Carcinogens

Carcinogens are agents that cause cancer, and include chemicals, radiation, and some viruses. While avoiding contact with carcinogenic agents is wise, it is virtually impossible to steer clear of them completely. Ultra-violet radiation from the sun, substances in food, and even oxygen can induce malignancies . In spite of the pervasive nature of carcinogens, however, not all individuals develop cancer, which suggests that mere contact with a carcinogenic agent is insufficient to produce this lethal disease. That is because organisms have evolved protective mechanisms to prevent cancer, and some of these defenses work by thwarting the potentially harmful effects of carcinogens.

Cancer-Causing Chemicals

References to cancer have been found in the annals of human disease since ancient times, but the disease's association with carcinogen exposure is a relatively new concept. Sir Percival Potts, a British physician who lived in the eighteenth century, was the first to suggest that the induction of cancer might be linked to agents in the environment. Potts had observed high rates of scrotal and nasal cancer among England's chimney sweeps, men who were exposed to accumulated fireplace soot during their work. After some careful studies, Potts suggested correctly that exposure to soot caused the high cancer rates, providing the impetus for identifying other carcinogens present in the environment.

In retrospect, it was fortuitous that soot was acknowledged as one of the first carcinogenic agents. Soot is a complex mixture of chemicals that arises from the combustion of organic material. As scientists and physicians separated soot's individual components, it became clear that chemicals called polycyclic aromatic hydrocarbons (PAHs) were among its principal carcinogenic compounds. The story became even more intriguing when it was shown that many PAHs behave as procarcinogens . Procarcinogens do not cause cancer per se, but they can be converted to active carcinogens by enzymes located in organs like the liver and lung. The implications of this discovery are noteworthy. For example, cigarette smoke contains a wide variety of procarcinogenic PAHs that are turned into active carcinogens in lung cells. Since smokers draw these PAHs deep into their lungs with each inhale on a cigarette, one reason that cigarette smoking correlates so highly with the induction of lung cancer becomes very clear.

Oncogenes and Tumor Suppressors

How do carcinogens cause cancer? Answering this question still forms the core of much basic research, but a common feature of many carcinogens, particularly chemicals and radiation , is that they act as mutagens. Mutagens are agents that generate changes in DNA, sometimes by reacting with the DNA building blocks, guanine, adenine, thymine, and cytosine, which results in damaged DNA. When such damage remains in chromosomes, genes are often mutated in a way that impairs their normal function and enhances cancer induction. Cells try to prevent such mutations by repairing DNA damage, but they are not always successful. In fact, some individuals are susceptible to hereditary skin and colon cancers because they lack the ability to remove damaged DNA from chromosomes.

There are two general classes of genes that contribute to malignant tumor formation when they are mutated by carcinogens: oncogenes and tumor suppressor genes. Oncogenes (the prefix "onco-" meaning "tumor") are altered versions of normal genes called proto-oncogenes. Protooncogenes encode proteins that are often involved in regulating normal cell growth and division. When a proto-oncogene is mutated by exposure to a carcinogen, the protein it encodes may lose its ability to govern cell growth and division, often giving rise to the rapid, unrestrained cell proliferation that is characteristic of cancer. In such a case, the mutations in the protooncogene convert it into an actual oncogene.

While many oncogenes have been identified, numerous cancers are associated with mutations in one particular proto-oncogene, called ras, which is an abbreviation for "rat sarcoma." "Ras" is written as Ras when biologists refer to the protein, and as ras when they refer to the gene that encodes the protein. The ras gene encodes Ras protein, which acts to regulate cell growth. Normally, Ras protein cycles between an "off" and "on" form. Many carcinogens induce mutations in the ras proto-oncogene, converting it to a ras oncogene, which encodes a form of the Ras protein that is locked in the "on" state. By abolishing Ras protein's regulatory off/on cycle, the accumulated mutations in the ras gene contribute to the formation of malignancies.

Not all oncogenes arise from mutations in normal cellular protooncogenes. In the early twentieth century, Peyton Rous discovered a carcinogenic virus that now bears his name, the Rous sarcoma virus. This virus harbors a gene called v-src (viral-sarcoma) that is a mutant form of a normal cellular proto-oncogene called c-src (cell-sarcoma). Like Ras protein, c-Src protein helps to regulate cell growth. When cells are infected by Rous sarcoma virus, the v-src gene, which is classified as an oncogene, is expressed in those cells. High amounts of mutant v-Src protein encoded by the v-src oncogene are made in the cell, and they dominate the normal cellular c-Src protein, an event that contributes to abnormal cell growth and proliferation, eventually leading to cancer.

Tumor suppressor genes encode proteins that tend to repress cancer formation. When tumor suppressor genes are mutated by carcinogens, they often lose their ability to stem tumor formation, resulting in cancer. Some hereditary forms of breast cancer are linked to mutations in a tumor suppressor gene called BRCA-1. BRCA is derived from BReast CAncer. The BRCA-1 gene encodes BRCA-1 protein, which participates in controlling cell division, preventing cells from growing out of control, thus contributing to the suppression of tumor formation. Mutations in the BRCA-1 gene result in altered BRCA-1 protein that no longer functions correctly in cell-growth regulation, contributing to the formation of tumors, particularly in breast tissue.

Reducing Exposure

Decreased carcinogen contact along with improved methods for treating cancer provide two important means for curtailing the suffering, expense, and death associated with the disease. The documented existence of carcinogens has prompted a worldwide effort to detect additional cancer-causing agents. A variety of toxicological assessments, including the Ames test, are used to identify potential mutagens and carcinogens. When possible, established carcinogens, such as asbestos, are removed from the environment, home, and workplace.

Exposure can also be reduced if the population is provided with protective warnings, like those advising the use of sunblock to shield skin from the cancer-causing effects of ultraviolet radiation in sunlight. The cost and manpower of such efforts are enormous, but carcinogen identification is critical for ensuring that exposure is minimized. A great challenge is reducing exposure to the carcinogens to which people actively expose themselves, most notably cigarette smoke. Prolonged education programs have helped cut down the use of cigarettes, but continued education is needed for each new generation.

see also Ames Test; Breast Cancer; Cancer; Cell Cycle; DNA Repair; Mutagen; Oncogenes; Tumor Suppressor Genes.

David A. Scicchitano