Colorectal cancers arise from the epithelium lining the colon (the large intestine) and rectum (the terminal segment of the gut). The organization of this tissue is broadly similar to that of the small intestine, discussed in detail in Chapter 22 (pp. 1217–1221). For both the small and large intestine, the epithelium is renewed at an extraordinarily rapid rate, taking about a week to completely replace most of the epithelial sheet. In both regions, the renewal depends on stem cells that lie in deep pockets of the epithelium, called intestinal crypts. The signals that maintain the stem cells and control the normal organization and renewal of the epithelium are beginning to be quite well understood, as explained in Chapter 22. Mutations that disrupt these signals begin the process of tumor progression for most colorectal cancers (Movie 20.6).
Colorectal cancers are common, currently causing nearly 60,000 deaths a year in the United States, or about 10% of total deaths from cancer. Like most cancers, they are not usually diagnosed until late in life (90% occur after the age of 55). However, routine examination of normal adults with a colonoscope (a fiber
Figure 20–33 An immunodeficient mouse, as used in transplantation assays to test human cancer cells for their ability to found new tumors. This nude mouse has a mutation that blocks development of the thymus and, as a side effect, robs it of hair. Because it has practically no T cells, it tolerates grafts of cells even from other species. (Courtesy of harlan Sprague Dawley.) optic device for viewing the interior of the colon and rectum) often reveals a small benign tumor, or adenoma, of the gut epithelium in the form of a protruding mass of tissue called a polyp (see Figure 22–4). These adenomatous polyps are believed to be the precursors of a large proportion of colorectal cancers. Because the progression of the disease is usually very slow, there is typically a period of about 10 years in which the slowly growing tumor is detectable but has not yet turned malignant. Thus, when people are screened by colonoscopy in their fifties and the polyps are removed through the colonoscope—a quick and easy surgical procedure—the subsequent incidence of colorectal cancer is much lower: according to some studies, less than a quarter of what it would be otherwise.
In microscopic sections of polyps smaller than 1 cm in diameter, the cells and their arrangement in the epithelium usually appear almost normal. The larger the polyp, the more likely it is to contain cells that look abnormally undifferentiated and form abnormally organized structures. Sometimes, two or more distinct areas can be distinguished within a single polyp, with the cells in one area appearing relatively normal and those in the other appearing clearly cancerous, as though they have arisen as a mutant subclone within the original clone of adenomatous cells. At later stages in the disease, some tumor cells become invasive in a small fraction of the polyps, first breaking through the epithelial basal lamina, then spreading through the layer of muscle that surrounds the gut, and finally metastasizing to lymph nodes via lymphatic vessels and to liver, lung, and other organs via blood vessels.
A Few Key Genetic Lesions Are Common to a Large Fraction of Colorectal Cancers
What are the mutations that accumulate with time to produce this chain of events? Of those genes so far discovered to be involved in colorectal cancer, three stand out as most frequently mutated: the proto-oncogene K-Ras (a member of the Ras gene family), in about 40% of cases; p53, in about 60% of cases; and the tumor suppressor gene Apc (discussed below), in more than 80% of cases. Others are involved in smaller numbers of colon cancers, and some of these are listed in Table 20–1.
The role of Apc first came to light through study of certain families showing a rare type of hereditary predisposition to colorectal cancer, called familial