 07
Warren, E.H. (University of Washington, Fred Hutchinson Cancer Research Center) Rearrangement and proteasome-mediated splicing of non-contiguous peptides encoded by the
SP110 gene create a human minor histocompatibility antigen.
2005
Jan. 14
Tsubata, T. (Laboratory of Immunology, School of Biomedical Science, Tokyo Medical and
Dental University) Regulation of the humoral immune response by membrane lectin molecules.
Mar. 29
Nomura, T. (Department of Gastrointestinal Surgery, Faculty of Medicine, University of Tokyo)
Polypeptide (TFF2) expressing metaplasia (SPEM): From clonality to bone marrow homing.
Jun. 13
Uchimura, K. (Department of Anatomy, University of California, San Francisco, CA, USA)
Regulation of lymphocyte homing to lymph nodes by cell surface sulfated glycoconjugates.
Dec. 14
Tauchi, H. (Faculty Science, Ibaragi University) NBS1 controls radiation induced DNA-damage
response and its reapir.
Dec. 19
Cheng, A. (Human Cancer Genetics Program, Comprehensive Cancer Centre, Ohio State
University, Columbus, OH, USA) Combinatorial regulation of estrogen signaling.
88
Institute Speakers
2004
Jan. 07
Ikehara, Y. (Oncological Pathology) Siglec-7 and Siglec-9 negatively regulate T cell receptor
activation.
Mar. 04
Nakamura, Hid. (Central Laboratory & Radiation Biology) Effects of low-dose- rate radiation on
human cells.
April 04
Hirose, K. (Epidemiology and Prevention) Risk and protective factors for breast cancer confirmed by HERPACC study - Obesity control against breast cancer risk among Japanese
postmenopausal women.
Jun. 17
Osada, H. (Molecular Oncology) Novel therapeutic approaches with RNAi targeting ASH1
based on molecular characteristics of lung cancer cells.
Sep. 09
Ohta, R. (Immunology) Therapeutic inhibition of a complement regulator enhances antibody
therapy in a model of mammary adenocarcinoma.
Nov. 30
Daikoku, T. (Virology) Molecular basis for Epstein-Barr virus genome replication.
2005
Jan. 24
Goto, H. (Biochemistry) Regulation of mitosis through the crosstalk among mitotic protein
kinases.
Feb. 10
Adachi, M. (Central Laboratory & Radiation Biology) Molecular mechanisms of cisplatin resistance in human head and neck squamous cell carcinoma cell lines.
Mar. 03
Taguchi, O. (Molecular Pathology) Roles of the thymus in recognition of auto-antigens.
Mar. 23
Tsukamoto, T. (Oncological Pathology) Stomach cancer and phenotypic differentiation.
May 12
Matsuo, K. (Epidemiology and Prevention) Gene-environment interactions of MTHFR gene
polymorphism with habitual drinking for gastrointestinal tract cancer risk.
Jun. 09
Ikehara, Y. (Oncological Pathology) A carbohydrate recognition based drug delivery system.
Sep. 08
Kondo, Y. (Molecular Oncology) Alterations of DNA methylation and histone modification in
human cancer.
Dec. 21
Suzuki, R. (Molecular Medicine) Lymphomagenesis : Translocation, oncogene, microRNA, and
beyond•••.
Dec. 27
Shirata, N. (Virology) 1. Interaction between Epstein-Barr virus immediate-early protein, BZLF1,
and p53. 2. Activation of ATM DNA damage checkpoint signal transduction elicited by Herpes
simplex virus infection.
89
Record
of Symposia
___________________________________________________________
The 11th Aichi Cancer Center International Symposium
“Forefront of Cancer Prevention Strategy in Asia”
Organizing Committee: Kazuo Tajima (Chairperson), Masae Tatematsu, Shigeo Nakamura, Kenji Wakai,
Hayao Nakanishi, Hirotaka Osada, Kaoru Hirose, Keitaro Matsuo, Hidemi Ito, Hiroshi Yamaguchi, Takanori Umeda
February 5, 2005, International Conference Hall, Aichi Cancer Center.
Program of symposium
Opening Remarks: Ryuzo Ohno (Aichi Cancer Center)
Comprehensive epidemiologic studies in hospital:
A Challenging strategy of cancer epidemiology in hospital.
Keitaro Matsuo (Aichi Cancer Center)
Diet and risk in Mediterranean countries
Carlo La Vecchia (Istituto di Ricerche Farmacologiche, Milan, Italy)
Cohort study and cancer risk assessment in Asia:
The Japan Collaborative Cohort (JACC) Study.
Kenji Wakai (Aichi Cancer Center)
Korean Multi-center Cancer Cohort Studies for Genomic Epidemiology: Current Status and Perspectives
Keun-Young Yoo（Seoul National University）
The Self Defense Forces Cohort Study
Suminori Kono (Kyushu University)
A population-based prospective study on cancer and major chronic diseases: the JPHC Study
Shoichiro Tsugane (National Cancer Center)
Infection and cancer prevention:
Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens
are associated with the presence of anti-Helicobacter pylori IgG antibodies.
Yuzuru Ikehara (Aichi Cancer Center)
Study of the Association of Human Papillomavirus Infection and Cervical Cancer in China
Wang Yixun (Liaoning province Tumor Hospital and Institute, Liaoning, P. R China)
Hepatitis virus and heapatocellular carcinoma
Hideo Tanaka (Osaka Medical Center for Cancer and Cardiovascular Diseases)
Liver flukes and Cholangiocarcinoma
Petcharin Srivatanakul (National Cancer Institute, Bangkok, Thailand)
Forefront strategy of cancer prevetion:
New strategies of individualized cancer prevention
Nobuyuki Hamajima (Nagoya University)
Breast cancer susceptibility and chemoprevention
T.Rajkumar (Cancer institute, Chennai, India)
Natural immunological host defense and cancer prevention
Kei Nakachi (Radiation Effects Research Foundation)
Forefront of cancer prevention in Asia
Robert Burton (Strategic Leader, UICC, Melbourne, Australia)
Concluding Remarks: Toshitada Takahashi (Aichi Cancer Center)
90
Abstracts
A challenging strategy for cancer epidemiology in hospital.
Keitaro Matsuo
Division of Epidemiology and Prevention, Aichi Cancer
Center Research Institute, Nagoya, Japan
Population-based approaches have been the
gold standard of analytical epidemiologic study in
the field of cancer, however, but are not practical in
certain conditions; e.g., where there is a low incidence or a requirement for biomarkers. In such
conditions, hospital-based efforts are advantageous.
We have developed a comprehensive cancer
epidemiology study system called HERPACC
(Hospital-based Epidemiologic Research Program
at Aichi Cancer Center), the first version (HERPACC-I) which was started in 1988. Every first
visit outpatient was systematically requested to enroll in the program and fill out a common questionnaire covering lifestyle factors. Case status was
identified via hospital-based cancer registration.
Until 2000, data for 12,500 cancer patients and
83,000 non-cancer outpatients were pooled in
HERPACC-I. In a second version of HERPACC,
started in 2001, we added a protocol for obtaining
blood samples and semi-quantitative food frequency questionnaire, and this is ongoing.
We are now planning to conduct a cohort study
using non-cancer subject enrolled in HERPACC.
Direct comparison of results of case-control studies
and cohort study using same HERPACC population
is a unique and challenging approach for cancer
epidemiology.
In this presentation, several results of HERPACC-based epidemiological studies will be introduced.
Diet and risk in Mediterranean countries
Carlo La Vecchia
Istituto di Ricerche Farmacologiche“Mario Negri”- Milano and Istituto di Statistica Medica e Biometria, Universita di Milano - Milano, Italy
Various aspects of the Mediterranean diet are
considered favourable not only cardiovascular disease, but also on several common epithelial cancers.
These include frequent consumption of vegetables and fruit, which was analyzed using data from
a series of case-control studies conducted in North-
ern Italy on over 12,000 cases of 20 cancer sites and
10,000 controls. For most epithelial cancers, the
risk decreased with increasing vegetable and fruit
consumption, with relative risks (RR) between 0.3
and 0.7 for the highest versus the lowest tertile. For
digestive tract cancers, the population attributable
risks for low intake of vegetables and fruit ranged
between 15 and 40%. A number of antioxidants
(including carotenoids, lycopene and flavonoids)
and other micronutrients showed an inverse relation
with cancer risk, but the main components responsible for the favourable effect of a diet rich in vegetables and fruit remain undefined. Fish, and consequently a diet rich in n-3 fatty acids, tended to be
another favourable diet indicator. In contrast, subjects reporting frequent red meat intake showed
RRs above unity for several common neoplasms.
Whole grain food (and hence possibly fiber) intake
was related to reduced risk of several cancers, particularly of the upper digestive tract. In contrast, refined grain intake and, consequently, glycemic load
and glycemic index were associated to increased
risk of different types of cancers.
In conclusion, a low risk diet for cancer in the
Mediterranean would imply increasing fruit and
vegetables as well as avoiding increasing meat and
refined carbohydrate consumption. Olive oil and
other unsaturated fats, which are also typical aspects of the Mediterranean diet, should also be preferred to saturated ones.
The Japan Collaborative Cohort (JACC)
Study
Kenji Wakai
Division of Epidemiology and Prevention, Aichi Cancer
Center Research Institute, Nagoya, Japan
The Japan Collaborative Cohort Study (JACC
Study; Chairman of the study group: Akiko Tamakoshi at Nagoya University Graduate School of
Medicine) is a nationwide, multicenter cohort study,
with 24 participating research institutions. The
study started in 1988 to 1990, when 110,792 inhabitants aged 40 to 79 years completed a baseline
questionnaire. They were enrolled from 45 study
areas throughout Japan.
The baseline questionnaire covered lifestyle
factors including smoking and drinking habits,
physical activity, and dietary habits, as well as
91
medical history, education, family history of cancer,
height and weight, and occupation. In addition to
completing the questionnaire survey, 39,242 participants donated peripheral blood samples at health
screening check-ups. The serum samples were
stored at -80. until analyzed for nested case-control
studies. For 61,557 subjects (55.6% of the total) in
selected areas, we ascertained the incidence of cancer by means of linkage with the records of population-based cancer registries, supplemented by a review of medical records. The vital and residential
status of subjects was determined using resident
registration records, and causes of death were identified from death certificates.
During the follow-up through 1999 for death and
through 1997 for cancer incidence, 4,528 cancer
deaths (in all study areas) and 3,437 incident cases
of cancer (in the selected areas) were documented.
Members of the JACC Study Group have extensively examined associations of lifestyle or other
factors and serum components with the risk of cancer incidence and death. More than forty original
articles have been published from the study including papers from nested case-control studies utilizing
the stored sera. The follow-up of subjects and the
analysis of data and serum samples are still on going.
The JACC Study has generated a significant
body of information for primary cancer prevention
in Asia. It also may provide a good model for nationwide or international multicenter cohort studies,
in which individual participating institutions are
independent and maintain their originality in research but all contribute to one large cohort.
Korean Multi-center Cancer Cohort Studies
for Genomic Epidemiology: Current
Status and Perspectives
Keun-Young Yoo
Department of Preventive Medicine, Seoul National
University College of Medicine, Seoul, Korea.
Human genome epidemiology is the systematic
application of the epidemiologic method to the genome to assess the impact of genetic variation on
health and disease. Cohort studies are the ultimate
application of human genome epidemiology. The
Korean Multi-center Cancer Cohort (KMCC) is a
multi-center prospective cohort to meet the requirement of genome epidemiological studies on
cancer etiology, which had been conducted since
1993. Data on general lifestyle, physical activity,
92
diet, reproductive factors, and agricultural exposures were obtained through direct interview using
a structured questionnaire. Anthropometric measurements and some clinical laboratory findings have
also been collected and stored in the web-based database system. A biological materials bank with
blood (serum, plasma, buffy coat, packed erythrocytes) stored at -70. and urine at -20. has been established for the genome epidemiological studies on
the cancer etiology. DNA yield study revealed the
PCR products for β-globin from nearly all of the
samples (98%) from the long term-stored buffy coat
specimen in the KMCC. Follow-up for the cancer
occurrence has been commencing based on an active surveillance system by health personnel in each
district, and a passive surveillance system through
record linkages between the central cancer registry,
the national death certificate, and the national health
insurance claim databases in Korea. As of August
2004, total number of observation for the cohort
with biologic specimen was 20,342. Until December 2002, total 382 incident cancer cases have been
identified by the passive surveillance and total
number of follow-up was 64,999 person-years. Five
leading sites of cancer incidence were stomach,
lung, liver, colorectum, esophagus in men, and
uterine cervix and breast in women. A fundamental
question about genomic cohort is how large should
it be in order to estimate the main effect of a SNP or
haplotype and to detect gene-environmental and
gene-gene interactions. On this purpose, the Korean
Genomic Epidemiology Society has recently been
founded, and a few of new genomic cancer cohorts,
i.e. KOEX, KCDC, KNCC, etc., have been
launched under the supervision of the Society. The
recruitment goal and the design of each cohort will
briefly be introduced. Along with other cancer cohorts in Japan, the Korean Genomic Cancer Cohort
could provide more convincing evidence on new
etiologies of cancer and on the cancer prevention
strategy in the Asian-Pacific region.
The Self Defense Forces Cohort Study
Suminori Kono
Department of Preventive Medicine, Kyushu University
Faculty of Medical Sciences, Fukuoka, Japan
Taking into account the advantage of the comprehensive medical examination for retiring
self-defense officials at the Self Defense Forces
(SDF) hospitals, the author initiated the SDF Health
Study at the SDF Fukuoka Hospital in October of
the year 1986, when he was a part-time physician
there. Sigmoidoscopy, abdominal ultrasonography,
and a 75-g oral glucose tolerance test were included
as a procedures in the preretirement health examination during a 5-day admission. This health examination was not mandatory, but was received by
almost all retiring officials. A lifestyle questionnaire was introduced to inquire about smoking, alcohol use, physical activity, and habitual consumption of limited items of foods and beverages. At the
time of the inception of the SDF Health Study,
much interest had been focused on increased risk of
colon or colorectal cancer associated with low
blood cholesterol levels observed in prospective
studies. Thus the first cancer-related study was to
examine the relation between serum lipids and colorectal adenomas, and the outcome was no material
relation with serum total cholesterol. The SDF
Health Study was once deployed at four SDF hospitals across the nation.
A series of studies have revealed increased risk
of colorectal adenomas associated with cigarette
smoking, alcohol use, physical inactivity, abdominal obesity, and non-insulin dependent diabetes
mellitus. Total colonoscopy was introduced as a
routine procedure in the year 1995; at that time the
study had retreated to Kyushu. This approach established that cigarette smoking and alcohol use were
associated with a greater risk of adenomas in the
distal segment of the colorectum while diabetes
mellitus was more markedly related to an increased
risk of proximal colon adenomas. It was also found
that the association between cigarette smoking and
colorectal adenomas did not vary with genetic
polymorphisms of CYP1A1, GSTM1, and GSTT1,
which are key enzymes in the metabolism of tobacco-related carcinogens. The SDF Health Study
evolved to a prospective cohort study in April of the
year 2004. Informed consent was obtained as regards the follow-up health survey as well as for donation of venous blood for genetic analysis. Details
of the design of the cohort study and conduct of the
baseline survey will be discussed.
A population-based prospective study on
cancer and major chronic diseases: the
JPHC Study
Shoichiro Tsugane
Epidemiology and Prevention Division, Research Center
for Cancer Prevention and Screening, National Cancer
Center, Tokyo, Japan
Lifestyle is closely related to occurrence of
cancer and other chronic diseases. Biological
specimens such as plasma and white blood cells are
expected to provide useful information on exposure-disease relations considering genetic susceptibility using recent biochemical and molecular techniques. To investigate factors associated with cancer and other chronic diseases in Japan where the
disease profile (coronary heart disease is a minor
cause of death and the stomach continues to be the
most frequent cancer site) and diet are substantially
different from Western countries, we launched a
population-based prospective study in 1990. Approximately 140,000 men and women aged 40-69
years were selected based on resident registration in
29 communities covered by 11 public health center
areas nationwide. At the baseline survey, a
self-administered questionnaire including items on
simple food frequency, blood (3 aliquots of plasma
and 1 buffy coat) and health check-up data (anthropometric measures, blood pressure, biochemical
measures such as lipids and liver function test) were
collected from 110,000 (80%), 49,000 (35%) and
48,000 (34%) persons, respectively. At year six, a
follow-up survey (same survey items as those at
baseline plus a semiquantitative food frequency
questionnaire with validity information compared
with 4 season 7 day diet records) was conducted,
and 100,000 questionnaires, 35,000 blood samples
and 33,000 health check-up reports were collected.
Further at year eleven, the self-administered questionnaire used at year six was repeated and collected from 97,000 persons. Mortality and immigration, as well as disease incidence (cancer, cerebrovascular disease, ischemic heart disease, diabetes, etc.), were treated as endpoints. Among all cohort subjects, 10,500 deaths, 8,900 cancers, 2,900
strokes and 600 myocardial infarctions were documented as of October 2004. Several findings from
the JPHC study will be presented.
Polymorphisms of two fucosyltransferase
genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of antiHelicobacter pylori IgG antibodies
Yuzuru Ikehara
Division of Oncological Pathology, Aichi Cancer Center
Research Institute Nagoya, Japan
Recent progress in the molecular analysis of H.
pylori infection has revealed that the bacteria attach
93
to the gastric mucosa through the blood group antigen-binding adhesin, BabA and a clinical relevance
has been shown for the babA2 gene encoding BabA
adhesin with regard to H. pylori-related diseases.
BabA binds to both Leb [Gal (α 1.2Fuc)β1.3
GlcNAc(α1.4Fuc)-R] and H type I blood group
carbohydrate structures [H type I structures; Gal
(α1.2Fuc)β1.3GlcNAc-R] expressed on the foveolar epithelium of the gastric mucosa.
We have been studying Lewis blood type antigens using biochemical and molecular biological
methods and have obtained the following results
concerning type I Le antigen synthesis. Individuals
homozygous for nonfunctional alleles of Le gene
(le/le) fail to express type I Le antigen (so called Le
negative). In the human fucosyltransferase family,
only the Le enzyme (FUT3, Fuc-T III) exhibits
fucose transfer activity toward a type I precursor
(Galβ1.3GlcNAc-R) or H type I structure with β1.4
linkage. The Se enzyme (FUT2, Fuc-T II) exhibits
fucose transfer activity toward the type I precursor
with α1.2 linkage and is responsible for Leb expression on erythrocytes, solely determining the secretor status, and making a marked contribution to Leb
expression in colorectal tissues.
Individuals homozygous for nonfunctional alleles of the Se gene fail to express ABH blood antigens in secreted fluids (so called for
non-secretors), whereas those very rare individuals
homozygous for nonfunctional alleles of the H gene
(h/h) fail to express ABH blood antigens on erythrocytes. Considering the type I Le antigen synthetic
pathway, it is possible that the type I precursor
structure for acceptor substrate is used by Se and Le
enzymes, with some competition between the two.
The present study was performed to investigate
the possibility that Se and Le gene polymorphisms
alter the risk of H. pylori infection. Two hundred
and thirty-nine participants were genotyped for Se
and Le and tested for the presence of anti-H. pylori
IgG antibodies. Using the normal gastric mucosa
from 60 gastric cancer patients, we further assessed
immunohistochemically whether type I Le antigen
expression depended on the Se and Le genotypes.
The H. pylori infection rate was positively associated with the number of Se alleles (se/se group,
45.1%; Se/se group, 64.6%; and Se/Se group,
73.3%) and negatively associated with the number
of Le alleles (le/le group, 76.4%; Le/le group,
68.3%; and Le/Le group, 55.6%).
When the subjects were classified into three groups
[low risk, (se/se, Le/Le) genotype; high risk, (Se/Se,
le/le), (Se/Se, Le/le), and (Se/se, le/le) geno-
94
types;moderate risk, other than low- or highrisk
group], the odds ratio relative to the low-risk group
was 3.30 (95% confidence interval, 1.40-7.78) for
the moderate-risk group and 10.33 (95% confidence
interval, 3.16-33.8) for the high-risk group (Figure
2). Immunohistochemical analysis supported the
finding that Se and Le genotypes affected the expression of H. pylori adhesin ligands.
We conclude that Se and Le genotypes impact on
susceptibility to H. pylori infection.
Study of the Association of Human Papillomavirus Infection and Cervical Cancer
in China
Wang Yixun
GYN Oncology Department, Liaoning province Tumor
Hospital and Institute, Liaoning, P. R China
It was in 1980s, the relationship of cervical
cancer to HPV started to be elucidated. HPV type
16 and 18 were first isolated directly from cervical
cancer in 1983. From that time the strong association between HPV and cervical neoplasms has been
reported worldwide. HPV DNA can be detected
from 99.7% of cervical cancer specimens. Approximately 90 types of HPV have been identified,
some of which are oncogenic or high risk types.
In order to investigate Human Papilloma virus
infection prevalence in China, The study of association between HPV infection and cervical cancer
was conducted in a high incidence area of cervical
cancer -Shanxi province. It was found that for
women from 35- 50, the high risk HPV infection
rate was 24%, which is much higher than 5%-10%
reported from the world. For a group of 1997 married women aged 35-45 : exfoliated cells were collected from cervix (by clinician) and from vagina
(by subject herself), Hybrid capture 2 assay, which
could detect 13 types HPV DNA of high risk, was
carried out. HPV DNA detection rate was 20.8%.
The infection rate increased with progression of
cervical lesions. (X2=444.04,P=0.000). Comparison
of 2 groups of aged 35-39 and 40- 45, there was no
significant difference of infection rate (20.9%;
20.6%, X2=0.03, P=0.86). While compared with
normal subjects: the risk odds ratio HPV infection
with cervical cancer/high grade CIN and low grade
CIN were 254.2 and 26.4 respectively, with attributive risk percentage (ARP) of 98.1% and 83.6%.
The sensitivity of the assay for high risk HPV DNA
from clinician collected sample was 98%, which
was higher than self collected samples of
84%(X2=5.92 P=0.015. No significant difference
can be seen in specificity. (86%:85%, X2=0.00,
P=0.997). We conclude that high risk HPV infection in female genital tract was the major risk factor
of cervical cancer and CINs in this area of China.
the age group of 40-70 years has been under the
process of development by local municipal governments since 2002. The effectiveness of this
screening system for preventing HCC will be
evaluated in the future.
Hepatitis virus and hepatocellular carcinoma
Liver flukes and Cholangiocarcinoma
Hideo Tanaka
Department of Cancer Control and Statistics, Osaka
Medical Center for Cancer and Cardiovascular Diseases,
Osaka, Japan
Chronic hepatitis B virus (HBV) infection is a
major risk factor of hepatocellular carcinoma
(HCC) in Asia. Immunization with HBV vaccine is
a most effective weapon against HBV infection and
its consequences, although the modality differs
among Asian countries. A recent cohort study in
Japanese blood donors showed coinfection with
HBV and hepatitis C virus (HCV) carried a superadditive risk for HCC.
HCV is a blood-borne virus which causes a
wide spectrum of liver diseases, ranging from acute
hepatitis to HCC. Parenteral infection through
blood transfusion, intravenous drug abuse (IVDU)
and tattooing, as well as occupational exposure to
blood, have been well defined as determinants of
HCV transmission. Recently, the incidence of HCV
infection among Japanese blood donors was estimated as 2-5 per 105 person-years.
Approximately 60% of persons infected with
HCV become HCV carriers and about 75% of
Japanese with HCC cases are associated with
chronic HCV infection. Life time risk of developing
HCC among HCV carriers has been estimated as
30% for males and 6% for females, based on data
for the age and sex specific incidence rates of HCC
among HCV carriers in Osaka. An older age, being
male, duration of HCV infection, type Ib infection,
co-infection with HBV, having a high serum
transaminase level, having a low platelet count, and
heavy drinking and smoking are independent factors associated with the development of HCC
among HCV carriers. Cohort studies have demonstrated that interferon therapy can significantly
lower the incidence of HCC among patients with
chronic hepatitis C who showed normalization of
the serum transaminase level after completion of
the therapy.
In Japan, a nationwide community-based
anti-HCV and HBsAg screening system targeting
Petcharin Srivatanakul
Cancer Control Unit, National Cancer Institute, Bangkok,Thailand
The liver flukes, Opisthorchis viverrini, Opisthorchis felineus and Clonorchis sinensis, are biologically similar, food-borne trematodes which
chronically infect the bile ducts and, more rarely,
the pancreatic duct and gall-bladder of human beings and other mammals. Infection is acquired by
eating raw or undercooked freshwater fish which
contain the infective stage (metacercaria) of flukes.
Immature flukes migrate up through the ampulla of
Vater to the biliary tree, mature in the small intrahepatic ducts and produce eggs, which are passed in
the faeces. If the eggs reach a water body and are
consumed by an appropriate species of snail, they
hatch and undergo asexual multiplication to produce free-swimming larvae, which can penetrate
freshwater fish and become encysted metacercariae.
Infection with Opisthorchis viverrini is carcinogenic to humans (Group 1). Infection with O.
felineus is not classifiable as to its carcinogenicity
to humans (Group 3). Infection with C. sinensis is
probably carcinogenic to humans (Group 2A).
Primary cancers of the liver in adults are of two
main histological types: hepatocellular carcinoma
which is derived from hepatocytes, and cholangiocarcinoma, (CCA) which is derived from the
epithelial lining of the intrahepatic bile ducts.
About 560,000 new cases of liver cancer, usually
hepatocellular carcinoma, occur annually, and contribute significantly to cancer mortality worldwide.
CCA is a relatively rare tumour in most populations but second among primary malignant liver
tumours; about 15% of liver cancers are estimated
to be CCA. The geographic distribution worldwide
coincides with endemic areas of the liver flukes O.
viverrini and C. sinensis. The interaction between
genes and the environment and the interplay of environmental factors, which include diet and lifestyle,
illustrate the complexity in understanding the susceptibility to environmental exposures.
The highest incidence of CCA is found in areas
of Laos and North and Northeast Thailand suffering
95
from endemic infection with the liver fluke, O.
viverrini. In Khon Kaen (the Northeast Thailand) ,
86.5% of liver cancer cases are CCA. In both endemic and non-endemic areas, there have been no
significant changes in the incidence of CCA in recent years. It is less than 10 years since O. viverrini
drug therapy was initiated;since it probably takes 30
years for CCA development after the infection, the
trends of CCA are probably not likely to change in
the next decade. Patients with CCA are elderly,
with no clear sex differences. CCA occurs at rather
older ages than hepatocellular carcinoma in most
clinical series.
C. sinensis parasitizes the bile ducts of millions
of individuals in the Far East, particularly China
and Korea. In the C. sinensis endemic area in Korea , there is also a high incidence of liver cancer.
About 20% of liver cancers in Pusan , Korea are
CCA.
Chronic infection with the liver fluke, O. viverrini is the major risk factor for the development of
CCA. Carcinogenesis of CCA is probably related to
the length and severity of infection, the host's immune response, and other variables such as ingestion of dietary carcinogens, for example nitrosamines. In northeast Thailand, several carcinogenic
N-nitroso compounds and their precursors exist at
low levels in the daily diet. In addition, endogenous
nitrosamine formation by liver fluke infection has
been reported. Increased levels of urinary nitrates
and salivary nitrites are found in O. viverrini infected individuals. The subjects living in high-risk
areas for fluke infection who had antibodies to O.
viverrini had a 10-fold greater potential for endogenous nitrosation, measured on the basis of urinary levels of N-nitrosoproline after praline ingestion, than individuals who did not have antibodies.
Vitamin C is found to be effective inhibitor for
prevention of the formation of endogenous nitrosation. In several studies in hamsters infected with O.
viverrini and treated with various carcinogenic Nnitrosamines, induction of cholangiocarcinomas and
of hepatocellular nodules was enhanced. These results suggest that the interaction between chemical
carcinogens, especially nitrosamines, and OV infestation may play role in the development of CCA
in Thailand. Both exogeneous and in situ nitrosamine formation may lead to DNA alkylation and
deamination. It seems that the presence of parasites
induces DNA damage and mutations as a consequence of the formation of carcinogens/free radicals
and of cellular proliferation of the intrahepatic bile
duct epithelium.
96
New strategies of individualized cancer prevention
Nobuyuki Hamajima
Department of Preventive Medicine / Biostatistics and
Medical Decision Making, Nagoya University Graduate
School of Medicine, Nagoya, Japan
Generally, health information based on the individuals' background allows a stronger message to
induce behavior changes in lifestyle, supplement
intake, health checkup motivation, and medical facility visits. The background for each individual is
made up of past exposure experiences, disease history, current biomarker conditions, and genetic
traits, as evidenced by a family history. In order to
provide attractive cancer prevention methods for
individuals, links to such individual background
information are becoming important.
To date, several individualized cancer prevention models have been introduced in practice. Preventive measures to block mother-to-child transmission of hepatitis B virus and thus liver cancer is
provided for carrier mothers. Preventive mastectomy against breast cancer is conducted for BRCA1
abnormal gene carriers. Intensive checkup and
counseling against colorectal cancer are provided
for those with FAP and HNPCC related genes.
These specific cancer prevention models for carriers
are accepted in several societies.
Recent biomarker studies on the most common
cancers indicate possible new strategies. Eradication of Helicobacter pylori seems effective to prevent gastric cancer for individual with heavy infection. Health services not covered by health insurance started in Japan for those who seek the test and
medication for the eradication. Reported
gene-environment interactions between genotypes
and interventions also provide new models for individualized cancer prevention. For example, the interaction between aspirin use and an A316G polymorphism of the ornithine decarboxylase gene suggests a possibility to recommend aspirin intake
more strongly for A-allele-possessing patients at
risk of colorectal adenoma/carcinoma.
Genotype announcement may be a new strategy
to induce behavior changes to a less risky lifestyle.
Awareness of susceptible genotypes or enhanced
health consciousness through genotyping could
provide opportunities to correct high risk behavior,
e.g., smoking and drinking. Concerning smoking,
the cessation rate was found to be higher for the
announced group in some studies, although not in
all cases.
Undoubtedly, the increasing number of available biomarkers will contribute to the establishment
of new modes of individualized cancer prevention.
Natural immunological host defense and
cancer prevention
Breast cancer susceptibility and chemoprevention
Department of Radiobiology/Molecular Epidemiology,
Radiation Effects Research Foundation, Hiroshima, Japan
Kei Nakachi
T. Rajkumar
Department of Molecular Oncology, Cancer institute
(WIA), Adyar, Chennai, India
Breast cancer is the second most common cancer among Indian women. The incidence of breast
cancer has shown a trend towards gradual increase
in the Chennai Metropolitan area over the past two
decades, with the current CIR of 19.9 /100,000.
While hereditary breast cancers account for 5-10%,
the vast majority is sporadic.
BRCA1 and BRCA2 are the major breast cancer
susceptibility genes identified to date. However,
contrary to the initial predictions, they account for
only 15-20% of hereditary cancers. In our series of
61 patients of Hereditary breast &/or ovarian cancers, 8 deleterious mutations were detected. Of the
24 Hereditary breast cancer families tested, four
were found to have a deleterious mutation (16%).
Only one of the thirteen families with Hereditary
breast and ovarian families were detected to have a
deleterious mutation in our series. Two out of 20, of
the early onset breast cancers (<35 years of age)
tested were found to have a disease causing mutation.
Apart from the high-risk genes several low risk
genes could also contribute to the development of
breast cancer. These low susceptibility genes include those that are involved in carcinogen activation and inactivation, estrogen metabolism, growth
factors and their receptors etc. Single nucleotide
polymorphisms in these genes could contribute to
changes in their functional efficiency. Examples of
these include Cyp19 (Trp39Arg), Cyp17 (T-34C)
GSTP1 (Ile462Val), GSTM1 (Present/Null), TGF
β (Leu10Pro) and c-erbB2 (Ile655Val).
Chemo-prevention is likely to contribute significantly in the prevention of several cancers including that of breast cancer. Tamoxifen for example has been shown to reduce the risk of contralateral breast cancers. The trials evaluating the role of
steroidal and non-steroidal aromatase inhibitors are
already underway and should provide the critical
answers to the efficacy of this approach in the
high-risk group.
The concept of multi-stage carcinogenesis implies that cancer prevention with different strategies
is feasible for each stage. Recently emphasis has
been placed on defense mechanisms existing in different stages of carcinogenesis, with the immune
system as the body's last line of defense against
cancer development. Cancer immunosurveillance-routinely eliminating nascent transformed
cells in the body-needs to be proven through investigations of general populations.
We previously reported an elevated incidence of
cancer among individuals showing low levels of
NK activity in peripheral blood lymphocytes, as
compared to medium or high levels, based on a
prospective cohort study of a Japanese general
population. Large differences were found among
individuals in NK activity, and lifestyle factors
seemed to explain only a part of these, so we investigated the genetic factors underlying individually
variation in NK activity. From the cohort members,
we selected two groups with low and high NK activity, each of which consisted of gender-and
age-matched individuals who had not experienced
any cancer. Next, a phenotype-genotype association
analysis was carried out, comparing these two
groups in terms of HLA class I genotypes and SNPs
in the NKG2D gene.
We found that specific HLA-B and C genotypes
were associated with NK activity, implying a role
of HLA class I molecules in maintaining a stable
repertoire of NK cells; furthermore we succeeded in
identifying two haplotype blocks in the NKG2D
gene region, each of which generated two major
haplotype alleles closely related to low and high
NK activity (P<0.0001). In addition, these haplotypes were found to be significantly associated with
cancer risk, in terms of a case-control study within
this cohort. We previously found that selected lifestyle factors known as good health practices were
associated with high NK activity. In our study, we
are looking for further evidence of “individualized
immuno-prevention of cancer”: NK activity-enhancing effects of lifestyle may differ among
individuals with different NKG2D haplotypes.
97
Forefront of cancer prevention in Asia
Robert Burton
International Union Against Cancer, Geneva, Switzerland, National Cancer Control Initiative, Melbourne,
Australia
Only primary prevention and early detection
and removal of pre-malignant lesions can reduce
cancer incidence, although early detection of many
cancers and effective treatment can cure the majority of cancer patients. The World Health Organization has estimated that failure to implement effective cancer prevention programs will result in the
global burden of cancer increasing from 10 million
new cases in the year 2000, to 15 million in 2020
with about 10 million cancer deaths in that year.
About 85 percent of cancer is caused by environmental exposure, most of which are due to noncommunicable diseases (NCD), and about 20 percent to communicable diseases. About half of the
10 million new cases of cancer in the year 2000
were preventable, using our current knowledge.
In Asia, NCD are now the commonest causes of
98
death and disability, and cancer is either the second
or third commonest cause of death in most Asian
countries. The major risk factors for NCD in Asia
are tobacco use, unhealthy nutrition, physical inactivity and alcohol abuse. In some Asian countries
more than half of all adult males use tobacco, and
overweight/obesity is a rapidly developing problem
in many countries. Therefore integrated NCD prevention programs are being developed and implemented in a number of Asian countries, of which
the Philippines is the leading example.
Vaccination (immunisation) is the great hope
for prevention of the infectious cancers, and hepatitis B vaccination of newborn children has been
progressively introduced in Asia since the early
1980's. Finally, cervical screening and removal of
premalignant lesions, using low technology screening tests and simple surgical procedures preformed
by trained health workers, has great potential to
dramatically decrease cervical cancer mortality,
which is the second commonest cancer of women in
Asia.
Author
index for research reports and publications
________________________________________________________________________________
Adachi, K.
56
Hara, M.
J256, A057
Akatsuka, Y.
30, 31, 32, 33, J066, J123, J124,
J179, J227, J243, J244, J255, J263,
J269, R001, R002, R003, R004,
R005, R006, R043, R044, A001,
A002, A055, A056
Harada, H.
J201
Harano, T.
J247, J262
Akazawa, T.
J002
Hatooka, S.
Aoki, K.
R036
7, 51, J133, J154, J298, J299,
A019
Arimura, N.
49, J005
Hayashi, N.
J279
Cao, X.
15, J010, J011, J157, J159, J160,
J194, J254
Hayashi, Y.
49, J067, J175, J184, J203
Hayashita, Y.
21, J041, J174
Chen, G.Y.
42, J306
Hida, T.
21, J154, J244
Daikoku, T.
35, J014, J015, J068, J130, J131,
J224, R007, A003, A004, A014,
A028
Hirai, T.
7, J134, J135, J151, J153, A042
Hirata, A.
15, J007, J043, J044, J060, J148,
J158, J272, J273, R059
Hirose, K.
5, 7, 12, J037, J046, J047, J057,
J151, J153, J161, J187, J188, J189,
J190, J191, J237, J261, J279, J298,
J299, R014, R035, R036, A006,
A019, A031, A038, A045, A064
Hishida, A.
J048, J049, J223
Horio, Y.
20, J116, J154, J205, J206
Hoshino, Y.
J106, J109, J228
Demachi-Okamura, A.
Hasegawa, Y. J034, J038, J073, J112, J126, J201
Hashimoto, A. J306
30, J243, J244
Fujii, K.
J023
Fujita, M.
J014, J015, J024, J130, J131, J224,
J229, R062
Fukami, H.
J133, J175, J272, J273
Fukui, F.
J197, R027
Fukui, T.
20, 21, J026, J079, J126, J230
Gao, C.
J030, J031
Goto, H.
47, 48, J020, J033, J035, J043,
J064, J144, J198, J259, J293, J308,
R008, R009, R010, R011, R012,
R022
Hosokawa, Y. 24, J050, J051, J172, J239, J312,
R015, R016
Huang, X-E.
12, J057, J225
Ichinose, M.
J146, J185
Ieda, T.
56
Iidaka, T.
J059, J060
Goto, M.
J034
Goto, Y.
20, 44, J035, J036, R027
Gotoh, M.
J062
Ikehara, S.
15, 16, J061, J062
Hagino, M.
55
Ikehara, Y.
Hagiwara, K.
44
Hamajima, N.
12, J030, J031, J035, J036, J037,
J047, J048, J049, J075, J076, J077,
J103, J108, J134, J135, J139, J149,
J150, J161, J169, J179, J187, J188,
J189, J190, J191, J192, J193, J198,
J223, J258, J279, R040, A017,
A026, A035, A036
15, 16, J009, J061, J062, J176,
J185, J194, J199, J290, J307,
R040, A008, A009, A010, A043
Imai, T.
J129
Inada, K.
J034, J043, J063, J146, J156, J158,
J185, J195, J211, J212, J254, J270,
R051, R064
Inagaki, M.
47, 48, 49, J001, J005, J020, J024,
J033, J038, J043, J083, J087, J170,
99
J171, J184, J203, J226, J245, J267,
J293, J302, J308, J309, R008,
R009, R019, R020, R021, R025,
R026, R032, A011, A012
Karnan, S.
26, 57, J092, J099, J177, J209,
J239, J240, J241, J242, J312
Kasugai, Y.
J101, J239
Kato, K.
57, J052, J081, J181, J182, J183
Kato, S.
15, J104, J158, J159, J160, J211,
J254
Kato, T.
7, J134, J135, J151, J153, J162,
A042
Inagaki, N.
49, J309
Inoko, A.
48, 49, J184, R022, A012
Inoue, M.
J065, J074, J108
Ishida, H.
44,
Ishida, T.
J066
Kawajiri, A.
47, J024, J033, J038, J302, R032
Ishizaki, K.
51, 52, J067, J132, J133, J175,
J201, J224, J230, A013, A029,
A030
Kimura, N.
42, J118, J289, R029, A066, A067,
A068
Kitamura, T.
J012, J203
Isomura, H.
37, J014, J015, J016, J068, J069,
J130, J131, J224, R023, R024,
A015
Kiyono, T.
32, 47, 49, J033, J130, J224, J229
J291, J292
Kobayashi, T. 16, J169, J297, A069
Ito, H.
5, 7, J036, J040, J046, J057, J074,
J075, J076, J077, J078, J151, J153,
J161, J178, J191, J237, J258, J298,
J299, A016, A017, A018, A019,
A031, A038, A045, A064
Kodera, Y.
31, 32, J058, J072, J103, J113,
J114, J115, J123, J124, J162, J176,
J179, J180, J196, J202, J236, J255,
J263, J307, R046, A042, A055,
A056
Ito, S.
J072, J113, J114, J115, J157, J162,
R045, A041, A042, A058
Koike, K.
J134, J135
Koike, T.
Ito, Y.
30, 32, J019, J080, J105, J106,
J110, J111, J243, J244,
41, 42, J118, J155, R028, R029,
A040
Kojima, N.
16, A008
Iwata, H.
7, J046, J047, J085, J086, J164
Kondo, E.
30, 32, J123, J124, J125
Izawa, I.
48, 49, J083, J087, J117, J184,
J302, J308, J309, R025, R026,
A012
Kondo, M.
20, J026, J073, J079, J126, J144
Kondo, Y.
20
41, 42, J155, J278, J306, R028,
R029, A040
Konishi, H.
J021, J145, J247
Kontani, K.
J127
Joh, T.
J156, J158, J160, J195, J254, J258,
A041
Koshikawa, K. J039, J262
Kagami, Y.
J006, J022, J048, J123, J150
Kameoka, Y.
J092, J101, J173, J242
Kanamori, A.
44, J291, J292, R013
Izawa, M.
Kozaki, K.
J276
Kudoh, A.
35, J014, J015, J016, J068, J130,
J131, J224, R024, R033, R061,
R062, A003, A004, A014, A027,
A028, A059, A060
Kanemitsu, Y. 7, J134, J135, J151, J153
Kannagi, R.
100
41, 42, 44, J045, J071, J091, J093,
J094, J118, J138, J155, J166, J197,
J210, J222, J232, J257, J277, J278,
J289, J291, J292, J306, R027,
R028, R029, R030, R031, R034,
R041, A020, A021, A022, A023,
A024, A025, A032, A040, A053,
A062, A066, A067, A068
Kumamoto, K. J118, J155, R034
Kumimoto, H.
51, J077, J132, J133, J230, A029,
A030
Kuriki, K.
7, 12, J012, J088, J089, J090, J134,
J135, J136, J259, J260, R042,
R055, R056, A031, A038, A064
Kuroishi, T.
R035, R036
Kuzushima, K. 30, 31, 32, 33, J002, J003, J008,
J032, J109, J123, J124, J179, J228,
J243, J244, J246, J263, J268, J269,
J287, R037, A001
Kuzuya, K.
J124, J187, J188, J189, J190, J191
Kyogashima, M.
44, J098, J138, J143, R038,
A032
Maeda, Y.
J129
Maeno, K.
J145, J174
Masuda, A.
J145, J174, J200
Masui, T.
A018
Matsudaira, Y. 33, J269
Matsukage, A. J229
Matsuo, K.
7, 12, J023, J025, J031, J035, J046,
J047, J048, J052, J053, J054, J055,
J056, J057, J058, J075, J076, J077,
J085, J086, J103, J129, J134, J135,
J149, J150, J151, J152, J153, J164,
J188, J189, J191, J230, J231, J237,
J240, J241, J242, J256, J258, J265,
J266, J276, J285, J295, J296, J297,
J298, J299, J300, J301, J310,
R017, R018, R039, R040, R063,
A005, A007, A017, A019, A026,
A031, A033, A034, A035, A036,
A037, A038, A039, A045, A057,
A061, A064, A069, A070, A071
Matsuzawa, K. J167
Mitsudomi, T. 7, 30, J021, J075, J100, J116, J128,
J154, J204, J243, J244, J247, J262,
J303, J304, J305, R057, A017
Miyazaki, K.
41, 42, J118, J155, J306, R029,
R041, A040
Morishima, Y. 7, 26, 30, 31, 32, J006, J048, J092,
J099, J101, J123, J124, J149, J150,
J177, J179, J208, J237, J240, J241,
J242, J244, J255, J263, J312,
R002, A036, A037, A055, A056
Murate, T.
44
Nagata, K.
J038, J170, J171, J184, J203, J226,
J302, A012
Nakagawa, M. J050, J172, J173
Nakagawa, T. J174
Nakamura, Hir. 55
Nakamura, Hid. 52, J067, J175
Nakamura, S. 7, 25, 26, J006, J029, J062, J064,
J088, J090, J092, J095, J099, J101,
J149, J150, J152, J156, J157, J177,
J207, J208, J234, J235, J237, J240,
J241, J242, J270, J271, J279, J312,
A009, A036, A037, A045
Nakamura, T.
25, J064, J157, A041, A058
Nakanishi, H.
15, 16, J029, J062, J072, J113,
J114, J115, J162, J176, J185, J194,
J196, J290, J307, J311, R045,
R046, A008, A009, A042, A043
Nakanishi, T.
7, 32, J187, J188, J189, J190, J191
Nakashima, Y. 26, J177
Nakasu, S.
37
Nawa, A.
32, J124, J187, J188, J189, J190,
J191
Nishi, Y.
55
Nishida, K.
30, 33, J095, J243, J244, J269
Nishida, T.
J179, J180, J255, A055, A056
Miyazaki, M.
31, J066, J263
Nishimoto, Y.
J133
Mizoshita, T.
15, 16, 17, J010, J011, J034, J043,
J063, J104, J148, J156, J157, J158,
J159, J160, J195, J211, J212, J254,
J270, J271, R052, R053, R054,
A041, A058
Nishio, M.
J234
Niwa, T.
16, J049, J062, J185, J186, J290,
A008, A009
Mizuno, M.
55
Nozaki, K.
J010, J011, J156, J194
Mizutani, K.
J298
Obata, Y.
33, J141, J269, R058
Mochizuki, Y.
J072, J115, J162, R045
Moore, M.
J260, R042, R056
Ogasawara, N. 16, J010, J148, J158, J195, J254,
A041
Morishima, S. 32, R043
Nishizawa, M. 48, 55, J184, A012
Ogura, M.
J048, J150
101
Oguri, T.
48, 49, J040, J293
Sugimoto, M.
49
Ohashi, N.
16, J196, J307
Sugiura, T.
7, J075, A017
Okada, Y.
J245
Okanami, Y.
33, J269
Suguro-Katayama, M.
J241, J242
Okuma, K.
J076, J077
Osada, H.
20, 21, J004, J021, J041, J100,
J145, J174, J204, J205, J206, J247,
J262
Oshiro, A.
J208
Ota, A.
J092, J209, J240, J242
Otsuka, T.
17, J157, J211, J212
Ozeki, S.
J269
Saito, H.
J204
Saito, N.
52
Saito, T.
Sakai, H.
26,
J092,
J099,
Suzuki, H.
24, J050, J051
Suzuki, R.
25, 26, J006, J085, J092, J099,
J137, J149, J150, J165, J172, J173,
J177, J180, J202, J207, J234, J235,
J236, J239, J240, J242, J312,
R050, A037
Suzuki, S.
J081, J088, J089, J090, J120, J122,
J142, J192, J193, J214, J233, J249,
J252, J253, J259, J260, J281, J283,
J284, J288, R055, R056
Suzuki, T.
7, J147, J151, J153, J200, J236,
J237, J296, J299, A045
7, J075, J076, J077, J134, J135,
J145, J151, J153, J187, J237, J298,
J299, A019, A031
Tagawa, H.
26, J092, J099, J101, J177, J208,
J209, J238, J239, J240, J241, J242,
J312, A037
J007, J043, J044, J059, J060, J218,
J272, J273
Taguchi, O.
33, 45, J127, J248, J269
Taji, H.
J048, J150, J180
Sato, N.
20, J001, J026
Tajima, Ka.
Sekido, Y.
20, 21, J026, J041, J049, J073,
J079, J112, J126, J144, J163,
R047
Seto, M.
24, 25, 26, 57, J022, J050, J051,
J064, J092, J095, J099, J101, J125,
J208, J238, J239, J149, J150, J172,
J177, J209, J223, J240, J241, J242,
J274, J312, R015, R048, A036,
A037
Shima, H.
49
Shimizu, N.
J011, J194, J266
5, 7, 12, J012, J013, J018, J030,
J031, J037, J046, J047, J048, J057,
J074, J075, J076, J077, J108, J134,
J135, J136, J139, J140, J147, J149,
J150, J151, J152, J153, J161, J168,
J169, J187, J188, J189, J190, J191,
J225, J230, J237, J258, J261, J279,
J298, J299, J300, J301, J313, ,
R014, R035, R040, R042, R036,
A006, A016, A017, A018, A019,
A026, A031, A034, A035, A036,
A037, A038, A045, A046, A047,
A048, A049, A050, A051, A052,
A064, A071
Shimizu, S.
J040, J178
Tajima, Ko.
30, J021, J123, J243, J244
Shinoda, M.
7, 51, J133, J154, J298, J299,
A019
Takahashi, M. J039, J102, J144, J163
Shirai, N.
J059, J060
Shirata, N.
36, J015, J016, J068, J131, J224,
A014, A028, A044
Shiromizu, T.
48, J038, R049
Sobue, S.
44
Sugaya, N.
J109, J228
Sugaya, Y.
J014, J015, J016, J130, J131, J224
102
Takahashi, Ta. 20, 21, J004, J021, J041, J042,
J084, J100, J116, J128, J145, J154,
J174, J200, J204, J205, J206, J247,
J262, J303, J304, J305, R057
Takahashi, To. 30, 31, 32, 33, J002, J066, J070,
J123, J124, J179, J243, J244, J262,
J263, J269, R058, A001
Takenaka, Y.
16, J010, J159, J160, J211, J271,
A041
Takezaki, T.
12, J012, J013, J030, J031, J057,
J140, J147, J168, J225, J279,
J313, , R035, R036
Tamiya-Koizumi, K. 44, J138
Tanaka, H.
Taniguchi, T.
17, J010, J100, J104, J160, J185,
J194, J212, J219, J254, J270, J271
Tatematsu, Y. 20, 21, J041, J100, J204, J205,
J206
Terashima, M. 55
56
Tokumasu, S. 55
Tomida, S.
21, J021, J041, J100, J247, J262,
R057
Tominaga, S.
J147, R035, R036
Torikai, H.
31, 32, J263
Tsujimura, K.
30, 31, 32, 33, J002, J070, J123,
J124, J179, J243, J244, J263, J269,
R058
Tsukamoto, T. 15, 16, 17, J007, J010, J011, J027,
J028, J034, J043, J044, J059, J060,
J063, J096, J097, J104, J146, J148,
J156, J157, J158, J159, J160, J185,
J186, J195, J211, J212, J254, J270,
J271, J272, J273, R051, R052,
R053, R054, R059, R060, R064,
A041, A058
Tsurumi, T.
Tsuzuki, S.
Uchida, K.
J276
Ueda, R.
57, J040, J064, J066, J075, J078,
J095, J145, J178, J236, J237,
A017, A045
Wakai, K.
7, 11, 12, J012, J013, J017, J046,
J057, J065, J077, J081, J082, J102,
J107, J112, J119, J120, J121, J122,
J141, J142, J151, J153, J167, J192,
J193, J198, J213, J214, J215, J216,
J217, J219, J220, J221, J233, J237,
J249, J250, J251, J252, J253, J279,
J280, J281, J282, J283, J284, J286,
J288, J298, J299, R065, R066,
A019, A026, A031, A038, A045,
A063, A064, A065
Watanabe, A.
J058
Yabuta, T.
J118
20, 21
Tatematsu, M. 15, 16, 17, J007, J010, J011, J027,
J028, J029, J034, J043, J044, J059,
J060, J062, J063, J072, J096, J097,
J104, J113, J114, J115, J146, J148,
J156, J157, J158, J159, J160, J162,
J176, J185, J186, J194, J195, J196,
J211, J212, J218, J254, J270, J271,
J272, J273, J290, J294, J307, J311,
R045, R046, R051, R052, R053,
R054, R059, R060, R064, A008,
A009, A041, A042, A054, A058
Teratani, M.
A037
35, 36, 37, J003, J014, J015, J016,
J032, J068, J069, J130, J131, J224,
J228, J229, R023, R024, R033,
R061, R062, A003, A004, A014,
A015, A027, A028, A044, A059,
A060
25, 26, 57, J092, J172, J209, J239,
J241, J242, J264, J274, J275, J312,
Yamachika, T. J290
Yamada, N.
J259
Yamaguchi, M. 44, J092, J099, J207, J242, J291,
J292
Yamaguchi, T. 48, 49, J181, J182, J183, J293
Yamamoto, M. 55, J007, J044, J059, J060, J273
Yamamura, Y. J072, J113, J115, J156, J157, J158,
J162, J211, J270, J271, A041,
A042, A058
Yamane, Y.
J132, J133
Yanagisawa, K. 21, J041, J100, J145, J174, J247,
J262, R057
Yang, C. X.
7, 12, J298, J299, J300, J301,
A038, A071
Yasuda, T.
56
Yasui, K.
J176, J290
Yasui, Y.
52, J067, J302
Yatabe, Y.
7, 20, 21, J021, J039, J041, J084,
J100, J116, J128, J154, J204, J206,
J247, J262, J303, J304, J305,
R057
Yin, J.
42, J306
Yokoyama, N. J009, J199
Yokoyama, T. 20, 21, 48, J126, J184, J219, J293,
J308, R019, R067
103
Yokoyama, Y. A043
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