Extracellular Hsp90 Mediates an NF- kBDependent Inflammatory Stromal Program: Implications for the Prostate Tumor Microenvironment

BACKGROUND The tumor microenvironment (TME) plays an essential role in supporting and promoting tumor growth and progression. An inflammatory stroma is a widespread hallmark of the prostate TME, and prostate tumors are known to co-evolve with their reactive stroma. Cancer-associated fibroblasts (CAFs) within the reactive stroma play a salient role in secreting cytokines that contribute to this inflammatory TME. Although a number of inflammatory mediators have been identified, a clear understanding of key factors initiating the formation of reactive stroma is lacking. METHODSWe explored whether tumor secreted extracellular Hsp90 alpha (eHsp90) may initiate a reactive stroma. Prostate stromal fibroblasts (PrSFs) were exposed to exogenous Hsp90 protein, or to conditioned medium (CM) from eHsp90-expressing prostate cancer cells, and evaluated for signaling, motility, and expression of prototypic reactive markers. In tandem, ELISA assays were utilized to characterize Hsp90-mediated secreted factors. RESULTSWe report that exposure of PrSFs to eHsp90 upregulates the transcription and protein secretion of IL-6 and IL-8, key inflammatory cytokines known to play a causative role in prostate cancer progression. Cytokine secretion was regulated in part via a MEK/ERK and NF-B dependent pathway. Secreted eHsp90 also promoted the rapid and durable activation of the oncogenic inflammatory mediator signal transducer and activator of transcription (STAT3). Finally, eHsp90 induced the expression of MMP-3, a well-known mediator of fibrosis and the myofibroblast phenotype. CONCLUSIONSOur results provide compelling support for eHsp90 as a transducer of signaling events culminating in an inflammatory and reactive stroma, thereby conferring properties associated with prostate cancer progression. Prostate 74:395-407, 2014. (c) 2013 Wiley Periodicals, Inc.