title: 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.
authors: Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
authors: J E
authors: JE
authors: Bohonowych
authors: M W
authors: MW
authors: Hance
authors: K D
authors: KD
authors: Nolan
authors: M
authors: M
authors: Defee
authors: C H
authors: CH
authors: Parsons
authors: J S
authors: JS
authors: Isaacs
mesh_terms: D002465:Cell Movement; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D019278:Matrix Metalloproteinase 3
keywords: CAF; ERK; MMP; STAT3; prostate cancer