Fas ligand upregulation is an early event in colonic carcinogenesis

Bachground/Aims-Fas ligand (FasL) is a mediator of apoptosis via the Fas re ceptor (Fas/CD95/A-PO-1). Normal colonic epithelium expresses Fas, and appe ars to be relatively sensitive to Fas mediated apoptosis. Colonic adenocarc inomas coexpress FasL and Fas without undergoing widespread apoptosis. This study investigates the expression of FasL in colonic carcinogenesis from t he earliest stages of the adenoma-carcinoma sequence. Methods-FasL expression was determined in colonic adenomas (n = 38) of vary ing degrees of dysplasia and histological type by immunohistochemistry. Ade nomas that contained areas of carcinomatous change were included (n = 12 of 38). Normal colonic epithelium (n = 10), hyperplastic polyps (n = 8), and serrated adenomas (n = 3) from patients without colonic adenocarcinomas wer e used for comparison. Cell death was detected in situ in adenomas using TU NEL (terminal transferase mediated dUTP nick end labelling). Results-In normal colonic epithelium and hyperplastic polyps, FasL expressi on was restricted to the luminal surface of the crypts, where Fas-FasL coex pression was coincident with a high frequency of TUNEL positive epithelial cells. All adenomas (n = 38) had an altered distribution of positive FasL s taining; FasL expression was found in most cells (> 70% of neoplastic cells ). Expression of Fas was also detected throughout the adenomas, but coexpre ssion of FasL and Fas was not associated with TUNEL positivity in most cell s. Conclusions-FasL upregulation occurs early in the adenoma-carcinoma sequenc e of colon carcinogenesis, and is evident at the level of mild dysplasia. T he lack of pronounced apoptosis in areas of adenomas coexpressing Fas and F asL suggests that colonocytes acquire resistance to Fas mediated apoptosis early in the transformation process.