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

Prostate - Tập 74 Số 4 - Trang 395-407 - 2014
JE Bohonowych1, MW Hance1, KD Nolan1, Michael DeFee2, C. W. PARSONS2, JS Isaacs1
1Cell and Molecular Pharmacology Medical University of South Carolina Charleston South Carolina
2Department of Dental Medicine Medical University of South Carolina Charleston South Carolina

Tóm tắt

BACKGROUNDThe 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 (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.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‐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.CONCLUSIONSOur 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. Prostate 74:395–407, 2014. © 2013 Wiley Periodicals, Inc.

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Tài liệu tham khảo

10.1530/ERC-12-0085

Tuxhorn JA, 2002, Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling, Clin Cancer Res, 8, 2912

Ayala G, 2003, Reactive stroma as a predictor of biochemical‐free recurrence in prostate cancer, Clin Cancer Res, 9, 4792

10.1016/j.humpath.2007.04.025

10.1038/nature03096

10.1038/nrc1877

10.1016/j.ccr.2012.02.022

10.1016/j.ccr.2009.12.041

10.1158/0008-5472.CAN-10-0785

10.1016/S0065-230X(08)60341-3

10.1056/NEJM198612253152606

10.1016/j.urology.2007.11.083

10.1128/MCB.10.5.2327

10.1074/jbc.M007532200

10.1038/sj.onc.1209942

10.1038/ni.2060

10.1016/j.ccr.2011.03.018

10.1126/science.8140422

10.1016/S1535-6108(03)00029-1

10.1074/jbc.M112.389015

10.1073/pnas.0908151106

10.1002/prca.200780073

10.1038/ncb1131

10.1074/jbc.M701803200

10.1038/sj.onc.1210897

10.1186/1471-2121-11-51

10.1038/sj.emboj.7601579

10.1128/MCB.01287-07

10.1074/jbc.275.1.189

10.1016/j.virol.2010.03.052

Defee MR, 2011, Extracellular Hsp90 serves as a co‐factor for NF‐kappaB activation and cellular pathogenesis induced by an oncogenic herpesvirus, Am J Cancer Res, 1, 687

10.1091/mbc.E11-06-0575

Olumi AF, 1999, Carcinoma‐associated fibroblasts direct tumor progression of initiated human prostatic epithelium, Cancer Res, 59, 5002

10.1038/nm.2890

10.1186/1471-2407-11-520

10.1371/journal.pone.0017649

10.1126/science.1090922

10.1073/pnas.1013805107

10.1016/S0002-9440(10)61776-2

10.1172/JCI46475

10.1038/nature04870

10.1016/j.cytogfr.2009.11.005

10.1016/j.ccr.2012.11.013

10.1158/0008-5472.CAN-10-0861

10.1074/jbc.M110.181941

10.1101/gad.211383.112

10.1016/j.ajpath.2011.06.041

10.1016/j.molcel.2012.01.015

10.1074/jbc.M800945200

10.1074/jbc.M110.139345

10.1038/onc.2009.279

10.1016/j.yexcr.2011.05.008

10.1038/nrc1275

10.1016/j.molcel.2012.06.014

10.1128/MCB.00204-12

10.1038/sj.onc.1204535

10.1158/1078-0432.CCR-0543-3

10.1158/1078-0432.CCR-06-0330

Inoue K, 2000, Interleukin 8 expression regulates tumorigenicity and metastases in androgen‐independent prostate cancer, Clin Cancer Res, 6, 2104

10.1002/pros.20223

10.1158/0008-5472.CAN-07-1162

Mora LB, 2002, Constitutive activation of Stat3 in human prostate tumors and cell lines: Direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells, Cancer Res, 62, 6659

10.1002/(SICI)1097-0045(20000215)42:3<239::AID-PROS10>3.0.CO;2-G

10.1186/1471-2407-1-19

10.1038/onc.2010.605

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Prostate

Tập 74 Số 4

395-407

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