The Multi-hit Model Can Explain the Progress of Cancer

As we have just seen, mutations cause cancer. However, luckily for us, multiple mutations are usually required to convert a normal body cell into a malignant one. According to this multi-hit model, cancers arise by a process of evolutionary (or “survival of the fittest”) clonal selection not unlike the selection of individual animals in a large population. Here is the scenario, which may or may not apply to all cancers: A mutation in one cell gives it a slight growth advantage. One of its progeny cells then undergoes a second mutation that allows its descendants to grow more uncontrollably and form a small benign tumor. A third mutation in a cell within this tumor allows it to outgrow the others and overcome constraints imposed by the tumor microenvironment, and its progeny form a mass of cells, each of which has these three genetic changes. An additional mutation in one of these cells allows its progeny to escape into the bloodstream and establish daughter colonies at other sites, the hallmark of metastatic cancer.

This model makes two easily testable predictions. First, all cells in a given tumor should have at least some genetic alterations in common. Systematic analysis of cells from individual human tumors supports the prediction that all the cells in a tumor are derived from a single progenitor. Second, cancer incidence should increase with age because it can take decades for the required multiple mutations to occur. Assuming that the rate of mutation is roughly constant during a lifetime, the incidence of most types of cancer would be independent of age if only one mutation were required to convert a normal cell into a malignant one. As the data in Figure 24-10 show, the incidence of many types of human cancer increases drastically with age. In fact, current estimates suggest that five to six “hits,” or mutations, must accumulate as the most dangerous cancer cells emerge.

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EXPERIMENTAL FIGURE 24-10 The incidence of human cancers increases as a function of age. The marked increase in the incidence of cancer with age is consistent with the multi-hit model of cancer induction. Note that the logarithm of annual incidence is plotted versus the logarithm of age.
[Data from B. Vogelstein and K. Kinzler, 1993, Trends Genet. 9:138–141.]
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EXPERIMENTAL FIGURE 24-11 The kinetics of tumor appearance in female mice carrying either one or two oncogenic transgenes shows the cooperative nature of multiple mutations in cancer induction. Each of the transgenes was driven by the mouse mammary tumor virus (MMTV) breast-specific promoter. The hormonal stimulation associated with pregnancy activates the MMTV promoter and hence the overexpression of the transgenes in mammary tissue. The graph shows the time course of tumorigenesis in mice carrying either MYC or rasV12 transgenes as well as in the progeny of a cross of MYC carriers with rasV12 carriers, which contain both transgenes. The results clearly demonstrate the cooperative effects of multiple mutations in cancer induction. See E. Sinn et al., 1987, Cell 49:465.

More direct evidence that multiple mutations are required for tumor induction comes from experiments with transgenic mice, which have shown that a variety of combinations of oncogenes can cooperate in causing cancer. For example, mice have been made that carry either the mutant rasV12 dominant oncogene (one version of rasD) or the MYC proto-oncogene, in each case under the control of a mammary-cell-specific promoter/enhancer from a retrovirus. This promoter is induced by endogenous hormone levels and tissue-specific regulators, leading to overexpression of MYC or rasV12 in breast tissue.

The MYC protein is a transcription factor that induces expression of many genes required for the transition from the G1 to the S phase of the cell cycle. Heightened transcription of MYC in these mice mimics previously identified oncogenic mutations that increase MYC transcription, converting the proto-oncogene into an oncogene. By itself, the MYC transgene causes tumors only after 100 days, and then in only a few mice; clearly only a minute fraction of the mammary cells that overproduce the MYC protein actually become malignant. Production of the mutant RasV12 protein alone causes tumors earlier, but still slowly and with about 50 percent efficiency over 150 days. When the MYC and rasV12 overexpressing transgenics are crossed, however, all mammary cells in their offspring overproduce both MYC and RasV12, tumors arise much more rapidly, and all animals succumb to cancer (Figure 24-11). Such experiments emphasize the synergistic effects of multiple oncogenes. They also suggest that the long latency of tumor formation, seen even in the double-transgenic mice, is due to the need to acquire still more mutations.

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