Epidemiology Of Human Cancer Research Articles

Differential carcinogenicity of cigarette smoke in mice exposed either transplacentally, early in life or in adulthood

Cigarette smoke (CS) plays a dominant role in the epidemiology of human cancer. However, it is difficult to reproduce its carcinogenicity in laboratory animals. Recently, we showed that CS becomes a potent carcinogen in mice when exposure starts soon after birth. In our study, we comparatively evaluated the carcinogenic response to mainstream CS in mice at different ages. Neonatal mice were exposed daily for 4 months to CS, starting within 12 hr after birth, and sacrificed at 8 months. Adult mice were exposed for the same time period (3-7 months) and sacrificed at 11 months. Other mice were exposed transplacentally or both transplacentally and early in life. A total of 351 neonatal mice and 80 adult Swiss H mice were used. With varying intensity depending on age, CS induced pulmonary emphysema, bronchial and alveolar epithelial hyperplasia, blood vessel proliferation and hemangiomas and microadenomas in lung as well as parenchymal degeneration of liver. Histopathological alterations of kidney were only observed in mice exposed to CS early in life. Lung adenomas and malignant tumors of various histopathological nature were detected in neonatally exposed mice but not in adults. Transplacental CS induced the formation of lung adenomas in the offspring 8 months after birth. Previous exposure during pregnancy attenuated CS-related alveolar epithelial hyperplasia induced after birth. In conclusion, the carcinogenic response to CS varies depending on the developmental stage. The early postnatal life and the prenatal life are particularly at risk for the later development of CS-related tumors.

Cancer Biology and Hormesis: Commentary

The observation of biphasic dose-response relationships following exposure to pharmacological and toxicological agents has been well documented. In this review Dr. Calabrese, using published data on human tumor cell lines treated with a variety of agents has provided additional support for the demonstration of hormesis in the cancer process. While this review has restricted the examination to human tumor cell lines, this limitation dose not take away from the value of the treatise and helps to point out the need for further analysis of the biphasic does response in other cancer models including in vivo carcinogenesis studies and human cancer epidemiology. This issue is further enhanced when the potential mechanisms for hormetic responses in the cancer cells are discussed, since the same mechanisms participate in the carcinogenesis process. Overall, this review provides an excellent opening examination into the definition of biphasic dose-response effects of toxic and pharmacological agents in cancer cells.

Angiogenesis in transgenic models of multistep angiogenesis.

The histopathology and the epidemiology of human cancers, as well as studies of animal models of tumorigenesis, have led to a widely accepted notion that multiple genetic and epigenetic changes have to accumulate for progression to malignancy. Formation of new blood vessels (tumor angiogenesis) has been recognized, in addition to proliferative capabilities and ability to down-modulate cell death (apoptosis), as essential for the progressive growth and expansion of solid tumors. Mice overexpressing activated forms of oncogenes or carrying targeted mutations in tumor suppressor genes have proven extremely useful for linking the function of these genes with specific tumor features such as continuous proliferation, escape from apoptosis, invasion and neo-angiogenesis. The interbreeding of these mice allows for studying the extent of cooperativity between different genetic lesions in disease progression, leading to a greater understanding of multi-stage nature of tumorigenesis.

Angiogenesis in transgenic models of multistep carcinogenesis.

The histopathology and the epidemiology of human cancers, as well as studies of animal models of tumorigenesis, have led to a widely accepted notion that multiple genetic and epigenetic changes have to accumulate for progression to malignancy. Formation of new blood vessels (tumor angiogenesis) has been recognized, in addition to proliferative capabilities and to the ability to down-modulate cell death (apoptosis), as essential for the progressive growth and expansion of solid tumors beyond microscopic sizes of about 1-2 mm in diameter. Mice overexpressing activated forms of oncogenes or carrying targeted mutations in tumor suppressor genes have proven extremely useful for to linking the function of these genes with specific tumor processes; the interbreeding of these mice let us study the extent of cooperativity between different genetic lesions in disease progression, leading to a greater understanding of multi-stage nature of tumorigenesis.

Dose-response relationships in chemical carcinogenesis reflect differences in individual susceptibility. Consequences for cancer risk assessment, extrapolation, and prevention.

The shape of the dose-cancer incidence curve observed in an animal bioassay for carcinogenicity of a chemical is the result of a superposition of various mechanisms contributing to the process of carcinogenesis. For genotoxic carcinogens, for instance, a sublinear (convex; up-bent) shape could be the result of a saturation of DNA repair or of a higher rate of cell turnover associated with high-dose cytotoxicity and regenerative hyperplasia. In human cancer epidemiology, the situation is more complex. The human population is very heterogeneous with respect to both genetic and life-style factors that modulate the process of tumor formation. Therefore, individuals are expected to show widely variable susceptibility to carcinogenic factors, and the dose-response curve is in fact a reflection of the tolerance distribution. Each modulating factor divides the population up into subpopulations of different susceptibility so that nonlinearities that could be present in a homogeneous population are flattened out. A linear extrapolation of a human cancer risk to low dose might therefore be appropriate under certain conditions even if the dose-response curve in animals has a strongly sigmoidal shape. For cancer prevention, the investigation of susceptibility factors is expected to be of great value. The elimination of concurrent risk factors in high-risk subpopulations or individuals might be more effective than a minor general reduction of a tolerable exposure level.

Diet and carcinogenesis.

In summary there is a wealth of information on dietary and nutritional effects on carcinogenesis in laboratory rodents. Experimental studies based on epidemiological evidence, earlier experimental studies and known or predicted cellular, biochemical and molecular effects of nutrients have produced clear evidence that carcinogenesis in laboratory rodents is influenced by dietary intake of calories, fat, lipotropes (choline, methionine), vitamin A and related retinoids, Se, calcium, zinc, fiber, ethanol and a large number of non-nutrient components of foods. For these substances or groups of substances mechanistic hypotheses supported by experimental data and are leading to further research. The information provided will contribute to understanding of basic processes in carcinogenesis as well as of the specific interactions studied, and should contribute to significant advances in preventive medicine. Restriction of caloric intake of rodents by amounts > 10% over a significant portion of their lifetime reduces tumorigenesis. That level of restriction reduces the rate of growth and maturation, and most experiments in this area employ greater restrictions that virtually abolish growth from a young age. Therefore, the observations are of interest in mechanistic studies, but their applicability to preventive medicine requires better definition of the degree and duration of restriction required for a significant effect and the age at which it must be imposed. Restriction of total fat intake and modifications to increase the intake of omega-3 fats have a reasonably consistent effect on tumorigenesis in rodents but a much less consistently demonstrable effect in humans. Again, the observations in rodents are providing a major stimulus to mechanistic studies. The lipotropes are extremely valuable as tools for investigating mechanisms of carcinogenesis in rodents. Their importance in the epidemiology of human cancer has yet to be demonstrated clearly and is a subject of research at present. The naturally occurring vitamins and minerals, as well as fiber, derive their importance in this context from investigations to explain the consistent epidemiological demonstrations of reduction of tumor risk with increased consumption of fruits and vegetables. The activity of the isolated nutrients as anticarcinogens in rodents has generally not matched the activity expected from epidemiological studies. The anticarcinogenic activity of many of the non-nutrient components of fruits and vegetables is remarkable in particular models, however, as is the activity of natural and synthetic retinoids. At present the results must be interpreted to indicate an important effect of combinations of the whole foods with identification of particular nutrients or non-nutrients in specific cases.(ABSTRACT TRUNCATED AT 400 WORDS)

A role for dietary lipids and antioxidants in the activation of carcinogens

Thw ways in which dietary polyunsaturated fats and antioxidants affect the balance between activation and detoxification of environmental precarcinogens is discussed, with particular reference to the polycyclic aromatic hydrocarbon benzo(a)pyrene. The structure and composition of membranes and their susceptibility to peroxidation is dependent on the polyunsaturated fatty acid (PUFA) content of the cell and its antioxidant status, both of which are determined to a large degree by dietary intake of these compounds. An increase in the PUFA content of membranes stimulates the oxidation of precarcinogens to reactive intermediates by affecting the configuration and induction of membrane-bound enzymes (e.g., the mixed-function oxidase system and epoxide hydratase); providing increased availability of substrates (hydroperoxides) for peroxidases that cooxidise carcinogens (e.g., prostaglandin synthetase and P-450 peroxidase); and increasing the likelihood of direct activation reactions between peroxyl radicals and precarcinogens. Antioxidants, on the other hand, protect against lipid peroxidation, scavenge oxygen-derived free radicals and reactive carcinogenic species. In addition some synthetic antioxidants exert specific effects on enzymes, which results in increased detoxification and reduced rates of activation. The balance between dietary polyunsaturated fats, antioxidants and the initiation of carcinogenesis is discussed in relation to animal models of chemical carcinogensis and the epidemiology of human cancer.

Cancer Epidemiology: Shortcomings and Possibilities

The development of the concepts of initiators and promoters in carcinogenesis necessitates deliberations of evidence from human cancer epidemiology. Recent arguments in favor of mortality data as a more reliable indicator of trends in cancer incidence than morbidity data collected from cancer registries are disputed. Inconsistency in the use of data is pointed out. Comparisons of data from cancer registration in Denmark with those from Connecticut and upstate New York show such congruity that it is impossible to accept suggestions of systematic bias of significance without direct evidence to that effect. Since accurate information on periods of exposure and on the onset of disease is fundamental to considerations of initiators and promoters the following proposals are made. Payrolls or similar data should be kept safe for 40 years for occupations where exposure to carcinogens may be suspected. Experience on latent periods from the last 100 years should be systematically reassured. Death certificates showing a diagnosis of malignant neoplasia should always state the histological diagnosis if any.

Cancer epidemiology: shortcomings and possibilities.

The development of the concepts of initiators and promoters in carcinogenesis necessitates deliberations of evidence from human cancer epidemiology. Recent arguments in favor of mortality data as a more reliable indicator of trends in cancer incidence than morbidity data collected from cancer registries are disputed. Inconsistency in the use of data is pointed out. Comparisons of data from cancer registration in Denmark with those from Connecticut and upstate New York show such congruity that it is impossible to accept suggestions of systematic bias of significance without direct evidence to that effect. Since accurate information on periods of exposure and on the onset of disease is fundamental to considerations of initiators and promoters the following proposals are made. Payrolls or similar data should be kept safe for 40 years for occupations where exposure to carcinogens may be suspected. Experience on latent periods from the last 100 years should be systematically reassured. Death certificates showing a diagnosis of malignant neoplasia should always state the histological diagnosis if any.