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BIO477
Cancer
Part I- Oct. 20, 2007
Part II- Oct. 27, 2007
Tim Westwood
Reading
Weinberg, R. A. (2007). The Biology of
Cancer. Garland Science, New York.
Chapter 2- The Nature of Cancer
Chapter 3- Tumor Viruses
Chapter 4- Cellular Oncogenes
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Outline
A. Introduction
- types, properties of cancer cells,
history, epidemiology
B. The “3” causes of cancer
1. Microbes
2. Mutagens (irritants)
3. Genetics
C. Epidemiology of Cancer
D. Mutagens and Carcinogens
- Ames test
E. Tumour Viruses and Oncogenes
1. Rous sarcoma virus
2. DNA and RNA Tumor viruses
3. Retroviruses and the discovery of
oncogenes
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Table 3.2 The Biology of Cancer (© Garland Science 2007)
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Table 23-1.
Variation
Between
Countries in
the Incidence
of Some
Common
Cancers
From:
Molecular
Biology of the
Cell,4th ed.
2002. B. Alberts
et al. Garland
Press, N.Y.,
N.Y.
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SITE OF
ORIGIN OF
CANCER
HIGH-INCIDENCE POPULATION
LOCATION
INCIDENCE*
LOW-INCIDENCE POPULATION
LOCATION
INCIDENCE*
* Incidence = number of new cases per year per 100,000 population
Lung
USA (New
Orleans, blacks)
110
India (Madras)
5.8
Breast
Hawaii
(Hawaiians)
94
Israel (non-Jews)
Prostate
USA (Atlanta,
blacks)
91
China (Tianjin)
1.3
Uterine cervix
Brazil (Recife)
83
Israel (non-Jews)
3.0
Stomach
Japan
(Nagasaki)
82
Kuwait (Kuwaitis)
3.7
Liver
China
(Shanghai)
34
Canada (Nova
Scotia)
0.7
Colon
USA
(Connecticut,
whites)
34
India (Madras)
1.8
Melanoma
Australia
(Queensland)
31
Japan (Osaka)
0.2
Lip
Canada
(Newfoundland)
15
Japan (Osaka)
0.1
Kidney
Canada (NWT
and Yukon)
15
India (Poona)
0.7
Leukemia
Canada (Ontario)
12
India (Nagpur)
2.2
14.0
Table 2.5
part 1 of 2 The
Biology of Cancer
(© Garland
Science 2007)
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Figure 2.20 The Biology of Cancer (© Garland Science 2007)
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Figure 23-17. The Ames test for mutagenicity. The test uses a strain of Salmonella bacteria
that require histidine in the medium because of a defect in a gene necessary for histidine
synthesis. Mutagens can cause a further change in this gene that reverses the defect, creating
revertant bacteria that do not require histidine. To increase the sensitivity of the test, the
bacteria also have a defect in their DNA repair machinery that makes them especially
susceptible to agents that damage DNA. A majority of compounds that are mutagenic in tests
such as this are also carcinogenic and vice versa.
From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.
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Figure from:
Genes and the
Biology of Cancer.
H. Varmus and R.
Weinberg. 1993.
Sci. Am. Library,
W.H. Freeman.
N.Y, N.Y.
Table 2.8 The Biology
of Cancer (© Garland
Science 2007)
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Figure 3.2 The Biology of Cancer (© Garland Science 2007)
Table 23-2. Viruses Associated with Human Cancers
VIRUS
ASSOCIATED TUMORS
AREAS OF HIGH
INCIDENCE
warts (benign)
worldwide
carcinoma of the uterine cervix
worldwide
liver cancer (hepatocellular carcinoma)
Southeast Asia, tropical Africa
Burkitt's lymphoma (cancer of B
lymphocytes)
West Africa, Papua New Guinea
nasopharyngeal carcinoma
southern China, Greenland
DNA Viruses
Papovavirus family
Papillomavirus
(many distinct strains)
Hepadnavirus family
Hepatitis-B virus
Herpesvirus family
Epstein-Barr virus
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RNA viruses
Retrovirus family
Human T-cell leukemia virus type I (HTLV-1)
adult T-cell
leukemia/lymphoma
Japan, West Indies
Human immuno-deficiency virus (HIV, the AIDS
virus)
Kaposi's sarcoma
(HIV-indirect; HPV,
herpesvisrus-direct)
Central and Southern
Africa
From:
Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.
Table 15.2. Tumor Viruses
Virus family
Human tumors
Genome size (kb)
DNA tumor viruses
Hepatitis B viruses
Liver cancer
3
SV40 and polyomavirus
None
5
Papillomaviruses
Cervical carcinoma, Kaposi’s
sarcoma
8
Adenoviruses
None
Herpesviruses
(e.g. Epstein-Barr virus)
Burkitt's lymphoma,
nasopharyngeal carcinoma,
Kaposi's sarcoma
35
100–200
RNA tumor viruses
Retroviruses
Adult T-cell leukemia
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Figure 5-73. The life cycle of a retrovirus. The retrovirus genome consists of an RNA
molecule of about 8500 nucleotides; two such molecules are packaged into each viral
particle. The enzyme reverse transcriptase first makes a DNA copy of the viral RNA molecule
and then a second DNA strand, generating a double-stranded DNA copy of the RNA genome.
The integration of this DNA double helix into the host chromosome is then catalyzed by a
virus-encoded integrase enzyme. This integration is required for the synthesis of new viral
RNA molecules by the host cell RNA polymerase, the enzyme that transcribes DNA into RNA
Figure 15.17. A typical retrovirus genome The DNA provirus, integrated into
cellular DNA, is transcribed to yield genome-length RNA. This primary transcript
serves as the genomic RNA for progeny virus particles, and as mRNA for the gag
and pol genes. In addition, the full-length RNA is spliced to yield mRNA for env.
The gag gene encodes the viral protease and structural proteins of the virus
particle, pol encodes reverse transcriptase and integrase, and env encodes
envelope glycoproteins.
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA
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Figure 15.18. Cell transformation
by RSV and ALV Both RSV and
ALV infect and replicate in chicken
embryo fibroblasts, but only RSV
induces cell transformation.
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA
Figure 15.19. The RSV genome RSV contains an additional gene, src, that is not
present in ALV and encodes the Src protein-tyrosine kinase.
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA
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Figure 3.20
The Biology of Cancer
(© Garland Science
2007)
Fig. 3.22 Capture of src by avian leukosis virus
The Biology of Cancer (© Garland Science 2007)
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Table 15.3. Retroviral Oncogenes
Oncogene
abl
Virus
Species
Abelson leukemia
Mouse
erbA
Avian erythroblastosis-ES4
Chicken
erbB
Avian erythroblastosis-ES4
Chicken
ets
Avian erythroblastosis-E26
Chicken
fes
Gardner-Arnstein feline
sarcoma
Cat
fms
McDonough feline sarcoma
Cat
fos
FBJ murine osteogenic
sarcoma
Mouse
fps
Fujinami sarcoma
Chicken
jun
Avian sarcoma-17
Chicken
kit
Hardy-Zuckerman feline
sarcoma
Cat
mos
Moloney sarcoma
Mouse
mpl
Myeloproliferative leukemia
Mouse
myb
Avian myeloblastosis
Chicken
myc
Avian myelocytomatosis
Chicken
p3k
Avian sarcoma-16
Chicken
qin
Avian sarcoma-31
Chicken
raf
3611 murine sarcoma
Mouse
rasH
Harvey sarcoma
Rat
rasK
Kirsten sarcoma
Rat
rel
Reticuloendotheliosis
Turkey
ros
UR2 sarcoma
Chicken
sea
Avian erythroblastosis-S13
Chicken
sis
Simian sarcoma
Monkey
ski
Avian SK
Chicken
src
Rous sarcoma
Chicken
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA
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The Biology of
Cancer (©
Garland Science
2007)
Figure 24-4. The identification and molecular cloning
of the rasD oncogene. Addition of DNA from a human
bladder carcinoma to a culture of mouse 3T3 cells
causes about one cell in a million to divide abnormally
and form a focus, or clone of transformed cells. To
clone the oncogene responsible for transformation,
advantage is taken of the fact that most human genes
have nearby repetitive DNA sequences called Alu
sequences. DNA from the initial focus of transformed
mouse cells is isolated, and the oncogene is
separated from adventitious human DNA by
secondary transfer to mouse cells. The total DNA
from a secondary transfected mouse cell is then
cloned into bacteriophage λ; only the phage that
receives human DNA hybridizes with an Alu probe.
The hybridizing phage should contain part or all of the
transforming oncogene. This expected result can be
proved by showing either that the phage DNA can
transform cells (if the oncogene has been completely
cloned) or that the cloned piece of DNA is always
present in cells transformed by DNA transfer from the
original donor cell.
From: Molecular Cell Biology. 4th ed. 2000.
Lodish et al. W.H. Freeman, NY, NY.
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From:
Molecular Biology
of the Cell,4th ed.
2002. B. Alberts
et al. Garland
Press, N.Y., N.Y.
Figure 23-24. Cancer-critical genes fall into two readily distinguishable categories, dominant
and recessive. Oncogenes act in a dominant manner: a gain-of-function mutation in a single
copy of the cancer-critical gene can drive a cell toward cancer. Tumor suppressor genes, on
the other hand, generally act in a recessive manner: the function of both alleles of the
cancer-critical gene must be lost to drive a cell toward cancer. In this diagram, activating
mutations are represented by solid red boxes, inactivating mutations by hollow red boxes.
Figure 23-27. Three ways in which a proto-oncogene
can be made overactive to convert it into an oncogene.
From:
Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.
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Fig. 3.23.
Insertional
mutagenesis.
The Biology of Cancer (©
Garland Science 2007)
Table 15.4. Representative Oncogenes of Human Tumors
Oncogene
Type of cancer
Activation mechanism
abl
Chronic myelogenous
leukemia, acute lymphocytic
leukemia
Translocation
akt
Ovarian and pancreatic
carcinomas
Amplification
bcl-2
Follicular B-cell lymphoma
Translocation
D1
Parathyroid adenoma, B-cell
lymphoma
Translocation
erbB-2
Breast and ovarian
carcinomas
Amplification
gip
Adrenal cortical and ovarian
carcinomas
Point mutation
gli
Glioblastoma
Amplification
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hox-11
Acute T-cell leukemia
Translocation
lyl
Acute T-cell leukemia
Translocation
c-myc
Burkitt's lymphoma
Translocation
c-myc
Breast and lung carcinomas
Amplification
L-myc
Lung carcinoma
Amplification
N-myc
Neuroblastoma, lung carcinoma
Amplification
PDGFR
Chronic myelomonocytic leukemia
Translocation
PML/RA
Rα
Acute promyelocytic leukemia
Translocation
rasH
Thyroid carcinoma
Point mutation
rasK
Colon, lung, pancreatic, and thyroid carcinomas
Point mutation
rasN
Acute myelogenous and lymphocytic leukemias,
thyroid carcinoma
Point mutation
ret
Multiple endocrine neoplasia types 2A and 2B
Point mutation
ret
Thyroid carcinoma
DNA rearrangement
SMO
Basal cell carcinoma
Point mutation
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA
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