Prognostic relevance of Fas (APO-1/CD95) ligand in human colorectal cancer.
OBJECTIVE
Fas ligand (FasL) is an important mediator of immune function and induces apoptosis by binding to its receptor Fas on sensitized cells. It has recently been shown that malignancies may express FasL and acquire immune privilege by inducing apoptosis of lymphocytes. Acquired resistance to Fas mediated apoptosis is known to be an early event in carcinogenesis. The aim of this study was to determine the extent of FasL expression in patients with colorectal cancer and examine its relationship with several prognostic pathological features and survival.


METHODS
Sixty-eight patients (median age 66 years) with colorectal cancer, whose diagnosis was made between 1988 and 1991 and in whom long-term follow-up was available, were evaluated. The tumours were of varying stages at diagnosis (eight Dukes' A, 28 Dukes' B, 23 Dukes' C and nine Dukes' D). The expression of FasL was detected immunohistochemically with a rabbit polyclonal IgG using the DAKO EnVision+ System. The specificity of FasL binding was confirmed by pre-incubation of the antibody with the immunizing peptide prior to staining. The relationship with several pathological features was determined using Kendall's tau-b correlation. Overall survival was estimated using the Kaplan-Meier product limit curves. Differences in observed survival were tested for statistical significance using the Mantel-Haenszel log rank test. Both the extent and intensity of staining were graded by a blinded observer.


RESULTS
FasL was predominantly expressed in tumour epithelial cells in 88% of the cases. The positive staining of tumours varied in extent. FasL staining was higher in earlier Dukes' stage tumours in that the extent of FasL staining negatively correlated with Dukes' stage (Kendall tau-b = -0.22, P = 0.038). Consistent with this, the overall survival was better with a greater extent of FasL expression (log rank chi2 = 5.68, P = 0.017). There was a lower extent of FasL expression in mucinous adenocarcinomas (Kendall tau-b = 0.288, P = 0.01) and in those tumours with neural invasion (Kendall tau-b = -0.26, P = 0.03). No relationship was detected between FasL and tumour site, size, margin, differentiation, vascular invasion, necrosis or Crohn's-like reaction.


CONCLUSIONS
FasL is widely expressed in colorectal cancers. This finding suggests that the extent of FasL expression in colorectal tumours is directly related to patients' survival.
Sheehan
Katherine M
KM
Department of Pathology, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin, Ireland. katherinesheehan@hotmail.com
O'Donovan
Deirdre G
DG
Fitzmaurice
Gillian
G
O'Grady
Anthony
A
O'Donoghue
Diarmuid P
DP
Sheahan
Kieran
K
Byrne
Michael F
MF
Conroy
Ronan M
RM
Kay
Elaine W
EW
Murray
Frank E
FE
D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis*; D000954:Antigens, Surface / Q000032:analysis; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D009367:Neoplasm Staging; D011379:Prognosis; D019014:fas Receptor / Q000032:analysis
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor