Fibroblast Activation Protein and Its Relationship to... : Pancreas (original) (raw)

Original Articles

Fibroblast Activation Protein and Its Relationship to Clinical Outcome in Pancreatic Adenocarcinoma

Cohen, Steven J. MD*; Alpaugh, R. Katherine PhD†; Palazzo, Irma MD‡; Meropol, Neal J. MD*; Rogatko, André PhD§; Xu, Zhiheng MS§; Hoffman, John P. MD∥; Weiner, Louis M. MD*; Cheng, Jonathan D. MD*

From the *Department of Medical Oncology; †Protocol Support Laboratory, Fox Chase Cancer Center; ‡Department of Pathology, Jeanes Hospital, Philadelphia, PA; §Department of Biostatistics, Emory University, Atlanta, GA; and ∥Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA.

Received for publication September 11, 2007; accepted December 10, 2007.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2004, New Orleans, LA.

This work was supported by Grant P30 CA006927 from the National Institutes of Health Cancer Center Core and Grant IRG9202710 from the American Cancer Society Institutional Review (S.J.C.).

Reprints: Steven J. Cohen, MD, Divisions of Medical and Population Science, Fox Chase Cancer Center, Room C307, 333 Cottman Avenue, Philadelphia, PA 19111-2497 (e-mail: [email protected]).

Abstract

Objectives:

Given the extensive desmoplastic response associated with pancreatic adenocarcinoma, we hypothesized that the stromal protein fibroblast activation protein (FAP) would be highly expressed and associated with the presence of fibrosis and other clinical features.

Methods:

Paraffin-embedded pancreatic adenocarcinomas that were resected with curative intent from 1992 to 2003 were used for this study. Fibroblast activation protein expression by immunohistochemical analysis was evaluated both by intensity (0-3+) and percentage. Fibrosis was estimated as a percentage of each tumor specimen.

Results:

Ninety percent (63/70) of specimens demonstrated FAP expression. Expression was significantly more pronounced in tumor-associated myofibroblasts immediately adjacent to tumor than in surrounding tumor-associated myofibroblasts (P < 0.001). Lower FAP expression in adjacent tumor-associated myofibroblasts was associated with increased fibrosis (P = 0.02). Greater FAP expression in surrounding tumor-associated myofibroblasts was associated with an increased chance of having positive lymph nodes for all patients (P = 0.03) and a higher risk of tumor recurrence (P = 0.015) and death (P = 0.02) for patients who did not receive preoperative therapy.

Conclusions:

Fibroblast activation protein is highly expressed in pancreatic adenocarcinoma, with greatest expression immediately adjacent to tumor. Higher FAP expression is associated with worse clinical outcome. The investigation of FAP inhibitors as a therapeutic strategy against pancreatic cancer should be considered.