Abberant Crypt Foci – Importance in Colorectal Carcinogenesis and Expression of p53 and mdm2: A Changing Concept

Abstract

The presence of aberrant crypt foci (ACF) represents an important preneoplastic condition of the large intestine. The ACF are used extensively as the biological end point to study the effects of diet, biological agents and chemotherapeutic agents as they undergo distinct morphological and genetic changes in response to these factors. Till date, in human ACF, K-ras, beta-catenin, carcinoembryonic antigen (CEA) and adenomatous polyposis coli (APC) protein expression have been investigated, but the expression of late markers of colon carcinogenesis have not been studied in great detail. To study the significance of ACF in carcinogenesis, the incidence of ACF in colorectal carcinoma (CRC) patients and the expression profiles of the tumor repressor protein p53 and the murine double minute (mdm2) protein in ACF. The pattern of expression, histology and immunohistochemistry of the p53 and mdm2 proteins were studied in 32 colectomy specimens. Careful scoring was carried out using standard criteria. The prevalence of ACF, types of ACF, surrounding mucosal changes and the relation of ACF with tumor morphology and aggressiveness were determined, as was any difference in the staining pattern between hyperplastic and dysplastic ACF. Aberrant crypt foci were present in a large number of cases (84.4%), of which 65% were hyperplastic. All hyperplastic and dysplastic ACF tested positive for p53 in the nucleus. Both the nucleus and cytoplasm tested positive for mdm2 irrespective of the degree of dysplasia. No correlation was noted between ACF and tumor histology. The p53 and mdm2 proteins are expressed during the very early stages of mucosal changes in ACF, irrespective of histological changes, but the pattern of expression can differ depending on geographical barriers, genetic factors, diet and environmental conditions. This results suggests that the conventional adenoma-carcinoma sequence is not completely correct. The detection of ACF and p53 and mdm2 expression can help to curtail the disease in its early stage by targeted therapy.