Fas ligand upregulation is an early event in colonic carcinogenesis.
OBJECTIVE
Fas ligand (FasL) is a mediator of apoptosis via the Fas receptor (Fas/CD95/APO-1). Normal colonic epithelium expresses Fas, and appears to be relatively sensitive to Fas mediated apoptosis. Colonic adenocarcinomas coexpress FasL and Fas without undergoing widespread apoptosis. This study investigates the expression of FasL in colonic carcinogenesis from the earliest stages of the adenoma-carcinoma sequence.


METHODS
FasL expression was determined in colonic adenomas (n = 38) of varying degrees of dysplasia and histological type by immunohistochemistry. Adenomas 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 were used for comparison. Cell death was detected in situ in adenomas using TUNEL (terminal transferase mediated dUTP nick end labelling).


RESULTS
In normal colonic epithelium and hyperplastic polyps, FasL expression was restricted to the luminal surface of the crypts, where Fas-FasL coexpression was coincident with a high frequency of TUNEL positive epithelial cells. All adenomas (n = 38) had an altered distribution of positive FasL staining; FasL expression was found in most cells (> 70% of neoplastic cells). Expression of Fas was also detected throughout the adenomas, but coexpression of FasL and Fas was not associated with TUNEL positivity in most cells.


CONCLUSIONS
FasL upregulation occurs early in the adenoma-carcinoma sequence of colon carcinogenesis, and is evident at the level of mild dysplasia. The lack of pronounced apoptosis in areas of adenomas coexpressing Fas and FasL suggests that colonocytes acquire resistance to Fas mediated apoptosis early in the transformation process.
Bennett
M W
MW
Department of Medicine, University College Cork, Cork, Ireland.
O'Connell
J
J
Houston
A
A
Kelly
J
J
O'Sullivan
G C
GC
Collins
J K
JK
Shanahan
F
F
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019014:fas Receptor