Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor microenvironment.
Extracellular Hsp90 mediates an NF-κB dependent inflammatory stromal program: implications for the prostate tumor microenvironment.
复制标题
DOI：
10.1002/pros.22761
复制
发表时间：
2014-04
期刊：
影响因子：
2.8
通讯作者：
Isaacs, J. S.
中科院分区：
文献类型：
--
作者：
Bohonowych, J. E.;Hance, M. W.;Nolan, K. D.;Defee, M.;Parsons, C. H.;Isaacs, J. S.
肿瘤微环境（TME）在支持和促进肿瘤生长和进展中发挥着重要作用。炎性基质是前列腺 TME 的普遍特征，已知前列腺肿瘤与其反应性基质共同进化。反应性基质内的癌症相关成纤维细胞 (CAF) 在分泌导致这种炎症性 TME 的细胞因子方面发挥着重要作用。尽管已经确定了许多炎症介质，但对引发反应性基质形成的关键因素仍缺乏清晰的了解。我们探讨了肿瘤分泌的细胞外 Hsp90 α (eHsp90α) 是否可能引发反应性基质。将前列腺基质成纤维细胞 (PrSF) 暴露于外源 Hsp90α 蛋白或来自表达 eHsp90α 的前列腺癌细胞的条件培养基 (CM)，并评估信号传导、运动性和原型反应标记物的表达。同时，利用 ELISA 测定来表征 Hsp90α 介导的分泌因子。我们报告说，PrSF 暴露于 eHsp90 会上调 IL-6 和 IL-8 的转录和蛋白质分泌，IL-6 和 IL-8 是已知在前列腺癌进展中发挥致病作用的关键炎症细胞因子。细胞因子分泌部分通过 MEK/ERK 和 NF-κB 依赖性途径进行调节。分泌的 eHsp90α 还促进致癌炎症介质信号转导子和转录激活子 (STAT3) 的快速且持久的激活。最后，eHsp90 诱导 MMP-3 的表达，MMP-3 是众所周知的纤维化和肌成纤维细胞表型的介质。我们的结果为 eHsp90α 作为最终导致炎症和反应性基质的信号事件转导器提供了令人信服的支持，从而赋予了与前列腺癌进展相关的特性。
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 (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. 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. 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.
登录
查看更多内容
影响因子：
3.7
作者：
Gopal U;Bohonowych JE;Lema-Tome C;Liu A;Garrett-Mayer E;Wang B;Isaacs JS
通讯作者：
Isaacs JS
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
50.3
作者：
Isaacs, JS;Xu, WP;Neckers, L
通讯作者：
Neckers, L
影响因子：
3.8
作者：
Barton BE;Murphy TF;Adem P;Watson RA;Irwin RJ;Huang HF
通讯作者：
Huang HF
影响因子：
5.3
作者：
Cheng, Chieh-Fang;Fan, Jianhua;Li, Wei
通讯作者：
Li, Wei