Abstract CN15-01: Aspirin, COX-2, and colorectal cancer

Abstract

Abstract CN15-01 Considerable experimental, epidemiological, and clinical data has provided strong evidence for a causative link between chronic inflammation and colorectal cancer, including the well-described association between inflammatory bowel disease and colonic dysplasia. However, beyond inflammatory bowel disease, the precise role of inflammation in sporadic colorectal cancer remains undefined. Inflammation may predispose to cancer through enhanced cellular proliferation and mutagenesis, inability to adapt to oxidative stresses, promotion of angiogenesis, inhibition of apoptosis, and secretion of mediators that may promote tumorigenesis. A specific mechanism through which inflammation promotes carcinogenesis is the pro-inflammatory cyclooxygenase-2 pathway (COX-2). A role for COX-2 in neoplasia is supported by several lines of evidence: 1) “knock-out” of the COX-2 gene inhibits development of polyps in the APC mutant mice; 2) host expression of COX-2, but not COX-1, is required for survival of mouse tumor xenografts; 3) COX-2, but not COX-1, is progressively overexpressed in human colorectal adenomas and cancers; 4) COX-2 gene expression is highly upregulated even in morphologically normal mucosa of APC mutant mice and human colorectal cancer patients; 5) agents with COX-2 activity are effective in inhibiting neoplasia in both animals and humans. In fact, at least six randomized trials have demonstrate that anti-inflammatory drugs such as aspirin and COX-2 selective inhibitors reduce the risk of colorectal adenoma among patients with a prior history of colorectal neoplasia. Recently, in two large prospective cohorts, we observed that aspirin reduces risk of COX-2 positive colorectal cancer but not risk of COX-2 negative colorectal cancer. This data suggest that the anti-cancer benefit of aspirin is primarily mediated through COX-2 inhibition. However, the optimal use of aspirin in light of its associated toxicities remains uncertain. Nonetheless, these results support the importance of continued investigation into COX-2 and related inflammatory pathways to both define markers of susceptibility to colorectal cancer as well as spur development of new preventive interventions. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN15-01.