The dietary factors most closely associated with increased colorectal cancer rates are low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat. In addition to dietary modification, pharmacologic chemoprevention has become an area of great interest. Several epidemiologic studies suggest that aspirin or other NSAIDs have a protective effect. This is consistent with studies showing that some NSAIDs cause polyp regression in patients with FAP in whom the rectum was left in place after colectomy. It is suspected that this effect is mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in 90% of colorectal carcinomas and 40% to 90% of adenomas and is known to promote epithelial proliferation, particularly in response to injury.
Studies of colorectal carcinogenesis have provided fundamental insights into the general mechanisms of cancer evolution. The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous and includes genetic and epigenetic abnormalities. At least two distinct genetic pathways, the APC/β-catenin pathway and the microsatellite instability pathway, have been described. In simplest terms, mutations involving the APC/β-catenin pathway lead to increased WNT signaling, whereas those involving the microsatellite instability pathway are associated with defects in DNA mismatch repair (see
Table 15.7).
Both pathways involve the stepwise accumulation of multiple mutations, but the genes involved and the mechanisms by which the mutations accumulate differ. Epigenetic events, the most common of which is methylation-induced gene silencing, may enhance progression along both pathways.
• The APC/β-catenin pathway. The classic adenomacarcinoma sequence, which accounts for as much as 80% of sporadic colon tumors, typically involves mutation of the APC tumor suppressor early in the neoplastic process (
Fig. 15.36 ). For adenomas to develop, both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events. APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway (Chapter 6). The APC protein normally binds to and promotes degradation of β-catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it activates the transcription of genes, such as those encoding MYC and cyclin D1, that promote proliferation. This is followed by additional mutations, including activating mutations in KRAS, which also promote growth and prevent apoptosis. The conclusion that mutation of KRAS is a late event is supported by the observations that mutations are present in fewer than 10% of adenomas less than 1 cm in diameter, 50% of adenomas greater than 1 cm in diameter, and 50% of invasive adenocarcinomas. Neoplastic progression also is associated with mutations in other tumor suppressor genes such as SMAD2 and SMAD4, which encode effectors of TGF-β signaling. Because TGF-β signaling normally inhibits the cell cycle, loss of these genes may allow unrestrained cell growth.