Glucose Regulated Protein-78 (GRP78) Expression in Urothelial Carcinoma: A Potential Marker for Chemotherapy Resistance
A Gorbonos, T Sondej, M Knesek, GA Barkan, GP Paner, M Woods, R Flanigan, ML Quek. Loyola University School of Medicine, Maywood, IL
Background: The majority of patients who recur after radical cystectomy will die from their disease, even with aggressive multi-agent chemotherapy. One potentially important mechanism for chemotherapy resistance involves the induction of stress response proteins referred to as glucose-regulated proteins (GRP). GRP78, the best characterized GRP, has been implicated in tumor proliferation and anti-apoptosis that may play a key role in resistance to systemic therapies. The aim of this study was to analyze the expression pattern of GRP78 in urothelial carcinoma of the bladder in radical cystectomy specimens.
Design: From February 2003 to September 2007, 110 patients underwent radical cystectomy with pelvic lymphadenectomy for urothelial bladder cancer. A total of 19/110 (17.3%) patients presented with metastasis in the lymph nodes (LN). Tissue microarrays were prepared using a representative section of the primary tumor, benign mucosa, and lymph node (involved or uninvolved) from formalin-fixed, paraffin-embedded blocks. Anti-GRP78 antibody was used for immunohistochemical analysis using the streptavidin-biotin-peroxidase complex method. Slides were interpreted by an uropathologist, blinded to the clinical outcome, recording the intensity of GRP78 staining (0 to 3+) as well as the fraction of cells stained (<15%, 15-50%, >50%).
Results: The presence of strong staining in both tumor and LN was almost always associated with mortality on follow up (7/8 patients, 88%), while weak staining of tumor and LN was associated with mortality in 3/5 patients (60%). The weak staining in either the tumor or LN tissue was associated with mortality in only 50% of these high-risk cases.
Conclusions: To our knowledge, this represents the first report of GRP78 expression in urothelial carcinoma. Underexpression of the GRP78 in the tumor and lymph node metastasis correlated with a favorable response to surgery with adjuvant chemotherapy. This intriguing correlation shows that GRP78 may have a potential role in the pathophysiology of urothelial carcinoma, and may also be of help in the approach to treatment of these patients.
Category: Genitourinary (including renal tumors)
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 101, Tuesday Morning