Tumor Classification Should Be Based on Biology and Not Consensus: Re-Defining Tumors Based on Biology May Accelerate Progress, An Experience of Gastric Cancer

Malignant tumors are a consequence of genetic changes mainly occurring during cell division, sometimes with a congenital component. Therefore, accelerated cell divisions will necessarily predispose individuals, whether due to conditions of chronic cell destruction or hormonal overstimulation. It has been postulated that two genetic hits are necessary for the development of malignancy (Knudson). The correct view is probably that the number of genetic changes needed depends on the role the mutated genes have in proliferation and growth control. Hormones should accordingly be regarded as complete carcinogens. In this review based upon experience of gastric cancer where gastrin is central in the pathogenesis, it is argued that oxyntic atrophy—and not metaplasia as postulated by Correa—is the central precancer change in gastric mucosa. Moreover, the target cell of gastrin, the enterochromaffin-like (ECL) cell, is central in gastric carcinogenesis and most probably the cell of origin of gastric carcinomas of the diffuse type according to Lauren (a classification probable in accordance with biology). The distinction between adenocarcinomas and neuroendocrine carcinomas based upon a certain percentage of cancer cells with neuroendocrine differentiation is questioned. To make progress in the treatment of cancer, a correct classification system and knowledge of the pathogenesis are necessary.

Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis

We have reviewed some of the data that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. While it is clear that these substances induce phenotypic changes characteristic of those produced by known carcinogens, the precise mechanisms by which these effects are produced require much further study. In vitro, it would appear that phagocyte-generated oxidants could be complete carcinogens, ie, could cause both tumor initiation and promotion. In vivo, however, these substances appear usually to function as tumor promoters or cocarcinogens perhaps because of high levels of endogenous antioxidant defenses. This suggests that there may be even more reason to be optimistic about the potential for positive results in cancer chemoprevention trials in humans, and provides further rationale for the continuing interest in the use of antioxidants and anti- inflammatory drugs in current and future trials. For example, the Chemoprevention Branch of the National Cancer Institute is currently sponsoring seven extramural human efficacy intervention trials testing whether the antioxidant beta carotene can prevent cancer.

Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis

We have reviewed some of the data that link the reactive oxygen species produced by inflammatory phagocytes to cancer development. While it is clear that these substances induce phenotypic changes characteristic of those produced by known carcinogens, the precise mechanisms by which these effects are produced require much further study. In vitro, it would appear that phagocyte-generated oxidants could be complete carcinogens, ie, could cause both tumor initiation and promotion. In vivo, however, these substances appear usually to function as tumor promoters or cocarcinogens perhaps because of high levels of endogenous antioxidant defenses. This suggests that there may be even more reason to be optimistic about the potential for positive results in cancer chemoprevention trials in humans, and provides further rationale for the continuing interest in the use of antioxidants and anti- inflammatory drugs in current and future trials. For example, the Chemoprevention Branch of the National Cancer Institute is currently sponsoring seven extramural human efficacy intervention trials testing whether the antioxidant beta carotene can prevent cancer.

Structure and carcinogenicity of Dibenzo(c,g)carbazole derivatives

The carcinogenicity of several groups of carcinogens is evoked with particular reference to Dibenzo(c,g)carbazole derivatives. The activity of these derivatives is discussed with respect to their species and organ specificity. The enzymatic equipment is decisive as to whether the compounds formed can react with DNA or are simply detoxified and eliminated. All these carcinogens are complete carcinogens, i. e. they have the property of both initiation and promotion.

Implications for the Future: Regulation of Chemicals and Prevention of Cancer

Lifetime feeding studies, when positive for cancer induction, do not provide information to differentiate between primary and secondary mechanisms of cancer induction. So many factors can influence the ultimate risk of incurring cancer in animals or humans that the observation of an increased incidence of cancer in association with exposure to any particular test substance should not lead automatically to the inference that the substance is a carcinogen per se. An increased incidence of cancer can result not only from exposure to “complete” carcinogens, but also from critical exposures to the following factors: those that decrease biological resistance to other independently occurring cancer risk factors, those that cause toxic hyperplasia, or those that act as classical promoters. Both initiation and promotion are prerequisites to cancer induction. Initiation can result independently from the effects of viruses, radiation, chemical initiators, and aging. For example: endogenously-formed nitrosamines are capable of effecting initiation in hepatic cells. Many non-genotoxic hepatic so-called “carcinogens” appear to be “promoters” of cancer induction rather than complete carcinogens. Hepatic cancer induction can be enhanced by classical promotion phenomena, by toxic hyperplasia, or by selective pressures on cell replication created by hormones. Substantial and consistent exposure doses are required to invoke secondary mechanisms of enhancing cancer induction; these secondary events occur in dosage ranges associated with observable histopathologic effects and thus can be detected and measured. By using combinations of in vitro and in vivo techniques, no-adverse-effect dosage levels can be determined whereby the risks for enhancing cancer induction can be avoided.