Each year about 57,000 people in the United States die from complications caused by colorectal cancer (CRC) and approximately 147,000 new cases are diagnosed. Moreover, at least 1 in 2 people worldwide will develop a benign colorectal tumor by the age of 70. In 10% of these cases, malignancy will develop and the cancer will spread to other sites. Colorectal cancer need not be life threatening if it is detected early and the tumor(s) is removed surgically. The initial signs of CRC are blood in the stool, diarrhea or constipation, and a persistent dull abdominal pain.
The walls of the colon and rectum are multilayered. The highly folded cell layer lining the lumen is composed of different types of glandular epithelial
Figure 16.12 Schematic representation of p53. The functional domains are transcriptional activation (TA), proline-rich (PR), DNA-binding (DB), tetramer-ization (T), and negative regulation (NR). N and C mark the amino- and carboxyl-terminal ends, respectively. The amino acid sites for the domains are numbered.
1-50 63-97 110-290 326-356 360-394
cells with secretory, receptor, and absorptive functions. Cells at the tips of the folds are continually being replaced by cells produced in the deep parts (crypts) of the folds. The epithelial layer is supported by a muscle layer. The other layers beneath the muscle layer include circular muscles and regions containing nerves that relay signals to the gland cells of the epithelial layer. Most colorectal cancers are derived from cells of the glandular epithelium.
Although it is difficult to track the development of all colorectal cancers, many probably begin as localized outcroppings of epithelial cells (polyps). A polyp that originates from a glandular epithelial cell is called an adenomatous polyp (adenoma). Polyps may have different colors and shapes. For example, fingerlike, villous polyps extend from the colonic epithelium into the lumen and are attached by a fibrous stalk to the muscle layer that lies beneath the epithelial layer. About 40% of villous polyps proceed to malignancy. As mutations occur, a polyp (an early adenoma) grows by cell proliferation into an advanced adenoma. With additional mutational events, it forms a large mass of growing cells (high-grade dysplasia), which eventually becomes a carcinoma that spreads through the entire wall of the colon. In addition, at the carcinoma stage, some cells metastasize and either invade other nearby tissues directly or are carried to other sites by the lymphatic system. Generally, an adenomatous polyp has a 5% chance of forming a colorectal cancer. The transition from early adenoma to carcinoma takes about five years.
Much of the understanding of the molecular basis of CRC is grounded on studies of the action of the genes that contribute to two hereditary forms. Specifically, familial adenomatosis polyposis (FAP) and hereditary nonpolypo-sis colorectal cancer (HNPCC) have been studied in detail. Overall, FAP and HNPCC account for less than 1% and about 10% of all colorectal cancers, respectively.
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