Carcinogens

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.