Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.

The sequential analysis of cancer development.

Mutagenic and carcinogenic N-nitroso compounds: possible environmental hazards.

Publisher Summary This chapter discusses some studies on the interaction of various compounds with cellular DNA and the biochemical and biological consequences of these reactions in a variety of cell systems and it focuses attention on DNA as the principal target for a number of chemotherapeutically useful cytotoxic agents and for numerous known carcinogens. The chapter further discusses some observations establishing that some DNA reactions are recognized and modified by various enzyme systems. These DNA repair processes clearly protect cells from lethal effects of DNA reactions in both bacterial and mammalian cells. Decreased sensitivity of sublines of cells in culture have been shown in some instances to be related either to their increased capacity for excision repair of damage to their DNA or to their greater capacity to carry out postreplication DNA repair. However, it is by no means established, although quite likely, that clinical resistance to cytotoxic agents in cancer chemotherapy is similarly characterized by the emergence of, or conversion of a tumor cell to, a cell with altered DNA repair capacity that confers decreased sensitivity to cytotoxic agents as compared with that of the original tumor cell.

The Repair of DNA Modified by Cytotoxic, Mutagenic, and Carcinogenic Chemicals

The concept that cell replication plays an essential role in the initiation of liver cell cancer is suggested by several lines of evidence. A single treatment of an adult animal with a hepatocarcinogen rarely induces liver cell cancer; the rate of cell replication in adult liver is very low. However, a single treatment does induce liver cell cancer in situations where the rate of cell replication is high, as in newborn animals, or in adult animals in which restorative hyperplasia of the liver has been induced by partial hepatectomy or by treatment with certain hepatotoxins. To produce liver cell cancer in the absence of an independent stimulus for mitosis, chronic administration of the carcinogen is usually necessary. This chronic administration can lead to progressive liver cell damage and hence to restorative hyperplasia, so that the carcinogen is in fact injuring cells which are replicating.

The explanation of the increased sensitivity of replicating cells is by no means certain, and may vary in different situations. However, there is evidence in a number of cases that cell replication alters neither the metabolism of the carcinogen, nor the nature, extent or persistence of the binding of the activated carcinogen to macromolecules. For cell replication, however, there must be replication of DNA, at least some of which has been damaged by the carcinogen. Thus the initiation of the carcinogenic process may result from the replication of DNA which takes place before the damage has been repaired by DNA repair systems of the cell. This aberrant replication may be essential to ‘fix’ a change in DNA, such as mispairing of bases at replication. Such mispairing may convert the transitory occurrence of abnormal bases formed by the reaction of the carcinogen into a stable inheritable form such as a change in base sequence. It is possible that an informational change of this kind in the genetic material could be an essential event in the initiation of cancer.

Chapter 8 – CELL PROLIFERATION AND EXPERIMENTAL LIVER CANCER

The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated or virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury specific intracellular processes are initiated to maintain the liver integrity. Inflammatory cytokines including tumour necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes as they can activate different cellular response such as proliferation, survival and death. TNFα induces specific signalling pathways in hepatocytes leading to the activation of either pro-survival mediators or effectors of cell death. While the activation of transcription factor NF-κB promotes survival, the induction of c-Jun N-terminal kinases (JNKs) and caspases represent the strategic effectors of cell death in the TNFα-mediated signalling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity, suggesting that NF-κB plays a protective activity against JNK-induced hepatocyte death. The identification of the mechanisms regulating the interplay between the NF-κB and JNK pathways are required to identify novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.

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Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.

Rats were given a single dose of dimethylnitrosamine (DMN, 20 mg/kg body weight) alone or 42 or 60 hours after a non-lethal hepatotoxic dose of carbon tetrachloride (CC14) and killed 12 months later. DMN alone produced no tumours in the kidney and a few in the liver, but when given 42 hours after CC14, tumours formed in the kidneys and the number in the liver was increased. When given after 60 hours, the incidence of kidney tumours was less but that of liver tumours was further increased. A larger dose of DMN (40 mg/kg) was tolerated 42 hours after CC14 and enhanced the number of kidney and liver tumours, the latter apparently due to an increased proportion of cholangiomata. Numerous small focal proliferations of atypical liver cells and of bile duct epithelium were observed after treatment with DMN. The incidence of these lesions in the different experimental treatments varied in a similar manner to the liver tumours.

Terence A Lawson

Papers

Increased carcinogenic action of dimethylnitrosamine after prior administration of carbon tetrachloride.