Aberrant Crypt Foci - Endpoint in Colorectal Cancer

Abstract

Abstract Aberrant crypt foci (ACF) can be used as the endpoint in colorectal cancer development because aberrant crypts are postulated to be the earliest identifiable potential precursors of colorectal cancer. ACF were first described by Bird and defined as crypt that: (1) have altered luminal openings; (2) exhibit thickened epithelia; (3) are larger than adjacent normal crypts. ACF may eventually evolve into polyps and, subsequently, colorectal cancer in the case of adenoma-carcinoma sequence; it provides a simple and economical tool for preliminary screening of potential chemopreventive agents, and it allows a quantitative assessment of the mechanisms of colon carcinogenesis. ACF are morphological lesions that represent an early stage in the stepwise progression of colon cancer. These surface abnormalities often appear in the distal colon within 2 weeks of carcinogen treatment. Sequential analyses suggest that these early lesions increase in size and multiplicity and often exhibit nuclear atypia and dysplasia. ACF also shows increased proliferative activity, growth factor signaling and K-Ras mutations, suggesting that at least a subset of ACF are putative precursors of colon cancer. Human ACF shares a similar morphology and is present in grossly normal-appearing colon tissue from patients with colorectal cancer (CRC). It has been suggested that the nature and order of acquired genetic changes can profoundly impact ACF morphology and the likelihood of tumor progression. Although limited in numbers, flat dysplastic ACF appeared to be more likely to become tumors than the elevated ACF. Clearly, the expanding diversity of ACF identified in rodent carcinogen models provides researchers with exciting new tools for studying the earliest stages of CRC. Lesions characterized in these models may ultimately become useful for predicting cancer risk in humans.