Carcinogenesis, stages

Figure 5.4. Stages of carcinogenesis. Stages have necessary biochemical and cellular changes that are either directly or indirectly produced by the carcinogen.

The simplest experimental model of carcinogenesis is the three-stage model (Pitot and Dragan, 1994) consisting of ... 

As we have seen, carcinogenesis is a prolonged multi-stage process which usually occurs over many years. Because of its complexity there are, in principle, many critical steps at which food-related substances or metabolic processes may interact with the sequence of events so as to accelerate, delay or even reverse it. Diet-related anti-carcinogenesis can usefully be classified into ... 

OGAWA K, HIROSE M, SUGIURA S, CUI L, IMAIDA K, OGISO T and SHIRAI T (2001) Dose-dependent promotion by phenylethyl isothiocyanate, a known chemopreventer, of two-stage rat urinary bladder and liver carcinogenesis , Nutr Cancer, 40 134-9. 

Reiners, J.J., Hale, M.A. and Cantu, A.R. (1988). Distribution of catalase and its modulation by 12-O-tetradecanoylphorbol-13-acetate in murine dermis and subpopulations of keratinocytes differing in their stages of differentiation. Carcinogenesis 9, 1259-1263. 

Gerster, H. 1995. Carotene, vitamin E and vitamin C in different stages of experimental carcinogenesis. EurJ Clin Nutr 49 155-168. 

Ponnamperuma, R.M., Shimizu, Y., Kirchhof, S.M., and De Luca, L.M. 2000. Beta-carotene fails to act as a tumor promoter, induces RAR expression, and prevents carcinoma formation in a two-stage model of skin carcinogenesis in male Senear mice. Nutr Cancer 37 82-88. 

Compared to animal assays, CTA is faster and cheaper. In vitro CTAs have been shown to involve a multistage process that closely resembles some stages of in vivo carcinogenesis and have the potential to detect both genotoxic and non-genotoxic carcinogens. 

CTAs are possible in vitro alternatives to the standard approach for the assessment of carcinogenicity (the 2-year bioassay in rodents), which have been shown to be a multistage process able to model the most important stages of in vivo carcinogenesis [50]. CTAs are faster and more economic than in vivo assay and they could be a valid and useful screening tool for chemicals. 

Carcinogenesis develops in three stages initiation, promotion, and progression. Chem-ical substances can act at the initiation stage or at the promotion stage. Moreover, some chemicals have both initiating and promoting activities. 

Figure 9.5 Karyotypic changes during initiation, promotion, and progression stages of carcinogenesis.

In contrast, promotion is reversible to some extent, and it is only effective following, not preceding, the initiating events. These discoveries suggest that only the initiation stage of carcinogenesis has an absolute requirement for the chemical carcinogen. 

Areas in which additional information is still needed relates to the role and relative importance of different adducts and the mechanisms by which they initiate cells. General principles are developing which will allow better predictions to be made at each of the stages of chemical carcinogenesis outlined in Table I. The ultimate goal therefore, would be, by a combined analysis of all these steps, to predict accurately the carcinogenicity of newly discovered or untested PAH derivatives. 

---