Role of Viruses in the Causation of Human Cancer

To prove a causal relationship between a putative cancer-causing virus and human cancer is not asimple task. Such proof relies on evidence that is to a fair extent circumstantial. This evidence includes(1) epidemiological data showing a correlation between living in an area of endemic viral infection and a type of cancer; (2) serological evidence of antibody titers to viral antigens in patients with a given cancer type; (3) evidence for insertion of viral DNA into a cancer-bearing host’s cell genome; (4) evidence for a consistent chromosomal translocation, particularly those...
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VIRAL CARCINOGENESIS

It has long been suspected that various forms of cancer, particularly certain lymphomas andleukemias, are caused or at least ‘‘co-caused’’ by transmissible viruses. This theory has had its upsand downs during the first half of this century, and it was not generally accepted until the 1950sthat viruses can cause malignant tumors in animals. The known carcinogenic effects of certainchemicals, irradiation, chronic irritation, and hormones did not fit with the idea of an infectiousorigin of cancer. In early experiments, the basic assay to determine whether cancer couldbe induced...
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DNA REPAIR MECHANISMS

Not all interactions of chemicals and irradiation with DNA produce mutations. In fact, all cellshave efficient repair mechanisms that repair such lesions. DNA repair mechanisms include sets ofenzymes that survey DNA for specific kinds of damage, remove the altered portion ofDNA, andthen restore the correct nucleotide sequence. The important role of DNA repair in humancancer has been established by the finding that a number of inherited defects in DNA repair systemspredispose individuals to getting cancer. These diseases include xeroderma pigmentosum,ataxia telangiectasia,...
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MULTIPLE MUTATIONS IN CANCER

In most cases, it takes years for a full-blown invasive, metastatic cancer to develop from asmall clone of initiated cells. This process might take 20 years or more, during which time aninitiated clone of cells undergoes clonal expansion via multiple cell doublings. As these clonesexpand, various cells in the population accumulate multiple genetic alterations, some of whichfacilitate dysregulated cell proliferation and some of which lead to cell death. These geneticalterations can include point mutations, chromosomal translocations, gene deletions, geneamplifications, loss...
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GENETIC SUSCEPTIBILITY AND CANCER

As was noted above, there are a number of inherited cancer susceptibility gene mutations,such as xeroderma pigmentosum, Fanconi’s anemia, and ataxia telangiectasia. These types ofinherited defects that lead to cancer are generally caused by a deficiency in DNA repair pathways.Almost certainly we have only scratched the surface of inherited cancer susceptibilitygenes that make an individual more prone to developing cancer. Other susceptibility genesmay include alterations in the metabolic enzymes that metabolize drugs and environmentaltoxins, polymorphisms in genes that...
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Ultraviolet Radiation

Ultraviolet radiation–induced lesions, generated by UV-B (280–320nm wavelength) or UV-A(320–400nm wavelength), result from DNA damage, which is converted to mutations duringcellular repair processes. UB-B and UV-A generate different types of DNA damage and DNArepair mechanisms (reviewed in Reference 113). Irradiation with UV-B produces cyclobutanepyrimidine dimers that are repaired by nucleotide excision repair. If left unrepaired,C?T and CC?TT base transitions occur. UVA- induced DNA damage produces mostly oxidativelesions via photosensitization mechanisms and is repaired...
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Ionizing Radiation

The history of radiation carcinogenesis goesback a long way.The harmful effects of X-rays were observedsoon after their discovery in 1895 by W. K. Ro¨ ntgen. The first observed effects were acute, such as reddening and blistering of the skin within hours or days after exposure. By 1902, it became apparent that cancer was one of the possible delayed effects of X-ray exposure. These cancers, which included  leukemia, skin cancers, lymphomas, and brain tumors, were usually seen in radiologists only after long-term exposure before adequate safety measures were adopted,...
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IRRADIATION CARCINOGENESIS

A number of the points made about chemical carcinogenesis are also true for radiation-inducedcarcinogenesis. Both X-rays and ultraviolet (UV) radiation, for example, produce damage to DNA.As with chemical carcinogens, this damage induces DNA repair processes, some of which areerror prone and may lead to mutations. The developmentofmalignanttransformationinculturedcells after irradiation requires cell proliferation to ‘‘fix’’ the initial damage into a heritable change andthen to allow clonal proliferation and expression of the typical transformed phenotype.105 Fixationappears...
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Experimental Models for the Study of Carcinogenesis

A number of models for the study of carcinogenesis have been developed over the years. Historically, two of the most useful ones have been the initiation-promotion model of mouse skin carcinogenesis (the ‘‘skin-painting’’ model) and the induction of liver cancers in rats. The classic model of carcinogenesis is the single application of an initiating agent such as a polycyclic aromatic hydrocarbon followed by thecontinuous application of a promoting agent like TPA to the backs of shaved mice. Much of what we know about tumor initiation, promotion, and progression has come...
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Mechanisms of Tumor-Promoting Agents

The terms tumor promotion, tumor progression, and multistage carcinogenesis are overlapping and somewhat redundant. Some people use these terms interchangeably and some use them to define discreet steps in the carcinogenesis process. Mechanistically, tumor promotion and progression are a continuum, even though they appear to be ‘‘multistage.’’ Promotion involves a clonal expansion (proliferative phase), and progression usually refers to the genetic alteration phase. But as was noted above, the genes involved in these steps are overlapping or similar. Nevertheless, studies...
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Central Dogma of Tumor Progression

The standard concept of how cancer starts is that malignant tumors arise from a single cell transformed by a chemical carcinogen, oncogenic virus, radiation damage, endogenous genetic damage caused by oxidative insult to DNA, or any of a host of other potential ways (e.g., chronic infections with a bacteria such as H. pylori or with a parasite such as schistosomiasis, or hormonal imbalance). Once the initiated cell starts to undergo clonal expansion, it undergoes multiple genetic changes, due to genetic instability,leading to an invasive metastatic cancer. This progression...
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Mechanisms of Tumor Promotion and Progression

Tumor-initiating agents most likely act by interacting with DNA to induce mutations, gene rearrangements, or gene amplification events that produce a genotypically altered cell. What happens next is that the initiated cells undergo a clonal expansion under the influence of promoting agents that act as mitogens for the transformed cell type. As will be discussed later, these promoting actions appear to be mediatedby cell membrane events, although a direct action of promoters on DNA has also been proposed.It is important to note that multiple clones of cells are likely to...
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Mechanisms of Tumor Initiation

Initiation of malignant transformation of normal cells by a carcinogenic agent involves a permanent,heritable change in the gene expression of the transformed cell. This could come about by either direct genotoxic or mutational events, in which a carcinogenic agent reacts directly with DNA, or by indirect or ‘‘epigenetic’’ events that modulate gene expression without directly reacting with the base sequence of DNA. Most investigators favor the mutational theory of carcinogenesis—that is, that the initiating events involve a direct action on the genome. The mutational theory...
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Tumor Initiation, Promotion, and Progression

 The idea that development of cancer is a multistage process arose from early studies of virusinducedtumors and from the discovery of the cocarcinogenic effects of croton oil. Rous and colleagues found that certain virus-induced skin papillomas in rabbits regressed after a period of time and that papillomas could be made to reappear if the skin was stressed by punching holes in it or by applying such irritant substances as turpentine or chloroform. These findings led Rous and his associates to conclude that tumor cells could exist in a latent or dormant state and that...
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