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Extracellular Hsp90 mediates an NF-?B dependent inflammatory stromal program: implications for the prostate tumor microenvironment.

ABSTRACT: 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.We 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.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-?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.Our 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.

SUBMITTER: Bohonowych JE

PROVIDER: S-EPMC4306584 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor microenvironment.

Bohonowych J E JE Hance M W MW Nolan K D KD Defee M M Parsons C H CH Isaacs J S JS

The Prostate 20131216 4

<h4>Background</h4>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 und ...[more]

PMID: 24338924

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Project description:IntroductionLeptin is a metabolic peptide hormone produced by adipocytes, with proven roles in proliferation of prostate cancer cells and of prostate cells in animal models of benign prostatic hyperplasia (BPH). Thus, the role of leptin as a molecular link connecting BPH and lower urinary tract symptoms (LUTS) suggestive of BPH with metabolic symptoms appears feasible but is still unknown. In fact, a connection between metabolic syndrome and BPH is becoming increasingly evident from epidemiologic studies. Key factors of Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS) are increased prostate smooth muscle tone, and prostate enlargement. Here, we examined the effects of leptin on contraction of human prostate smooth muscle and on growth of stromal cells.MethodsWe performed microarray analysis to identify genes (fold change ≥ 1.5) associated with BPH/LUTS progression, such as those involved in proliferation, apoptosis, and mitochondrial metabolism, in rat prostate tissue (data from GSE129561). We then used electric field stimulation (EFS) to induce frequency-dependent, neurogenic contractions of human prostate strips, which were enhanced by leptin. We also examined the effect of leptin on human prostate stromal cells (WPMY-1) and found increased cell proliferation and viability upon exposure. To explore the underlying mechanism, we conducted mitochondrial stress assay using near-infrared (NIR) fluorescent dye and flow cytometry (FACS) analysis and observed reduced cellular apoptosis and preserved mitochondrial membrane potential (∆ψM) after leptin treatment.ResultsMicroarray analysis reveals that leptin regulates prostate smooth muscle contraction and stromal cell proliferation, shedding new light on its involvement in BPH/LUTS pathogenesis and mitochondrial function. We found that leptin enhanced the proliferation rate of prostate stromal cells relative to the control group (0.67 ± 0.05 vs 0.54 ± 0.08, p-value= 0.024). Moreover, leptin (100 ng/mL) potentiated the frequency-dependent, neurogenic contractions of prostate strips elicited by EFS (p= 0.047 between leptin and control group). We also show that leptin treatment increased the mitochondrial membrane potential of prostate stromal cells and inhibited mitochondrial apoptosis.DiscussionOur results indicate that leptin stimulates the contractility and proliferation of smooth muscle and stromal cells in the human prostate, implying a potential role for leptin in exacerbating BPH/LUTS in obese men. Leptin modulation may be a beneficial therapeutic strategy for patients with metabolic syndrome and BPH/LUTS. Further studies are warranted to elucidate the mechanisms and implications of the leptin system in BPH/LUTS.

Dataset Information

Extracellular Hsp90 mediates an NF-?B dependent inflammatory stromal program: implications for the prostate tumor microenvironment.

Publications

Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor microenvironment.

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