Abstract 545: Heat Shock Protein 90 (eHsp90): A novel modulator of the tumor microenvironment and cancer progression

Abstract

Prostate Cancer (PCa) is one of the most lethal diseases afflicting men. Although early cancer detection and treatment is often curative, subsequent metastatic spread of tumor cells renders the disease untreatable. Treatment failure is also due to a poor understanding of the contribution of the tumor microenvironment to disease progression. We find that a number of PCa cells secrete heat shock protein 90 (Hsp90). Extracellular Hsp90 (eHsp90) acts in a manner distinct from the intracellular chaperone and possesses ‘chaperokine’ properties. The ability of chaperones to buffer against cellular stress and promote survival of malignant cells led us investigate the potential role of eHsp90 in PCa progression. Interestingly, we find that eHsp90 expression correlates with PCa aggressiveness. Consistently, the more aggressive and metastatic PCa cells exhibit several fold higher eHsp90 secretion relative to their weakly tumorigenic matched counterparts. Interference with this pathway by antibody or drug-mediated neutralization dramatically impaired tumor cell migration. Concomitant with inhibition of eHsp90, the activation of several critical downstream signaling mediators of cell motility were attenuated. The multifunctional receptor LRP-1 (LDL-receptor Related protein-1) has been proposed as the receptor for eHsp90. The silencing of LRP1 dramatically suppressed PCa signaling and cell migration. The ability of LRP1 knockdown to recapitulate the drug dependent inhibition of eHsp90 strongly supports the requirement for an Hsp90-LRP1 signaling axis in PCa progression. A major component of the solid tumor microenvironment is the stromal fibroblast, which acts to potentiate both tumor growth and metastatic spread. Addition of Hsp90 to prostate stromal fibroblasts, which do not secrete Hsp90 protein, potently stimulates ERK activation and cell motility, demonstrating that the eHsp90 chaperokine possess paracrine effects upon the tumor stroma and induces properties associated with a reactive phenotype. The ability of eHsp90 to induce both ERK activation and cell motility was inhibited by an MMP inhibitor, suggesting that eHsp90 dependent modulation of MMP activity is a requirement for its downstream effects on stromal signaling and cell motility. Our data implicate that eHsp90 secretion may represent a critical component of PCa aggressiveness via its ability to initiate multiple signaling events in stromal fibroblasts that enable these cell to further drive tumor growth. Our studies raise the possibility that approaches designed to curtail eHsp90 activity may be a useful strategy to intercept tumor-stromal dynamic signaling, which is predicted to have a favorable impact upon the progression of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 545.