Colorectal cancer (CRC) is the second most common fatal
malignancy in the Western world, with more than 150,000 new cases accounting for 55,000 deaths in the United States every year. Surgical resection is an effective treatment for localized disease, achieving a 5-year survival rate of 90%; but
chemotherapy and other novel treatments for metastatic disease remain ineffective. There have been significant efforts to identify risk factors associated with the development of CRC and to explore potential preventive
therapies. Both genetic and epigenetic factors contribute to the development of
colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of CRC. Cooperative genetic aberrations involving APC (
adenomatous polyposis coli), beta-catenine, K-ras, and p53 are involved in the multistep
adenoma-
carcinoma sequence of CRC. Emerging data have implicated
cyclooxygenase-2 (COX-2) and
prostanoid production in the pathogenesis of
colorectal carcinoma. Several reports indicate a close relation between the intake of nonsteroidal antiinflammatory drugs (
NSAIDs) and a decreased risk for developing
colorectal cancer. Epidemiologic studies indicate a 40% to 50% reduction in mortality due to
colorectal cancer in individuals taking
NSAIDs (e.g.,
aspirin). Epigenetic factors including age, diet, angiogenesis, and immune responses also appear to contribute to the development of CRC. Combining knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of CRC. These developments may yield benefits in earlier detection and in the design of better antitumor interventions.