Cellular localization of thrombin in prostate: Implications for thrombin targeted therapy in prostate cancer

Abstract

14527 Background: Tumor and coagulation interaction is complex and heterogeneous. Expression of an intact repertoire of coagulation proteins is not detected in all tumor types. Thrombin, a key coagulation protein, which has been observed to promote tumorigenesis in experimental models, is not expressed on breast, colon and squamous lung cancer cells, but has been detected on small cell lung, melanoma and renal cancer epithelium. In prostate cancer, expression of its receptor, protease activated receptor-1 (PAR-1) has been previously reported but thrombin expression on epithelium not determined. Therefore, we evaluated thrombin and prothrombin expression in prostate specimens. Methods: Quantitative real-time PCR was performed for (pro)thrombin mRNA expression in fresh prostate cancer tissue lysates obtained from localized disease (n = 9 prostatectomy specimens) and advanced disease (n = 7 channel trans-urethral prostate resection specimens). Prothrombin and thrombin protein immunohistochemistry was performed on anonymized prostate tissue micro arrays which included benign (n = 117), prostate intra-epithelial neoplasia (PIN; n = 26) and prostate cancer (n = 112) cores. Results: (Pro)thrombin mRNA expression (normalized to 18s mRNA) was detected in all cancer tissue lysates. Mean intensity of expression in advanced cancer specimens was 20.3 compared to 14.0 for local stage specimens (p = 0.09; Wilcoxon rank sum test). Spatially, expression of thrombin was detected in stroma, benign and malignant epithelium (see Table) and on vascular endothelium. Prothrombin localization was similar to thrombin expression. Conclusions: Thrombin’s tumorigenic effects via PAR-1 activation provide novel therapeutic targets in tumors expressing thrombin-PAR1 axis. The current study confirms thrombin expression on prostate epithelium and taken with previous results of PAR1 epithelial expression, provides a rationale for exploring specific thrombin inhibitors and/or PAR inhibitors in prostate cancer. [Table: see text] No significant financial relationships to disclose.