Extracellular Hsp90 mediates an NF‐κB dependent inflammatory stromal program: Implications for the prostate tumor microenvironment

Abstract

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. Methods We explored whether tumor secreted extracellular Hsp90 alpha (eHsp90α) may initiate a reactive stroma. Prostate stromal fibroblasts (PrSFs) were exposed to exogenous Hsp90α protein, or to conditioned medium (CM) from eHsp90α-expressing prostate cancer cells, and evaluated for signaling, motility, and expression of prototypic reactive markers. In tandem, ELISA assays were utilized to characterize Hsp90α-mediated secreted factors. Results We 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-κB dependent pathway. Secreted eHsp90α 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. Conclusions Our results provide compelling support for eHsp90α as a transducer of signaling events culminating in an inflammatory and reactive stroma, thereby conferring properties associated with prostate cancer progression.

Regulation and function of the human HSP90AA1 gene

“…This reprogramming of the extracellular milieu surrounding malignant adenocarcinoma cells is understood to stimulate prostate cancer progression. Extracellular HSP90α induces inflammation through activation of the NF-kB (RELA) and STAT3 transcription programs that include the pro-inflammatory cytokines IL-6 and IL-8 (Bohonowych et al 2014). Coincidentally NF-kB also induces expression Hsp90α (Ammirante et al 2008), thus providing a model where newly-expressed Hsp90α would also be secreted from the stimulated fibroblast thereby creating positive autocrine and paracrine feedback loops resulting in an inflammatory storm at the site of malignancy.…”

Tumor-secreted Hsp90 Subverts Polycomb Function to Drive Prostate Tumor Growth and Invasion

“…Nuclear fractionation, where indicated, was performed as described previously (31). All blots are representative of a minimum of two independent experiments.…”

Effect of Previous High Glutamine Infusion on Inflammatory Mediators and Mortality in an Acute Pancreatitis Model

“…HSP90 also has cytoprotective properties, but most of its target proteins are kinases and transcription factors that can act as cellular regulators of gene expression, including the transcription of proinflammatory molecules via nuclear factor kappa B [34, 35]. However, we found no systemic detrimental increase in proinflammatory cytokines in parallel with increased HSP90 in the glutamine group.…”