Epigenetic Mechanisms of Chemical Carcinogenesis: Commentary

R. Julian Preston, Ph.D.

Environmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711

Tel: (919)-541-0276

Fax: (919)-541-0694

E-mail: preston.julian@epa.gov

The article by Klaunig et al. is a comprehensive review of the general principles underlying the induction of tumors by epigenetic mechanisms. The review describes the roles of cell proliferation, loss of apoptotic function, gap junctional intercellular communication, P450 induction, oxidative stress, and altered gene expression in carcinogenesis. Further, it places these processes in the context of the dose response relationship for "nongenotoxic" chemical carcinogenesis. Thus, it leads the reader through the cancer paradigm of induction, promotion and progression where the drivers of the process are chemicals that do not directly interact with DNA.

I would like to consider this as the jumping off point for entry into a new and different approach for considering the framework for the production of cancer as elegantly reviewed and conceptualized in a recent review by Hanahan and Weinberg1. In the terms described by these authors, the review by Klaunig et al., would be considered to present the reductionist view of cancer as opposed to the heterotypic cell biology view of cancer. It is proposed that, although considerable progress has been made based upon the former view, the way forward is through the latter approach. In the heterotypic cell biology view of cancer, tumors are regarded as "complex tissues in which mutant cancer cells have conscripted and subverted normal cell types to serve as active collaborators in their neoplastic agenda". Such a model allows for the complex biology of the total cell to be taken into account when seeking perturbations as a result of an exposure to a chemical carcinogen, for example, be it genotoxic or epigenetic.

The review by Klaunig et al. is set in the context of the multistage model of carcinogenesis leading along the pathway from a normal cell to a metastatic tumor. This model has progressed from that originally described by Foulds2 to that developed by Kinzler and Vogelstein3 for colon cancer, in which specific phenotypic steps are linked to genotypic alterations. This latter version of the multistage model can be considered as representing an idealized template that is perhaps relevant for some tumors and for some proportion of cells in any one tumor, appreciating the clonal nature of tumors. Hanahan and Weinberg1 present a different kind of template to help explain the wide range of tumor types and the wide range of genotypes among any one tumor type. It is this type of template that is extremely useful for viewing the mechanisms of carcinogenesis by epigenetic chemicals. The aim of the model is to explain further how cells can overcome their inherent ability to protect against transformation. The six essential alterations or acquired capabilities presented in the Hanahan and Weinberg model are: self-sufficiency in growth signals (e.g., activate H-ras oncogene); insensitivity to anti-growth signals (e.g., lose retinoblastoma suppressor); evading apoptosis (e.g. produce IGF survival factors); limitless replicative potential (e.g. turn on telomerase); sustained angiogenesis (e.g., produce VEGF inducer); tissue invasion and metastasis (e.g., inactivate E-cadherin). As can be seen, it is readily possible to view the various cellular events discussed by Klaunig et al. as being induced or altered by epigenetic carcinogens within the framework of the Hanahan and Weinberg model. The order of these acquired capabilities can vary among and within tumor types, and the impact of a particular change can be quite variable depending upon, for example, the cell type or the timing of the production of the alteration along the pathway.

An additional hallmark of cancer is the development of genomic instability, whereby tumor cells at some stage during their development, quite possibly early on, exhibit a broad range of karyotypic abnormalities (chromosomal structural and numerical alterations) along with gene mutations. The level of this instability is clearly shown by the study of Stoler et al.4, who showed that colon carcinoma cells contained on the order of 11,000 genomic alterations. In addition, colorectal premalignant polyps early in the tumor progression pathway contained a similar number of alterations, supporting the view of genomic instability being an early event. This high level of genomic instability needs to be put in the context of the rather straightforward model of Kinzler and Vogelstein3 with its 5 steps from a normal cell to a malignant one. It is clear that genomic instability is the driver of the process be it some tumor-specific number of steps or a compilation from the set of six acquired capabilities.

Cahill et al.5, have addressed this dilemma in their discussion of the potential role of a "darwinian selection" in tumor development. The general model is that natural selection is the driving force in cellular evolution during tumor progression. From the wide range of genotypic alterations produced by genomic instability specific phenotypes are selected that confer a growth advantage to the mutant cell over the normal cell. The result is progression along a defined (but variable) pathway to tumorigenesis, with the resulting tumor being a heterogeneous population.

In the context of the review by Klaunig et al., it is relevant to extend the concept of multistage carcinogenesis to include genomic instability. This inclusion is regardless of whether the carcinogen involved is mutagenic or epigenetic. Any discussion of mechanism of carcinogenesis has to include the development of mutations since cancer is a genetic disease. In these terms the distinction between mutagenic and epigenetic becomes somewhat moot.

The impact of the acquired capability model of Hanahan and Weinberg1 and the development of rampant genomic instability, from what could be a single mutation in a caretaker gene, on the shape of dose response curves will be considerable. It is prudent to begin to consider all tumor dose response curves as being complex irrespective of whether a carcinogen is mutagenic or epigenetic. This is indeed an exciting time for research into carcinogenesis in general, and chemical carcinogenesis in particular. The review by Klaunig et al. sets the stage and I trust that my contribution helps point the way forward.


1. Hanahan D, Weinberg RA. The hallmark of cancer. Cell 2000: 100:57-70.

2. Foulds L. The Experimental Study of Tumor Progression, Volumes I-III. Academic Press: London, 1954

3. Kinzler KW and Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996:87:159-170.

4. Stoler DL, Chen N, Basik M, Kahlenberg MS, Rodriquez-Bigas MA, Petrelli NJ, and Anderson GR. The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci 1999:96:15121-26.

5. Cahill DP, Kinzler KW, Vogelstein B, and Lengauer C. Genetic instability and darwinian selection in tumors. Trend Genet 1999:15:M57-M61.