Carcinogenesis events

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 ... 

O Exposure to ultraviolet radiation from the sun is recognized as one of the primary triggers for skin carcinogenesis. Based on their wavelengths, UV radiation is divided into three components UVA (320 00 nm), UVB (280-320 nm), and UVC (200-280 nm).15 UVB accounts for only 5% of the solar radiation that reaches the earth, but it is the primary carcinogenic component in the UV spectrum.15 The following sequence of events describes the process in which UV radiation causes skin cancer (1) UV radiation reaches the earth, and on the skin, it reaches the cells in the epidermal layer (i.e., squamous cells, basal cells, and melanocytes),16 (2) the UV radiation (specifically... 

Roy, H.K., Olusola, B.F., Clemens, D.L. et al. 2002. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23 201-305. 

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. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

The base substitutions are primarily transversions at G C base pairs and the available evidence suggests that these mutations are induced by apurinic sites which are generated as secondary consequences of the initial alkylation event. The significance of these results in the context of carcinogenesis is briefly considered. 

Random somatic mutation is thought to he a major event in carcinogenesis which may result from exposure to radiation,... 

Carcinogenesis involves a complex series of genetic and biochemical events that enable transformed cells to proliferate, metastasize, migrate to secondary sites, and, sometimes, acquire resistance to chemotherapy. In Sect. 25.4.1, we will discuss how caveolin-1 expression correlates with cancerous growth, a potential mechanism of chemotherapy drug resistance, and how caveolae may be particularly exploited for cancer therapeutic strategies. 

A 1954 pnblication in the British Journal of Cancer by Peter Armitage and Richard Doll" (whom we mentioned a few pages back) entitled The age distribntion of cancer and a multi-stage theory of carcinogenesis can be seen as a seminal event in the evolution of onr understanding of the way in which cancers develop. Although there have been a nnmber of snccessfnl modifications and refinements of the Armitage-Doll model in the 50 years since its publication, it is still seen as broadly correct. 

These above-mentioned studies quantifying bile acid reflux have been fundamental to allowing in vitro analysis of bile acid effects at physiological doses (Table 6.2). These in vitro studies have crucially, identified molecular mechanisms important in bile-driven carcinogenesis. These molecular events will undoubtedly be important in future years as drug-able targets and as biomarkers of cancer risk. Prior to bile acid quantification in the refluxate, there... 

Toxicological studies have suggested that the species specificity for induction of ovarian tumors (produced in mice but not rats) occurs because the blood level of the ovotoxic VCH metabolite VCH-1,2-epoxide is dramatically higher in VCH-treated female mice compared with rats. VCH has been shown to be metabolized by the liver of mice to the ovotoxic metabolite (VCH-1,2-epoxide), which circulates in blood and is delivered to the ovary, where it destroys small oocytes. This destruction of small oocytes is considered to be an early event in carcinogenesis. Species difference in epoxidation of VCH by hepatic micro-somes correlates well with the differences observed in the blood concentration of VCH-1,2-epoxide and VCH ovarian toxicity. Further in vitro studies have found that the rate of VCH epoxidation in humans by human hepatic microsomes was 13- and 2-fold lower than epoxidation by mouse and rat systems respec-tively. Therefore, if the rate of hepatic VCH epoxidation is the main factor that determines the ovotoxicity of VCH, rats may be a more appropriate animal model for humans. 

T. A. Gasiewicz. Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate. Carcinogenesis 1998 19(11) 2037-2042. 

Navarro, et al. Effect of olive oil on early and late events of colon carcinogenesis in rats modulation of arachi-donic acid metabolism and local prostaglandin E2 synthesis. Gut 2000 46(2) 191-199. 

It is not known how chemicals cause cancer. A fascinating aspect of the story is that many "carcinogenic" chemicals are in fact, not the culprits responsible for cancer induction. The metabolic processes of the body change the chemicals from relatively innocuous substances into reactive intermediates which in as yet unknown fashion, trigger the chain of events which finally result in tumor formation. In other words, chemical carcinogenesis is an effect of "failed" detoxification. 

Pai, S.B., Steele, V.E., and Nettesheim, P. (1983). Quantitation of early cellular events during neoplastic transformation of primary tracheal epithelial cell cultures, Carcinogenesis 4,369. 

---