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Normal colon cells

A polyp (small growth) forms on the colon wall

Normal colon cells

A polyp (small growth) forms on the colon wall

A benign, precancerous tumor grows

A class II adenoma (benign) grows

A class III adenoma (benign) grows

A malignant carcinoma develops

Lumen of colon

Wall of colon

A class II adenoma (benign) grows

A class III adenoma (benign) grows

Loss of p53 tumor-suppressor gene (chromosome 17)

Invasive tumor cells

Normal colon epithelial cells Basal lamina

Loss of APC tumor-suppressor gene (chromosome 5)

A malignant carcinoma develops

metastasizes (spreads to other tissues)

Invasive tumor cells

Blood vessel

Normal colon epithelial cells Basal lamina

Tumor cells invade blood vessels, allowing metastasis to occur

Blood vessel

Activation of K-ras oncogene (chromosome 12)

Loss of tumor-suppressor gene in region of DCC (chromosome 18)

Loss of p53 tumor-suppressor gene (chromosome 17)

Other changes

Other changes

▲ FIGURE 23-7 The development and metastasis of human colorectal cancer and its genetic basis. A mutation in the APC

tumor-suppressor gene in a single epithelial cell causes the cell to divide, although surrounding cells do not, forming a mass of localized benign tumor cells, or polyp. Subsequent mutations leading to expression of a constitutively active Ras protein and loss of two tumor-suppressor genes—an unidentified gene in the vicinity of DCC and p53—generate a malignant cell carrying all four mutations. This cell continues to divide, and the progeny invade the basal lamina that surrounds the tissue. Some tumor cells spread into blood vessels that will distribute them to other sites in the body. Additional mutations permit the tumor cells to exit from the blood vessels and proliferate at distant sites; a patient with such a tumor is said to have cancer. [Adapted from B. Vogelstein and K. Kinzler, 1993, Trends Genet. 9:101.]

DNA from different human colon carcinomas generally contains mutations in all these genes—loss-of-function mutations in the tumor suppressors APC and p53, the as yet mysterious gene, and an activating (gain-of-function) mutation in the dominant oncogene K-ras—establishing that multiple mutations in the same cell are needed for the cancer to form. Some of these mutations appear to confer growth advantages at an early stage of tumor development, whereas other mutations promote the later stages, including invasion and metastasis, which are required for the malignant phenotype. The number of mutations needed for colon cancer progression may at first seem surprising, seemingly an effective barrier to tumorigenesis. Our genomes, however, are under constant assault. Recent estimates indicate that sporadically arising polyps have about 11,000 genetic alterations in each cell, though very likely only a few of these are relevant to oncogenesis.

Colon carcinoma provides an excellent example of the multi-hit mode of cancer. The degree to which this model applies to cancer is only now being learned, but it is clear that multiple types of cancer involve multiple mutations. The advent of DNA microarray technology is allowing more detailed examination of tumor properties by monitoring the spectrum of mRNA molecules from tens of thousands of genes, and recent data have provided some challenges to the multi-hit model. Not surprisingly, primary tumors can often be distinguishable from metastatic tumors by the pattern of gene expression. More interestingly, a subset of solid primary tumors has been found to have characteristics more typical of metastatic tumors, suggesting that it may be possible to identify primary tumors that have a greater probability of becoming metastatic. This also raises the possibility that, at least for some types of cancer, the initiating events of the primary tumor may set a course toward metastasis. This hypothesis can be distinguished from the emergence of a rare subset of cells within the primary tumor acquiring a necessary series of further mutations.

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