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Prognostic relevance of Fas (APO-1/CD95) ligand in human colorectal cancer

Sheehan, Katherine Ma; O'Donovan, Deirdre Gb; Fitzmaurice, Gilliana; O'Grady, Anthonya; O'Donoghue, Diarmuid Pe; Sheahan, Kierand; Byrne, Michael Fb; Conroy, Ronan Mc; Kay, Elaine Wa; Murray, Frank Eb

European Journal of Gastroenterology & Hepatology: April 2003 - Volume 15 - Issue 4 - p 375-380
Original articles: 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.

Design and 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 τ–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 τ–b = −0.22, P = 0.038). Consistent with this, the overall survival was better with a greater extent of FasL expression (log rank χ2 = 5.68, P = 0.017). There was a lower extent of FasL expression in mucinous adenocarcinomas (Kendall τ–b = 0.288, P = 0.01) and in those tumours with neural invasion (Kendall τ–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.

Departments of aPathology, bGastroenterology and cEpidemiology, Royal College of Surgeons in Ireland and Beaumont Hospital; and Departments of dPathology and eGastroenterology, St Vincent's Hospital, Dublin, Ireland.

Correspondence to Dr Katherine M. Sheehan, Department of Pathology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. Tel: +353 1 809 2638; fax: +353 1 809 2955; e-mail:

Received 21 May 2002 Revised 29 September 2002 Accepted 6 November 2002

© 2003 Lippincott Williams & Wilkins, Inc.