Prevention of Colon Cancer and Modulation of Aberrant Crypt Foci, Cell Proliferation, and Apoptosis by Retinoids and NSAIDs

Abstract

Cancer is a multistage process involving multiple rare events with each suggesting a mutational or chromosomal alteration. At the different steps along the progression to cancer, the cells accumulate selective growth advantage that could be manifested by an increase in cell proliferation and/or a decrease in apoptosis and terminal differentiation. Promotion of the progression to cancer could therefore involve agents, growth factors, proto-oncogenes, etc., which enhance cell proliferation while decreasing apoptosis. Chemopreventive agents, on the other hand, would be agents that decrease cell proliferation while enhancing apoptosis resulting in a decrease in the selective growth advantage of precancerous lesions. A putative early precancerous lesion in the colon is the aberrant crypt focus (ACF) described and reviewed by Bird.¹ Increased cell proliferation appears to result in the accumulation of epithelial cells at the lumina of the crypts and hence the larger appearance of the aberrant crypts. In laboratory animals ACF are induced by chemical carcinogens and presumably contain precancerous cells that have many characteristics in common with colon tumors including in some dysphasia and an activated K-ras oncogene.^2–4 K-ras and APC mutations have also been demonstrated in ACF in human colon.^5–7 ACF are proposed to progress further to adenomas and finally cancer. During this progression, there is an increase in the level of cell proliferation with less of an increase in apoptosis, resulting in the overall growth of the lesions.