The word tumor, or neoplasm, indicates a swelling that results from the abnormal growth of cells. If the growth remains within a defined region and is not carried to other areas by the circulatory system, it is a benign tumor. If the abnormal growth spreads or metastasizes to other parts of the body, it is a malignant tumor or cancer. It is estimated that less than one in 10,000 tumor cells that escape the primary tumor survives to colonize another tissue. Because this discussion is concerned only with primary tumors, the term tumor exclusively will be synonymous with abnormal growth. The term cancer denotes a life-threatening tumor.
Tumors result when the controls for cell growth and differentiation do not function properly. To grow and differentiate properly, cells must synthesize key proteins at the proper times and in the correct amounts. These proteins include those that are involved in cell-to-cell communication as well as those that regulate key activities within cells. Such synthesis requires the appropriate activation of genes at specific times in the cell cycle (up-regulation) and their silencing at other times (down-regulation). If these key genes do not function properly, then abnormal growth resulting in tumor formation may result.
One important class of regulatory genes in the host cell that are commonly involved in tumor formation caused by viruses are the proto-oncogenes. These genes code for proteins that activate gene transcription. It is very important that these genes function properly to regulate cell growth and development. (Tumor viruses have similar genes, termed oncogenes, which will be discussed shortly.) Mutations in proto-oncogenes result in altered proteins that cause the cells to grow abnormally. Proto-oncogenes were identified by two microbiologists, Dr. Michael Bishop and Dr. Harold Varmus, who in 1989 were jointly awarded the Nobel Prize for their studies.
358 Chapter 14 Viruses, Prions, and Viroids: Infectious Agents of Animals and Plants
Proto-oncogenes are most commonly altered in function through mutation. If the proto-oncogenes fail to function properly, abnormal growth and tumor formation may result. Mutations can arise if the repair systems that operate in DNA replication or mismatch repair are defective. How these repair systems function has already been discussed for bacteria. When mutagens in the environment mutate the genes, the frequency of tumor formation increases. Recall that Bruce Ames pointed out that all carcinogens are mutagens because they affect the DNA of the organism. If the altered genes are essential for growth, such as the genes of macromolecule synthesis, then the cell will die. If the genes are one of the proto-oncogenes, then a tumor may well develop. It is not surprising that mutations in genes concerned with the repair of damaged DNA lead to an increased rate of tumor formation. ■ mismatch repair, p. 196 ■ Ames test, p. 201 ■ mutations, p. 192
Many proto-oncogenes exist. Some human cancers, such as those of the colon, require that several of the proto-oncogenes be mutant simultaneously. A mutation in only one of these genes leads to slightly abnormal growth; a second mutation results in somewhat more abnormal growth, and so on. This explains why certain cancers develop in stages.
Abnormal growth can also be caused by viruses. Tumor viruses, like mutations, alter the activity of the proto-oncogenes. Viruses are recognized as a frequent cause of tumors in animals, but they are not a frequent cause of tumors in humans. Only 15% of all human tumors are estimated to be caused by viruses. This number, however, will likely be revised upward because of AIDS. At least 30% of people with AIDS also develop cancer. A popular view is that the majority of these cancers are caused by viruses.
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