As we shall see, mutations in oncogenes and tumor suppressor genes can have similar effects in promoting the development of cancer; overproduction of a signal for cell proliferation, for example, can result from either kind of mutation. Thus, from the point of view of a cancer cell, oncogenes and tumor suppressor genes—and the mutations that affect them—are flip sides of the same coin. The techniques that led to the discovery of these two categories of genes, however, are quite different.
The mutation of a single copy of a proto-oncogene that converts it to an oncogene has a dominant, growth-promoting effect on a cell (Figure 20–17A). Thus, we can identify the oncogene by its effect when it is added—by DNA transfection, for example, or through infection with a viral vector—to the genome of a suitable type of tester cell or experimental animal. In the case of the tumor suppressor gene, on the other hand, the cancer-causing alleles produced by the change are generally recessive: often (but not always) both copies of the normal gene must be removed or inactivated in the diploid somatic cell before an effect is seen (Figure 20–17B). This calls for a different experimental approach, one focusing on discovering what is missing in the cancer cell.
functionally eliminate the tumor suppressor gene, promoting cell transformation
We begin by discussing some examples of each class of cancer-critical genes to illustrate basic principles. These examples are chosen also for their historical importance: the experiments that led to their discovery—at different times and by different methods—marked turning points in the understanding of cancer.
Retroviruses Can Act as Vectors for Oncogenes That Alter Cell Behavior
The search for the genetic causes of human cancer took a devious route, beginning with clues that came from the study of tumor viruses. Although viruses are involved only in a minority of human cancers, a set of viruses that infect animals provided critical early tools for studying cancer.
One of the first animal viruses to be implicated in cancer was discovered over 100 years ago in chickens, when an infectious agent that causes connective-tissue tumors, or sarcomas, was characterized as a virus—the Rous sarcoma virus. Like all the other RNA tumor viruses discovered since, it is a retrovirus. When it infects a cell, its RNA genome is copied into DNA by reverse transcription, and the DNA is inserted into the host genome, where it can persist and be inherited by subsequent generations of cells. Something in the DNA inserted by the Rous sarcoma virus made the host cells cancerous, but what was it? The answer was a surprise. It turned out to be a piece of DNA that was unnecessary for the virus’s own survival or reproduction; instead, it was a passenger, a gene called v-Src, that the virus had picked up on its travels. v-Src was unmistakably similar, but not identical, to a gene—c-Src—that was discovered in the normal vertebrate genome. c-Src had evidently been caught up accidentally by the retrovirus from the genome of a previously infected host cell, and it had undergone mutation in the process to become an oncogene (v-Src).
This Nobel Prize-winning finding was followed by a flood of discoveries of other viral oncogenes carried by retroviruses that cause cancer in nonhuman animals. Each such oncogene turned out to have a counterpart proto-oncogene in the normal vertebrate genome. As was the case for Src, these other oncogenes generally differed from their normal counterparts, either in structure or in level of expression. But how did this relate to typical human cancers, most of which are not infectious and in which retroviruses play no part?
Figure 20–17 Cancer-critical mutations fall into two readily distinguishable categories, dominant and recessive.