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Carcinogenesis: Are the toxicity models correct? Comments by Kenneth L. Campbell, Department of Biology, University of Massachusetts Boston The Traditional Carcinogenesis Model: The definitions given by Casarett & Doull (Pitot III & Dragan, Chapter 8: Chemical Carcinogenesis, In: Klaassen, Ed., Casarett & Doull’s Toxicology: The Basic Science of Poisons, 6th Ed., McGraw-Hill: New York, NY, 2001, 241-319) tend to rule out endogenous hormones as being classed as carcinogens unless they are exogenously administered. But what about endogenous overproduction of trophic or growth factors? Or, incidental exposures through food and the environment? The toxicology text provides a disappointingly naive discussion of endocrine systems given the similarities of toxicology, pharmacology, and endocrinology with respect to methods and many of the central concepts concerning mechanisms of action, chemical kinetics, clearance, and general physiological function. The current carcinogenesis model looks at three stages in the "natural history of neoplasia:" 1. Initiation (primary molecular lesion formation, adducts, mutation; reversible) 2. Promotion (enhanced ability to escape normal controls for removing adducts or mutations and to allow abnormal cell proliferation; may still be reversible) 3. Progression (overt cell transformation, nuclear instability coupled with loss of mitotic controls and metastatic behavior; irreversible) A chemical may play a role in the actual induction of mutation or the initial stages of neoplastic transformation in the first cell involved. It may play a role in preserving that cell and making certain it can continue to divide. Or, it may play a role in allowing the initial cell mass to invade other tissue and/or to metastasize to other sites. If the model is correct there should be examples of chemicals among the thousands examined that can be identified with each of these steps. Yet there are few, if any, that can unequivocally be assigned to initiation and progression. This would suggest there may be a problem with the specification or design of the current model. Or, it may simply be a reflection of our current ignorance about the mechanisms by which many of these chemicals exert their toxic effects. Why screen breast cancers for estrogen sensitivity if hormones are not directly involved in initiation of neoplastic growth as suggested by Pitot III & Dragan? Breast tumors are screened for the presence of estrogen receptors because estrogen acts through such receptors to promote expression of those genes that lead to cellular replication via mitosis. Estrogen is pro-mitotic in many of the tissues in which it normally acts. Thus, knowing if a tumor is sensitive to estrogen can provide a means to suppress tumor growth. Aromatase inhibitors can be given to suppress ovarian (if a pre-menopausal woman is involved) or peripheral production of estrogens. This will often slow the tumor growth or its production and response to paracrine growth factors like EGF, or TGF. In turn, this provides more opportunity to apply radiation, surgery, and/or directed chemotherapy agents to ablate the tumor. Obviously, if the tumor does not have estrogen receptors, it will not respond to such treatments. Likewise, testosterone or dihydrotestosterone are pro-mitotic in male secondary structures like the prostate. Here anti-androgens can be applied to good effect so screening could be used for some tumors of the prostate. (Normally slow progression of these growths and the lack of ready anatomic access to the prostate tends to make this a less frequently used approach.) Pitot III & Dragan point to the actions of growth hormone and other growth factors and suggest these may be considered chemical carcinogens. This is contrary to the definition of toxicants (toxic substances produced by anthropogenic actions or natural forces, e.g., fire) and really only fits the notion of toxins (toxic substances produced by biological systems) except that both definitions refer to substances administered or derived from exogenous sources. Certainly hormones are not exogenous. Their actions at the high levels characteristic of endocrinopathies may eventuate in neoplastic conditions. Whether they are truly the initiators of these neoplasias can probably be questioned (environmental factors, exogenous radiation, etc.). Model systems such as knockout or overexpression models do, however, suggest that hormones can, if not initiating cancers, at least act as sensitizing or predisposing agents. Such is probably the case for the elevation of dimethylbenz[a]anthracene (DMBA) tumor formation seen in rats expressing high levels of prolactin. Both estrogens and prolactin are mitogens in rat breast tissue. Their actions will increase the number of cells undergoing division in any given time. If DMBA is applied simultaneously, or subsequent to this action, the intercalating agent DMBA will have additional opportunities to disrupt the crucial machinery involved in DNA synthesis and repair associated with mitosis. That does not make estrogen or prolactin cocarcinogens, but it does mean that they will predispose responsive tissues to agents that interact with DNA. The same situation will also apply to dimethylnitrosourea application to prostate tissue simultaneous with or subsequent to promitotic androgens such as testosterone. In fact, it should apply in any situation where a hormone alone stimulates a tissue to increase mitotic activity. Note the dates of the references in Pitot III & Dragan’s Table 8-2 concerning the development of tumors subsequent to disruption of normal hormonal feedback cycles (publications from 1944, 1975, 1980, 1989, 1991, and 1994). Certainly there has been work done in these areas over the past decade that may be pertinent to these discussions. Hormones and their control circuits are natural, homeostatic mechanisms. They are only carcinogenic if the stimulation of cell division processes, especially mitosis, becomes disrupted due to high rates of division coupled with failures of checkpoints or apoptotic controls and immune surveillance that normally remove aberrant cells. We think of carcinogens as inducers of transformation/ mistakes/ mutations. Hormones don't do that, thus, they are probably best classed as promoters, or possibly supporters of progression (including suppression of apoptosis, stimulation of angiogenesis, and/or suppression of immune surveillance). Alternative Views of Carcinogenesis: The text authors Pitot III & Dragan also seem to hold a somewhat dated understanding of how hormones and genes play roles in neoplastic and cancer development and growth. I would definitely refer you to the publications of Drs. Robert Weinberg of the Whitehead Institute at MIT and Polly Matzinger of NIH with respect to critical factors involved in the processes of cellular transformation and immune surveillance associated with cellular transformation, respectively (see below). Weinberg, in a lecture to the Endocrine Society in Denver in 2001, mentioned at least four cellular features that had to be altered before a cell could undergo transformation from a normal to a cancerous cell. First, mutations or alterations had to occur in one or both the the cellular mitotic checkpoint proteins, pRb, and p53. Second, a change in expression of proteins involved in the apoptotic pathways had to occur so that this process was either not initiated or was actively blocked. Third, telomerase had to be expressed so that the cell could overcome the limitation on division normally encountered due to shortening of the telomeres in each round of cellular division. Normal differentiated cells express little or no telomerase. Transformed cells express significant levels. Finally, to actually form a tumor, the transformed cell has to avoid immune surveillance. The latter point is probably best addressed by Matzinger's work which posits that the immune system is not active as normally thought, but rather, reacts only to the products of cell death. Either released cytokines or chemicals that ultimately cause production of immunoattractants like leukotrienes or interleukins (or possibly released cytochrome c?). Note that the complex of steps required for expression of full-blown carcinogenesis means that the frequency of truncated events that fail to reach this level is probably considerable under normal circumstances. The elevation in this basal rate is what can be associated with carcinogenic toxicants. Review the description of proto-oncogenes, oncogenes, and oncogene products that occurs in an endocrinology or cell biology text. Note that proto-oncogenes are normal genes, they are not strictly associated with transformation. Oncogenes are normal genes that are inappropriately expressed with respect to developmental timing or level. They may be, but do not have to be, altered structurally. In fact, many are structurally normal, but are altered in genetic position or in their regulatory domains so that they are inappropriately expressed. Those that have been described often include elements of transmembrane signaling pathways associated with cellular growth and division. Note the proto-oncogenes or the oncogenes themselves may be quite neutral in cellular transformation; what is important is the inappropriate expression and subsequent actions of the oncogene products. If chemicals cause alterations in DNA synthesis or repair that result in mutations to proto-oncogenes or their regulatory regions, the result is the oncogenic expression of the altered protooncogene (now referred to as an oncogene). The only other route to this condition is a toxicant alteration of the expression of a particular proto-oncogene (or a set of such genes) so that it acts as an oncogene. This might be via a targeted mutation or a specific alteration in the biochemical pathways leading to expression (or suppression) of that particular gene product. Note that the above view of the integration of proto-oncogenes and oncogenes into cellular physiology seems to differ from the picture of the "foreign invader" provided by Pitot III & Dragan. It views cellular transformation as a natural process exacerbated by the presence of toxicants, not as a novel process imposed on the system by the presentation of a toxicant. Several pertinent files or articles are linked to these lecture notes: Tyler Jacks, Robert A. Weinberg, Cell-cycle control and its watchman, Nature 381: 643-644, 20 June 1996. Kathleen Collins, Tyler Jacks, Nikola P. Pavletich, The cell cycle and cancer, Proc. Natl. Acad. Sci. USA Vol. 94, pp. 2776–2778, April 1997 Ante S. Lundberg, Robert A. Weinberg, Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes, Mol Cell Biol, Vol. 18, No. 2:753761, February 1998. Terry L. Orr-Weaver, Robert A. Weinberg, A checkpoint on the road to cancer, Nature Vol 392:223-224, 19 March 1998. Tyler Jacks, Robert A. Weinberg, Cell Cycle: The Expanding Role of Cell Cycle Regulators, Science 15 May 1998: Vol. 280. no. 5366, pp. 1035 - 1036 DOI: 10.1126/science.280.5366.1035. Weinberg, Telomeres: Bumps on the road to immortality, Nature 396:23-24, 5 November 1998. Christopher M. Counter, William C. Hahn, Wenyi Wei, Stephanie Dickinson Caddle, Roderick L. Beijersbergen, Peter M. Lansdorp, John M. Sedivy, Robert A. Weinberg, Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization, Proc. Natl. Acad. Sci. USA, Vol. 95:14723–14728, December 1998. Jacqueline A. Lees, Robert A. Weinberg, Commentary: Tossing monkey wrenches into the clock: New ways of treating cancer, Proc. Natl. Acad. Sci. USA, Vol. 96:4221–4223, April 1999. Russell E. Vance, Cutting Edge Commentary: A Copernican Revolution? Doubts about the Danger Theory, The Journal of Immunology, 2000, 165: 1725–1728. Nevins, The Rb/E2F pathway and cancer, Human Molecular Genetics, 2001, Vol. 10, No. 7: 699703. William C. Hahn, M.D., PH.D., Robert A. Weinberg, PH.D., Rules for making human tumor cells, N Engl J Med, Vol. 347, No. 20, November 14, 2002 · www.nejm.org · 1593- 1603 + erratum Telomeres William C.Hahn, Robert A.Weinberg, Modelling the molecular circuitry of cancer, Nature Reviews | Cancer Volume 2 | May 2002 | 331 – 341. Polly Matzinger, The real function of the immune system or tolerance and the four D's (danger, death, destruction and distress), http://glamdring.ucsd.edu/others/aai/polly.html Polly Matzinger, Turned on by Danger, BBC TV Programme Notes, 2002. Ittai Ben-Porath, Robert A. Weinberg Review: The signals and pathways activating cellular senescence, The International Journal of Biochemistry & Cell Biology 37 (2005) 961–976. More on carcinogenesis stages and mechanisms (PowerPoint Slides).