Download Cell Proliferation as a Major Risk Factor for

RESEARCH 55. 375<)-3762, September l, 1W5)
Perspectives in Cancer Research
Cell Proliferation as a Major Risk Factor for Cancer: A Concept of Doubtful
Validity1
Emmanuel Farber2
Departments of Paihiilogv anil Riochemistry, Medical Sciences Building. University of Toronto. Toronto. Ontario. Canuda M5S IAH, and Department of Pathology. Anatomy and
Cell liiology. Jefferson Medical College. Philadelphia. Pennsylvania I9I07-67W
Introduction
An old idea, now being regenerated anew, focuses a major aspect of
risk assessment for cancer on cell proliferation (1-11). It is now being
proposed that the presence of cell proliferation by itself or the stim
ulation of cell proliferation ¡na quiescent tissue or organ with low
mitotic activity should be in and of themselves major concerns for
cancer development in the particular tissue or organ. Also, the ability
of an agent to induce cell proliferation in a target organ or tissue
would be considered to have predictive value as a valid index of the
probable carcinogenicity of that agent.
It is axiomatic that cell proliferation plays an important and even
critical role in many steps in cancer development. As discussed briefly
in a fairly recent article (12), cell proliferation, either of a limited
degree (1 cell cycle) or of a more extended degree (12 or more cell
cycles), plays a key role in initiation, promotion or selection, and
progression during cancer development in several organs and tissues
(Table 1). Of course, cell proliferation with altered control is the
prime property that is the first characteristic phenotypic feature of a
malignant neoplastic cell population.
However, whether cell proliferation, per se, is a risk factor for the
long process of cancer development has not been demonstrated sci
entifically but remains in the realm of conjecture and speculation. No
one has yet described a system in which continual cell proliferation
can be induced or arrested under controlled conditions so that cell
proliferation becomes the only or at least a major variable under study.
Until this is done, cell proliferation as a risk factor must remain in the
realm of unproven speculation. Of course, a single cycle of cell
proliferation without carcinogen exposure, such as in the normal or
control adult liver during liver regeneration, has not been shown or
proven to be carcinogenic in many hundreds of studies reported over
the past several decades.
Theoretical Scientific Bases for Considering Cell Proliferation
as a Risk Factor
In addition to the general importance of cell proliferation at all steps
in cancer development, there appear to be two other major consider
ations that underlay this speculation. These are: (a) importance of cell
proliferation in initiation of cancer development with carcinogenic
agents, especially those that interact with DNA or the genome; and (/;)
importance of cell proliferation ¡nthe genesis of mutations.
Cell proliferation is the central and key phenotypic expression in all
Received 2/10/95; accepted 6/28/95.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
1The author's research discussed in this analysis was supported by research grants
from the National Cancer Institute. NIH. the Medical Research Council of Canada
(MT-5994), and the National Cancer Institute of Canada.
2 To whom requests for reprints should be addressed, at Department of Pathology.
Anatomy, and Cell Biology. Jefferson Medical College, 1020 Locust Street. Philadelphia.
PA 19107-6799.
types of malignant neoplasia. Cell proliferation in cancer is accom
panied not only by disturbances in the fine balance between cell gain
and cell loss (Table 1), leading to net growth, but also by two other
associated changes: invasion and metastasis.
Because of its pivotal role in cancer, and because of the distur
bances in its control in cancer, it is widely assumed that disturbed
control of cell proliferation is also the most important and critical
property of potential neoplastic cells or so-called "preneoplastic" or
"precancerous" cells throughout the carcinogenic process. This ap
pears to be an almost universal misconception in studies on cancer.
There is neither a rational hypothesis nor any accompanying concrete
factual evidence for this concept in cancer development. In fact, as
listed in Table 1, and as discussed previously (12), a highly controlled
balance between cell proliferation and cell loss is clearly in evidence
during the inordinately long process of cancer development until the
late appearance of unequivocal cancer with an upset ¡nthis normal
balance.
Where studied, cancer development in vivo and in vitro with dif
ferent types of "genotoxic" agents requires a single round of cell
proliferation to initiate the process (13-30). Although this dependence
on one cycle of cell proliferation has been demonstrated in several
tissues and organs in vivo, such as in skin, colon, liver, and urinary
bladder, and in different cells in vitro, it is particularly clear-cut and
unequivocal in the liver for at least three reasons: (a) the hepatocyte
population in the adult is almost totally quiescent with respect to cell
proliferation; (b) cell proliferation can be readily induced or stimu
lated by several types of procedures, both regenerative and primary
hyperplastic; and (c) several of the steps between the original hepa
tocyte exposed to the carcinogen and the ultimate appearance of
cancer are highly synchronized during much of the cellular evolution
to malignancy but especially during the initiation and promotionselection periods (31). This synchrony is of the greatest importance
because the sequential step-by-step analysis of any multistep process,
be it molecular, biochemical, genetic or biological, necessitates a
synchronous system if precursor-product relationships are to be es
tablished at each major step. This synchrony, together with a short
time frame (hours to days instead of many months) makes it feasible
to analyze the varying roles of cell proliferation in select models of
liver carcinogenesis (12, 31).
Many different carcinogenic agents, including chemicals, radia
tions, and viruses, interact with the genome of target cells and gen
erate a variety of mutations. The fixation of the genomic changes to
generate mutations often requires a round of cell proliferation.
If it is assumed that such mutations play an important role in
initiating the carcinogenic process and in facilitating further progres
sion, the round of cell proliferation is essential for the carcinogenic
process with genotoxic agents. Because potential or actual mutagens
are widespread in all areas of the human environment, it is assumed
that the rate-limiting step in the carcinogenic process is often cell
proliferation, not exposure to an adequate level of a carcinogen, and
that cell proliferation per se thus becomes a risk factor, providing one
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CEI.1 PROLIFERATION
AS A MAJOR RISK FACTOR FOR CANCER
Table 1 Cell prolifération in chemical (genoloxici hepatocarcinogenesis
Also, in the development of hepatocellular carcinoma in the rat with
initiation-promotion regimens, differential inhibition of cell prolifer
linn.¡non.single cycle
Regenerative: effective
Hyperplastic: ineffective
ation, not cell proliferation, is a major mechanism for promotion (31).
In addition, one of the promoters used commonly, phénobarbital,has
only very limited mitogenic activity for the liver (47, 48). After a brief
episode of cell proliferation, this agent is more of an inhibitor of cell
proliferation than a mitogen. Visible evidence of promotion can be
seen many weeks later. Also, with at least some nongenotoxic car
cinogens, such as clofibrate, cell proliferation is seen only transitorily
during the first week or so and not subsequently during the very
prolonged period of cancer development until focal proliferations
(nodules, "adenomas") appear (49).
Promotion: clonal proliferation (10-12 cycles)
Regenerative: no cell loss, effective
Hyperplastic: cell loss (so-called "apoptosis") as well as cell proliferation,
ineffective
Progression: all hyperplaslic (seemingly autonomous cell proliferation)
Precancer: cell loss (so-called "apoptosis") almost equal to cell proliferation, slow
growth
Cancer: loss of balance of cell loss and cell proliferation, growth and invasion
speculates that the possible exposure to potential carcinogens (in the
air, food, water, air pollutants etc.) is not often rate limiting (1-11).
This simple conjecture concerning how humans interact with the
environment is the major basis for the theory that cell proliferation is
an important risk factor for cancer development.
Critique
There are at least two serious criticisms of the conjecture that cell
proliferation is a risk factor for cancer. These concern: (a) the lack of
association between cell proliferation and cancer occurrence in sev
eral organs and tissues; and (b) the common property of genotoxic
chemical carcinogens as inhibitors of cell proliferation, rather than
stimulators, in several organs and tissues.
Cell proliferation is not a risk factor for cancer in several situations
i/i vivo that readily come to mind (the skin in psoriasis, the normal
small intestine, the breast, the liver, and the stomach).
Psoriasis is a chronic disease in which focal or regional prolifera
tion of the epidermis is a prominent feature (32-38). This great
increase in cell proliferation is of long duration, often lasting decades.
Yet, cancer development in psoriatic lesions is uncommon or rare
(34, 35, 38, 39), despite the fact that the skin in humans, as in some
species of animals (e.g., mouse), is a common target organ for a
virtually universal carcinogen (UV light) and for many chemical
carcinogens, and is one of the commonest sites for the development of
epithelial cancers of several types.
The normal small intestine is the site of vigorous cell proliferation.
In fact, Leblond (40) has estimated that the total production of cells by
the digestive tract to replace the normal cell loss over a period of
20-30 days is equal to the total number of cells in the body. The small
intestine is a major contributor. Despite this enormous cell prolifera
tion, epithelial cancer in the small intestine, especially the jejunum
and ileum, is extremely rare and is among the least common types of
cancer by far (41, 42). This is in contrast to the segments of the
digestive tract immediately below (colon) and above (stomach), sites
where malignant disease is very common. Unfortunately, the expla
nation that is offered as a possible basis for this unusual distribution
of cancer evidence is based on a failure to appreciate (43, 44) that the
changes in the intestinal epithelial cells in the small and large intestine
after the exposure of the organism to various cytotoxic agents are not
due to a primary effect in killing the mucosal epithelial cells but are
secondary to previous changes in the underlying lymphoid cells
(45, 46). The latter, of course, may well vary considerably in different
segments of the intestine.
The breasts are common sites for the development of epithelial
cancer in women. The epidemiological data on women indicate
clearly that the disease is more common in women who have never
had children than in women who have (41, 42). This is also true in
the mouse models where pregnancy is protective. Pregnancy is
associated with a vigorous cell proliferation of all epithelial cells
in the breast.
Another interesting example is the occurrence of epithelial cancers
of the stomach in people of certain countries. It is now well docu
mented that atrophie gastritis, with low levels of cell proliferation, not
hyperplastic or hypertrophie gastritis, is a risk factor for the develop
ment of cancer (50).
Ward et al. (51) have critically reviewed a large body of data in
animals, in particular rodents and some in humans, and have con
cluded that cell proliferation is not a major risk factor for cancer
development in many instances. Very recently, Huff (52) has arrived
at a similar conclusion.
Thus, in several common circumstances, there is no relationship
between the degrees of cell proliferation generally in an organ or
tissue and cancer development. If anything, negative correlations
between cell proliferation and cancer incidence, at least in some
instances, can be seen. A key characteristic of almost all examples of
cancer development in humans and animals is the focal nature of the
few cells in any organ that do show increased cell proliferation in
comparison to the vast number of surrounding cells, not apparently
directly involved in carcinogenesis, that often show inhibition of cell
proliferation.
The animal and human data will have to be much more convincing
if the property of inducing cell proliferation is to be considered
seriously as an important risk factor of carcinogenicity (e.g., Refs.
53-55).
It is now well documented that many if not all genotoxic carcino
gens are inhibitors of DNA synthesis and/or cell proliferation ("mitoinhibition") in several organs or tissues. Carbon tetrachloride,
ethionine, 2-acetylaminofluorene,
4-dimethylaminoazobenzene
derivatives, thioacetamide, aflatoxin B,, 3-methylcholanthrene,
and
ben-
zo(fl)pyrene, dimethylnitrosamine, diethylnitrosamine, pyrrolizidine
alkaloids, 7,12-dimethyl-benzo(a)anthracene,
urethane, and /V-methyl-A'-nitrosourea are among the many chemical carcinogens that have
been shown to inhibit cell proliferation and/or DNA synthesis (see
Refs. 56 and 57 for list of references).
These data are consistent with the hypothesis proposed in 1938 by
Haddow (58). On the basis of his research on the inhibition of cell
growth of normal and cancer cells with some pure polycyclic aromatic
hydrocarbons that were being identified and synthesized at the Ches
ter Beatty Research Institute, Haddow suggested that inhibition of cell
proliferation could be an early effect of carcinogens and that, in such
an environment, resistant cells may arise and be encouraged to pro
liferate selectively relative to the surrounding cells. This hypothesis
was further analyzed in many subsequent reports (e.g., 56, 57, 59, 60).
This differential between a focal population and the surrounding cells
is also seen when rats are exposed continuously for many weeks to
two quite different carcinogens, 2-acetylaminofluorene and ethionine
(61). Inhibition of cell proliferation after an initial brief stimulation of
cell proliferation is also seen with some nongenotoxic carcinogens,
such as clofibrate (49, 62).
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CELL PROLIFERATION
AS A MAJOR RISK FACTOR FOR CANCER
Special Circumstances
It must be emphasized that the criticism concerning the major role
of cell proliferation as a risk factor pertains to the generalization in a
broad spectrum of cancer developments in a variety of organs and
tissues.
There are special instances where cell proliferation does appear to
be the rate-limiting step or the major determinant for cancer devel
opment. For example, in organs such as liver and urinary bladder in
the adult, in which cell proliferation is indeed minimal, it can be
shown that cell proliferation does play an important role in the
carcinogenic process in the presence of nonnecrogenic doses of chem
ical carcinogens. In experimental animals, single doses of many
different chemical carcinogens are or may not be necrogenic and thus
may not stimulate cell proliferation.
However, I know of no circumstance where stimulation of cell
proliferation in such quiescent organs can induce cancer in the ab
sence of an exposure to the appropriate carcinogen, either with a or
without prior metabolic activation.
transformed state in X-ray involved transformation. Proc. Nati. Acad. Sci. USA,
57: 1522-1527, 1967.
14. Pound, A. V. Carcinogenesis and cell proliferation. N. Z. Med. J., 67: 88-99, 1968.
15. Warwick, G. P. Effect of the cell cycle in carcinogenesis. Fed. Proc., JO: 1760-1765.
1971.
16. Kakunaga, T. Requirement for cell proliferation in the fixation and expression of the
transformed state in mouse cells treated with 4-nitroquinoline-l-oxide.
Int. J. Cancer,
14: 736-742, 1974.
17. Rajewsky, M. F. Prolifcrative parameters of mammalian cell systems and their role in
tumor growth and carcinogenesis. Z. Krebsforsch., 78: 12-30. 1972.
18. Craddock, V. M. Cell proliferation and experimental liver cancer. In: H. M. Cameron,
D. A. Lin-sell, and G. P. Warwick (eds.), Liver Cell Cancer, pp. 153-201. Amsterdam:
Elsevier Science Publishers B.V., 1976.
19. Cayama, E., Tsuda, H., Sarma, D. S. R., and Farber. E. Initiation of liver carcino
genesis requires cell proliferation. Nature (Lond.), 275.- 60-61,
formation. Verh. Dtsch. Ges. Pathol., 63: 18-39, 1979.
21. Pilot, H. C.. and Sirica, A. E. The stages of initiation and promotion in hepatic
carcinogenesis.
23.
25.
If it were assumed that cell proliferation is rate limiting in the
carcinogenic process, there would follow a totally new and radical
orientation to the primary prevention of cancer with known or sus
pected carcinogens. The vigorous search and elimination of possible
primary or even promoting carcinogenic agents becomes of secondary
importance in any program for cancer prevention because the number
and levels of present carcinogenic agents would already be saturating
if cell proliferation is rate limiting. This new emphasis in cancer
prevention, as nonexplicitly implied from the writings of Ames et al.
(e.g., 1, 2, 63, 64), would encourage us to pay much less attention to
our environment, such as smoking and occupation, than we do cur
rently. This new radical suggestion for cancer prevention would
demand accurate and detailed factual documentation, rather than the
(current) undocumented opinion, if we are to give it serious consid
eration in the rational development of approaches to cancer control
and if we are to redirect an important focus of attention in cancer
prevention away from the environment. The justification for this
reorientation requires a careful documentation of facts that are
unavailable at this time.
27.
28
29
30.
3]
32
33
34.
35.
References
36.
1. Ames, B. N., and Gold, L. S. Chemical carcinogenesis: loo many roden! carcinogens.
Proc. Nati. Acad. Sci. USA, 87: 772-776, 1990.
2. Ames. B. N.. and Gold, S. L. Too many rodent carcinogens: mitogenesis increases
mutagenesis. Science (Washington DC). 249: 970-971, 1990.
3. Cohen, S. M., and Ellwein, L. B. Cell proliferation in carcinogenesis. Science
(Washington DC), 249: 1007-1011, 1990.
4. Preston-Martin, S., Pike, M. C, Ross, R. K., Jones, P. A., and Henderson, B. E.
Increased cell division as a cause of human cancer. Cancer Res.. 50: 7415-7421,
1990.
5. Cohen, S. M., and Ellwein, L. B. Genetic errors, cell proliferation, and carcinogenesis.
Cancer Res., 51: 6493-6505, 1991.
6. Cohen, S. M., Purtilo, D. T., and Ellwein, L. B. Pivotal role of increased cell
proliferation in human carcinogenesis. Mod. Pathol., 4: 371-382, 1991.
7. Clayson, D. B., Iverson, F., Nera, E. A., and Lok, E. The importance of cellular
proliferation induced by BHA and BHT. Toxicol. Ind. Health. 9: 231-242, 1993.
8. Butterworth, B. E., and Goldsworthy, T. L. The role of cell proliferation in multistage
carcinogenesis. Proc. Soc. Exp. Biol. Med., 198: 683-687, 1991.
9. Berman, J. J. Cell proliferation and the aetiology of hepatocellular carcinoma.
J. Hepatol., 7: 305-309, 1988.
10. Clayson, D. B., Iverson, F., Nera, E. A., and Lok, E. Early indicators of potential
neoplasia produced in the rat forestomach by non-genotoxic agents: the importance of
induced cellular proliferation. Mutât.Res., 248: 321-331, 1991.
11. Butterworth, B. E., Slaga, T. J., Farland, W.. and McClain. M. (eds.). Chemically
Induced Cell Proliferation: Implications for Risk Assessment. New York: Wiley-Liss,
1991.
12. Farber, E. Hepatocyte proliferation in stepwise development of experimental liver
cancer. Dig. Dis. Sci., 36: 973-978, 1991.
13. Borek, C., and Sachs, L. The number of cell generations required to fix the
Biochim. Biophys. Acta, 605.- 191-215, 1980.
22. Ishikawa, T., Takayama. S., and Kitagawa. T. Correlation between time of partial
24.
Implications
1978.
20. Rabes, H. M. Proliferative Vorgängewährendder Frühstadiender malignen Trans
37.
38.
39.
40.
41.
42.
43.
hepatectomy after a single treatment with diethylnitrosamine
and induction of
adenosine-triphosphate-deficient
islands in rat liver. Cancer Res.. 40: 4261-4264,
1980.
Columbano. A.. Rajalakshmi, S., and Sarma, D. S. R. Requirement of cell prolifer
ation for the induction of presumptive preneoplastic lesions in rat liver by a single
dose of 1,2-dimethylhydrazine. Chem. Biol. Interact., 32: 347-351, 1980.
Emmelot. P., and Schcrer. E. The first relevant cell stage in rat liver carcinogenesis:
a quantitative approach. Biochim. Biophys. Acta, 605: 247-304. 1980.
Columbano, A., Rajalakshmi, S., and Sarma. D. S. R. Requirement of cell prolifer
ation for the initiation of liver carcinogenesis as assayed by three different procedures.
Cancer Res., 41: 2079-2083, 1981.
Ying, T. S., Sarma, D. S. R., and Farber, E. Role of acute hepatic necrosis in the
induction of early steps in liver carcinogenesis by diethylnitrosamine. Cancer Res.,
41: 2096-2102, 1981.
Ying, T. S., Enomoto, K., Sarma, D. S. R., and Farber, E. Effects of delays in the cell
cycle on the induction of preneoplastic and ncoplastic lesions in rat liver by 1,2dimethylhydrazine. Cancer Res., 42: 876-880, 1982.
Grisham. J. W., Kaufmann, W. K., and Kaufman, D. G. The cell cycle and chemical
carcinogenesis. Surv. Synth. Pathol. Res., /: 49-66, 1983.
Moore, M. A., and Kitagawa, T. Hepatocarcinogenesis
in the rat: the effect of
promoters and carcinogens in vivo and in vitro. Int. Rev. Cytol., 101: 125-173, 1986.
Farber. E., Chen, Z-Y., Lee, G., Rinaudo, J. S., Roomi, M. W., Rotstein. J., and
Semple, E. The biochemical-molecular pathology of the stepwise development of
liver cancer: new insights and problems. In: P. Bannasch, D. Keppler, and G. Weber
(eds.). Liver Cell Carcinoma, pp. 273-291. United Kingdom: Kluwer Academic
Publishers, 1989.
Farber, E., and Sarma, D. S. R. Hepatocarcinogenesis: a dynamic cellular perspective.
Lab. Invest., 56: 4-22, 1987.
Ackerman, A. B. Histologie Diagnosis of Inflammatory Skin Diseases, pp. 250-256,
577-578. Philadelphia: Lea & Febiger, 1978.
Gelfanl. S. The epidermal cell cycle and its significance in psoriasis. In: E. M. Farber,
A. J. Cox, L. Nail, and P. H. Jacobs (eds.). Psoriasis, pp. 53-59. New York: Gruñe
& Stratton, Inc., 1982.
Wright. N. A., and Camplejohn, R. S. (eds.) Psoriasis: Cell Proliferation. Edinburgh,
Scotland: Churchill Livingstone, 1983.
Wright, N. A. Changes in epidermal cell proliferation in proliferative skin diseases.
Curr. Top. Pathol., 74: 141-166, 1985.
Pollen, C. S. Possible defects in the proliferative organization and control mecha
nisms in psoriasis. In: E. M. Farber, L. Nail. V. Morhenn, and P. H. Jacobs (eds.),
Psoriasis, pp. 15-35. New York: Elsevier Science Publishing Co., Inc., 1987.
Farmer, E. R., and Hood. A. F. Pathology of the skin. Norwalk. CT: Applclon &
Lange, 1990.
Petrozzi, J. K., Barton, J. O., and Kaidbey. K. K. Updating of the Goeckerman regime
for psoriasis. Br. J. Dermatol., 98: 437-444. 1978.
Lindelöf. B., Eklund, G., Liden, S.. and Stern. R. S. The prevalence of malignan!
tumors in patients with psoriasis. J. Am. Acad. Dermatol.. 22: 1056-1060. 1990.
Lehlond, C. P. The time dimension in histology. Am. J. Anat., /16: 1-27, 1965.
Rubin, E., and Farber, J. L. Pathology, Ed. 2. Philadelphia: J. B. Lippincott, 1994.
Cotran, R. S., Kumar, V., and Robbins, S. L. Pathologic Basis of Disease, Ed. 5.
Philadelphia: W. B. Saunders Co.. 1994.
Li, Y. 0., Fan, C. Y., O'Connor, P. J., Winlon. D. J.. and Pollen, C. S. Target cells
for the cytotoxic effects of carcinogens in the murine small bowel. Carcinogenesis
(Lond.), 13: 361-368, 1992.
44. Pollen. C. S.. Li, Y. 0.. O'Connor. P. J., and Winter, D. J. A possible explanation for
the differential cancer incidence in the intestine, based on distribution of the cytotoxic
effects of carcinogens in the murine large bowel. Carcinogenesis (Lond.), 13:
2305-2312, 1992.
45. Hugon, J., and Borgers, M. Ultrastructural and cytochemical studies on karyotic
bodies in the epithelium of the duodenal crypts of whole body X-irradiated mice. Lab.
Invest., 15: 1528-1543, 1966.
46. Verbin, R. S.. Diluiso, G., Liang, H., and Farber, E. The effects of cytosine arabinoside upon proliferating epithelial cells. Cancer Res.. 32: 1476-1488, 1972.
47. Barbason. H.. Rassenfosse, C., and Beiz, E. H. Promotion mechanism of phénobar
bital and partial hepatectomy of DENA hepatocarcinogenesis cell kinetics effect. Br.
J. Cancer, 47:517-525,
1983.
48. Eckl, P. M., Meyer. S. A.. Whitcomb, W. R., and Jirtle, R. L. Phénobarbitalreduces
3761
Downloaded from cancerres.aacrjournals.org on April 29, 2017. © 1995 American Association for Cancer Research.
CELL PROLIFERATION AS A MAJOR RISK HACIOR H)R CANCI-.K
49.
50.
51.
52.
53.
54.
55.
56.
EOF receplors and Ihc ability of physiological concenlrations of calcium to suppress
hepatocyte proliferation. Carcinogenesis (Lond.), 9: 479-483, 1988.
Nagai. M. K., Prior. I... and Farber, E. Possible mechanism of tumor promotion
by the non-genotoxic carcinogen clofibrate. Proc. Am. Assoc. Cancer Res., 35:
1004, 1994.
Correa, P. Human gastric Carcinogenesis: A multistep and multifactorial process: first
American Cancer Society award lecture on cancer epidemiology and prevention.
Cancer Res., 52: 6735-6740, 1992.
Ward, J. M., Uno, H., Kurata, Y., Weghost, C. M., and Jang, J-J. Cell proliferation not
associated with Carcinogenesis in rodents and humans. Environ. Health Perspect., 101
(Suppl. 5): 125-136, 1993.
Huff, J. Mechanisms, chemical Carcinogenesis and risk assessment: cell proliferation
and cancer. Am. J. Ind. Med., 27: 293-300, 1995.
Melnick, R. L. Does chemically induced hepatocyte proliferation predict liver Carci
nogenesis? FASEB J., 6: 2698-2706, 1992.
Zito, R. Cell proliferation in experimental Carcinogenesis. Exp. Clin. Cancer Res., II:
3-6, 1992.
Weinstein, I. B. Toxicity, cell proliferation, and Carcinogenesis. Mol. Carcinog., 5:
2-3, 1992.
Farber, E. The pathology of experimental liver cell cancer. ///: H. M. Cameron, D. A.
57.
58.
59.
60.
61.
62.
63.
64.
Linsell, and G. P. Warwick (eds.), Liver Cell Cancer, pp. 243-277, Amsterdam:
Elsevier Science Publishers B.V., 1976.
Farber, E. Clonal adaptation during Carcinogenesis. Biochem. Pharmacol., .W: 18371846, 1990.
Haddow, A. Cellular inhibition and the origin of cancer. Acta Unió Int. Contra
Cancrum, 3: 342-352, 1938.
Laws, J. O. Tissue regeneration and tumour development. Br. J. Cancer, /.?. 669674, 1969.
Vasilev, J. M., and Guelstein, V. I. Sensitivity of normal and neoplastic cells to the
damaging action of carcinogenic substances: a review. J. Nati. Cancer Inst., 31:
1123-1141, 1963.
Farber, E., Parker, S., and Gruenstcin, M. The resistance of putative premalignant
liver cell populations, hyperplastic nodules, to the acute cytotoxic effects of some
hepalocarcinogens. Cancer Res. 36: 3888-3893, 1976.
Nagai, M. K. The biochemical pathology of cancer development with the nongenotoxic carcinogen, clofibrate. PhD Thesis, University of Toronto, 1993.
Ames, B. N., Profet, M., and Gold. L. S. Dietary pesticides (99.99% all natural). Proc.
Nati. Acad. Sci. USA, 87: 7777-7781, 1990.
Ames, B. N., Profet, M.. and Gold, L. S. Nature's chemicals and synthetic chemicals:
comparative toxicology. Proc. Nati. Acad. Sci. USA, 87: 7782-7786,
1990.
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Cell Proliferation as a Major Risk Factor for Cancer: A Concept
of Doubtful Validity
Emmanuel Farber
Cancer Res 1995;55:3759-3762.
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