Abstract A74: Tumor secreted Hsp90 initiates tumor growth and the epithelial to mesenchymal transition (EMT) in prostate cancer

Prostate cancer (PCa) is the most frequently diagnosed malignancy and second most common cause of cancer related lethality in men. Disease mortality is due primarily to metastatic spread, highlighting the urgent need to identify factors involved in this progression. Increased secretion of heat shock protein 90 (Hsp90) has been reported in diverse cancer cells, and secreted, or extracellular Hsp90 (eHsp90) is also found in patient plasma. Although eHsp90 promotes cancer cell motility and invasion and facilitates tumor metastasis, the mechanistic basis for its activity has remained unknown. The goal of this study was to explore whether extracellular Hsp90 (eHsp90) may play a role in PCa progression. To explore this, 3 sets of lineage-related differentially metastatic cell pairs were utilized to evaluate eHsp90 expression and activity. We found that eHsp90 secretion correlated with PCa aggressiveness. To evaluate the functional role of eHsp90, we modulated its expression and activity. Upregulation of eHsp90 was accomplished by exposure of prostate epithelial cells to exogenous Hsp90 protein, or alternatively, cells were transduced with a lentivirus directing the secretion of Hsp90. Blockade of eHsp90 function was accomplished by exposure of cells to anti-Hsp90 antibodies or to a cell-impermeant specific inhibitor of Hsp90. We demonstrate that eHsp90 is a critical factor required for PCa cell motility and for initiation of the epithelial to mesenchymal transition (EMT) genetic program. Moreover, modest increases in eHsp90 were sufficient to induce tumor growth and localized invasion in a subrenal capsule xenograft model of PCa. Finally, eHsp90 was detected in human cancer specimens and its expression was correlated with upregulated expression of pro-invasive genes. Our findings offer insights into the mechanistic basis of eHsp90 in PCa, and further support a putative clinical role for eHsp90 as a potential driver of PCa progression. Citation Format: Michael W. Hance, Krystal Nolan, Udhayakumar Gopal, Jessica E. Bohonowych, Agnieszka Jezierska-Drutel, Carola A. Neumann, Haibo Liu, Garraway P. Isla, Omar E. Franco, Simon W. Hayward, Jennifer S. Isaacs. Tumor secreted Hsp90 initiates tumor growth and the epithelial to mesenchymal transition (EMT) in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A74.