Abstract 4172: Overexpression of Cathepsin L is associated with prostate cancer development, progression, and reduced patient survival

Abstract Although an estimated 217,730 men will develop prostate cancer in 2010, only 15% (32,050) will die of this disease. To avoid overtreatment, new biomarkers for early detection of potentially lethal prostate cancers are needed. Cathepsin L (Cat L), also known as the major excreted protein (MEP), is a cysteine proteinase capable of degrading the extracellular matrix. Increased levels of Cat L are found in ras transformed cells and in human prostate cancer cell lines (PC3, DU 145) and are associated with tumor cell invasion and metastasis in these experimental models. Since invasion and metastasis are the lethal aspects of cancer, we hypothesized that overexpression of Cat L will be associated with prostate cancer development and progression in men and with poor clinical outcome. Forty one prostate cancers (CaP), including all Gleason grades, and 62 specimens of benign prostate hyperplasia (BPH) were stained by immunohistochemistry in histologic sections of archival FFPE tissues for Cat L, Cat B and their endogenous inhibitors cystatin C and stefin A. Stain was evaluated according to intensisty (I) and % of epithelium stained (A). Semiquantitative observations were expressed as histoscores (HS = I × A). Histoscores were compared to proliferation (Ki67) and apoptosis (TUNEL) in adjacent histologic sections. Data were compared to five year recurrence and survival. The Institutional Review Board of St. Elizabeth Medical Center (Edgewood, KY) gave approval for this study. Expression of these cysteine proteinases and their inhibitors was confined to the epithelial portion of prostate tissues but was heterogeneous. Increased frequency of near uniform expression of Cat L was found in CaP relative to BPH from patients with or without CaP (p = 0.001) and was significantly correlated with cystatin C expression (p = 0.0044). The Cat L HS in CaP was 285% of that in BPH from patients without CaP, whereas the HS for Cat B was unchanged, suggesting that Cat L was the more predominant cysteine proteinase in neoplastic growth. Increased Cat L expression in neoplastic growth was not matched quantitatively by increased endogenous inhibitor expression. Cat L HS was significantly correlated with cell proliferation (p = 0.0001) and with apoptosis (p = 0.0180). Higher Gleason grade tumors had significantly higher Cat L HS as well as higher proliferation and apoptosis. Importantly, Cat L and proliferation, but not apoptosis, were significantly increased (p < 0.05) in CaP patients who recurred or died from CaP within 5 years of diagnosis compared to patients who survived without a recurrence. We conclude that Cat L is a significant factor in CaP development, progression and outcome and therefore is both a potential prognostic marker and target for CaP therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4172. doi:10.1158/1538-7445.AM2011-4172