Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype.

摘要

The purpose of this DOD PRTA is to investigate the role of epithelial plasticity in the promotion of metastasis in advanced prostate cancer through a sequential interrogation of biomarkers in primary prostate tumors, metastases, and circulating tumor cells (CTCs). In this 2011-2012 annual report, we provide updates on our investigation of EMT biology in metastatic prostate cancer, with particular emphasis on CTC biology as a biomarker of disease progression and metastasis. We also describe our ongoing investigation into novel CTC phenotypes in men with metastatic castration- resistant prostate cancer (CRPC), localized PC, and the investigation of CTCs for DNA biomarkers (copy number variatiations) that may each shed light on the molecular pathophysiology of metastatic spread. We provide evidence for the common co-expression of epithelial and mesenchymal/EMT biomarkers in CTCs from patients with metastatic castration-resistant prostate cancer (CRPC) as well as the common expression of stem cell biomarkers in these CTCs. This data provides strong evidence for the importance of EMT to prostate cancer metastasis in humans. Based on these results, we have developed a novel CTC capture method based on this EMT biology to identify non-epithelial OB-cadherin positive cells/CTCs which are previously underdetected using conventional CTC assays; further molecular characterization of these cellular events is ongoing. Together these aims will provide insight into metastasis biology in PC and lead to the identification of relevant therapeutic targets directed against this lethal metastatic process.