Cell Proliferation As a Major Risk Factor for Cancer: a Concept of Doubtful Validity1

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 types of malignant neoplasia. Cell proliferation in cancer is accom panied not only by disturbances in the fine balance between cell gain An old idea, now being regenerated anew, focuses a major aspect of and cell loss (Table 1), leading to net growth, but also by two other risk assessment for cancer on cell proliferation (1-11). It is now being associated changes: invasion and metastasis. proposed that the presence of cell proliferation by itself or the stim Because of its pivotal role in cancer, and because of the distur ulation of cell proliferation Â¡na quiescent tissue or organ with low bances in its control in cancer, it is widely assumed that disturbed mitotic activity should be in and of themselves major concerns for control of cell proliferation is also the most important and critical cancer development in the particular tissue or organ. Also, the ability property of potential neoplastic cells or so-called "preneoplastic" or of an agent to induce cell proliferation in a target organ or tissue "precancerous" cells throughout the carcinogenic process. This ap would be considered to have predictive value as a valid index of the pears to be an almost universal misconception in studies on cancer. probable carcinogenicity of that agent. There is neither a rational hypothesis nor any accompanying concrete It is axiomatic that cell proliferation plays an important and even factual evidence for this concept in cancer development. In fact, as critical role in many steps in cancer development. As discussed briefly listed in Table 1, and as discussed previously (12), a highly controlled in a fairly recent article (12), cell proliferation, either of a limited balance between cell proliferation and cell loss is clearly in evidence degree (1 cell cycle) or of a more extended degree (12 or more cell during the inordinately long process of cancer development until the cycles), plays a key role in initiation, promotion or selection, and late appearance of unequivocal cancer with an upset Â¡nthis normal progression during cancer development in several organs and tissues balance. (Table 1). Of course, cell proliferation with altered control is the Where studied, cancer development in vivo and in vitro with dif prime property that is the first characteristic phenotypic feature of a ferent types of "genotoxic" agents requires a single round of cell malignant neoplastic cell population. proliferation to initiate the process (13-30). Although this dependence However, whether cell proliferation, per se, is a risk factor for the on one cycle of cell proliferation has been demonstrated in several long process of cancer development has not been demonstrated sci tissues and organs in vivo, such as in skin, colon, liver, and urinary entifically but remains in the realm of conjecture and speculation. No bladder, and in different cells in vitro, it is particularly clear-cut and one has yet described a system in which continual cell proliferation unequivocal in the liver for at least three reasons: (a) the hepatocyte can be induced or arrested under controlled conditions so that cell population in the adult is almost totally quiescent with respect to cell proliferation becomes the only or at least a major variable under study. proliferation; (b) cell proliferation can be readily induced or stimu Until this is done, cell proliferation as a risk factor must remain in the lated by several types of procedures, both regenerative and primary realm of unproven speculation. Of course, a single cycle of cell hyperplastic; and (c) several of the steps between the original hepa proliferation without carcinogen exposure, such as in the normal or tocyte exposed to the carcinogen and the ultimate appearance of control adult liver during liver regeneration, has not been shown or cancer are highly synchronized during much of the cellular evolution proven to be carcinogenic in many hundreds of studies reported over to malignancy but especially during the initiation and promotion- the past several decades. selection periods (31). This synchrony is of the greatest importance because the sequential step-by-step analysis of any multistep process, Theoretical Scientific Bases for Considering Cell Proliferation be it molecular, biochemical, genetic or biological, necessitates a as a Risk Factor synchronous system if precursor-product relationships are to be es tablished at each major step. This synchrony, together with a short In addition to the general importance of cell proliferation at all steps in cancer development, there appear to be two other major consider time frame (hours to days instead of many months) makes it feasible to analyze the varying roles of cell proliferation in select models of ations that underlay this speculation. These are: (a) importance of cell proliferation in initiation of cancer development with carcinogenic liver carcinogenesis (12, 31). Many different carcinogenic agents, including chemicals, radia agents, especially those that interact with DNA or the genome; and (/;) tions, and viruses, interact with the genome of target cells and gen importance of cell proliferation Â¡nthe genesis of mutations. erate a variety of mutations. The fixation of the genomic changes to Cell proliferation is the central and key phenotypic expression in all generate mutations often requires a round of cell proliferation. If it is assumed that such mutations play an important role in Received 2/10/95; accepted 6/28/95. The costs of publication of this article were defrayed in part by the payment of page initiating the carcinogenic process and in facilitating further progres charges. This article must therefore be hereby marked advertisement in accordance with sion, the round of cell proliferation is essential for the carcinogenic 18 U.S.C. Section 1734 solely to indicate this fact. 1The author's research discussed in this analysis was supported by research grants process with genotoxic agents. Because potential or actual mutagens from the National Cancer Institute. NIH. the Medical Research Council of Canada are widespread in all areas of the human environment, it is assumed (MT-5994), and the National Cancer Institute of Canada. that the rate-limiting step in the carcinogenic process is often cell 2 To whom requests for reprints should be addressed, at Department of Pathology. Anatomy, and Cell Biology. Jefferson Medical College, 1020 Locust Street. Philadelphia. proliferation, not exposure to an adequate level of a carcinogen, and PA 19107-6799. that cell proliferation per se thus becomes a risk factor, providing one 3759

Table 1 Cell prolifÃ©rationin chemical (genoloxici hepatocarcinogenesis Also, in the development of hepatocellular carcinoma in the rat with linn.Â¡non.single cycle initiation-promotion regimens, differential inhibition of cell prolifer Regenerative: effective ation, not cell proliferation, is a major mechanism for promotion (31). Hyperplastic: ineffective In addition, one of the promoters used commonly, phÃ©nobarbital,has Promotion: clonal proliferation (10-12 cycles) Regenerative: no cell loss, effective only very limited mitogenic activity for the liver (47, 48). After a brief Hyperplastic: cell loss (so-called "apoptosis") as well as cell proliferation, episode of cell proliferation, this agent is more of an inhibitor of cell ineffective proliferation than a mitogen. Visible evidence of promotion can be Progression: all hyperplaslic (seemingly autonomous cell proliferation) Precancer: cell loss (so-called "apoptosis") almost equal to cell proliferation, slow seen many weeks later. Also, with at least some nongenotoxic car growth cinogens, such as clofibrate, cell proliferation is seen only transitorily Cancer: loss of balance of cell loss and cell proliferation, growth and invasion during the first week or so and not subsequently during the very prolonged period of cancer development until focal proliferations (nodules, "adenomas") appear (49). speculates that the possible exposure to potential carcinogens (in the Another interesting example is the occurrence of epithelial cancers air, food, water, air pollutants etc.) is not often rate limiting (1-11). of the stomach in people of certain countries. It is now well docu This simple conjecture concerning how humans interact with the mented that atrophie gastritis, with low levels of cell proliferation, not environment is the major basis for the theory that cell proliferation is hyperplastic or hypertrophie gastritis, is a risk factor for the develop an important risk factor for cancer development. ment of cancer (50). Ward et al. (51) have critically reviewed a large body of data in Critique animals, in particular rodents and some in humans, and have con There are at least two serious criticisms of the conjecture that cell cluded that cell proliferation is not a major risk factor for cancer proliferation is a risk factor for cancer. These concern: (a) the lack of development in many instances. Very recently, Huff (52) has arrived association between cell proliferation and cancer occurrence in sev at a similar conclusion. eral organs and tissues; and (b) the common property of genotoxic Thus, in several common circumstances, there is no relationship chemical carcinogens as inhibitors of cell proliferation, rather than between the degrees of cell proliferation generally in an organ or stimulators, in several organs and tissues. tissue and cancer development. If anything, negative correlations Cell proliferation is not a risk factor for cancer in several situations between cell proliferation and cancer incidence, at least in some i/i vivo that readily come to mind (the skin in psoriasis, the normal instances, can be seen. A key characteristic of almost all examples of small intestine, the breast, the liver, and the stomach). cancer development in humans and animals is the focal nature of the Psoriasis is a chronic disease in which focal or regional prolifera few cells in any organ that do show increased cell proliferation in tion of the epidermis is a prominent feature (32-38). This great comparison to the vast number of surrounding cells, not apparently increase in cell proliferation is of long duration, often lasting decades. directly involved in carcinogenesis, that often show inhibition of cell Yet, cancer development in psoriatic lesions is uncommon or rare proliferation. (34, 35, 38, 39), despite the fact that the skin in humans, as in some The animal and human data will have to be much more convincing species of animals (e.g., mouse), is a common target organ for a if the property of inducing cell proliferation is to be considered virtually universal carcinogen (UV light) and for many chemical seriously as an important risk factor of carcinogenicity (e.g., Refs. carcinogens, and is one of the commonest sites for the development of 53-55). epithelial cancers of several types. It is now well documented that many if not all genotoxic carcino The normal small intestine is the site of vigorous cell proliferation. gens are inhibitors of DNA synthesis and/or cell proliferation ("mi- In fact, Leblond (40) has estimated that the total production of cells by toinhibition") in several organs or tissues. Carbon tetrachloride, the digestive tract to replace the normal cell loss over a period of ethionine, 2-acetylaminofluorene, 4-dimethylaminoazobenzene and 20-30 days is equal to the total number of cells in the body. The small derivatives, thioacetamide, aflatoxin B,, 3-methylcholanthrene, ben- intestine is a major contributor. Despite this enormous cell prolifera zo(fl)pyrene, dimethylnitrosamine, diethylnitrosamine, pyrrolizidine tion, epithelial cancer in the small intestine, especially the jejunum alkaloids, 7,12-dimethyl-benzo(a)anthracene, urethane, and /V-meth- and ileum, is extremely rare and is among the least common types of yl-A'-nitrosourea are among the many chemical carcinogens that have cancer by far (41, 42). This is in contrast to the segments of the been shown to inhibit cell proliferation and/or DNA synthesis (see digestive tract immediately below (colon) and above (stomach), sites Refs. 56 and 57 for list of references). where malignant disease is very common. Unfortunately, the expla These data are consistent with the hypothesis proposed in 1938 by nation that is offered as a possible basis for this unusual distribution Haddow (58). On the basis of his research on the inhibition of cell of cancer evidence is based on a failure to appreciate (43, 44) that the growth of normal and cancer cells with some pure polycyclic aromatic changes in the intestinal epithelial cells in the small and large intestine hydrocarbons that were being identified and synthesized at the Ches 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 ter Beatty Research Institute, Haddow suggested that inhibition of cell secondary to previous changes in the underlying lymphoid cells proliferation could be an early effect of carcinogens and that, in such (45, 46). The latter, of course, may well vary considerably in different an environment, resistant cells may arise and be encouraged to pro segments of the intestine. liferate selectively relative to the surrounding cells. This hypothesis The breasts are common sites for the development of epithelial was further analyzed in many subsequent reports (e.g., 56, 57, 59, 60). cancer in women. The epidemiological data on women indicate This differential between a focal population and the surrounding cells clearly that the disease is more common in women who have never is also seen when rats are exposed continuously for many weeks to had children than in women who have (41, 42). This is also true in two quite different carcinogens, 2-acetylaminofluorene and ethionine the mouse models where pregnancy is protective. Pregnancy is (61). Inhibition of cell proliferation after an initial brief stimulation of associated with a vigorous cell proliferation of all epithelial cells cell proliferation is also seen with some nongenotoxic carcinogens, in the breast. such as clofibrate (49, 62). 3760

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3762

Emmanuel Farber

Cancer Res 1995;55:3759-3762.

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