Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria.
Division of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
Int J Cancer. 2018 Jul 15;143(2):383-395. doi: 10.1002/ijc.31316. Epub 2018 Mar 1.
Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri-tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF-associated marker expression and migration of TGFβ1-activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA-mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1-driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1-activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4- and TGFβ receptor-dependent manner. Importantly, GKT137831 also attenuated PCa cell-driven fibroblast activation. Collectively, these findings suggest the TGFβ-Nox4 signaling axis is a key interface to dysregulated reciprocal stromal-epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal-targeted approach to complement current PCa treatment modalities.
癌相关成纤维细胞（CAFs）在前列腺癌（PCa）发展和进展中起着关键的肿瘤支持作用。我们之前报道过，活性氧（ROS）产生酶 NADPH 氧化酶 4（Nox4）对于 TGFβ1 介导的原代前列腺人成纤维细胞向 CAF 样表型的激活是必不可少的。本研究旨在进一步研究前列腺 Nox4 的功能相关性，并确定是否抑制基质 Nox4 可阻断旁分泌介导的与 PCa 相关的过程。原位杂交显示，临床 PCa 中 Nox4 mRNA 水平明显升高，主要位于肿瘤周围基质中，肿瘤灶周围基质中 Nox4 染色强烈，表达大量 TGFβ 蛋白水平。在药理相关浓度下，Nox1/Nox4 抑制剂 GKT137831 可减弱 ROS 产生、CAF 相关标志物表达和 TGFβ1 激活但非非激活原代人前列腺成纤维细胞的迁移。Nox4 但不是 Nox1 的 shRNA 介导沉默获得了相似的效果，表明 GKT137831 主要通过 Nox4 抑制来阻断 TGFβ1 驱动的成纤维细胞激活。此外，抑制基质 Nox4 可阻断 TGFβ1 激活的前列腺成纤维细胞条件培养基诱导的 PCa 细胞系的增殖和迁移增强。这些作用不仅限于重组 TGFβ1，因为内源分泌高水平 TGFβ1 的 PCa 细胞系的条件培养基以基质 Nox4 和 TGFβ 受体依赖的方式诱导成纤维细胞激活。重要的是，GKT137831 还可减弱 PCa 细胞诱导的成纤维细胞激活。总之，这些发现表明 TGFβ-Nox4 信号轴是失调的基质-上皮相互作用的关键界面在 PCa 病理生理学中，并为进一步研究 Nox4 抑制作为补充当前 PCa 治疗方式的基质靶向方法的适用性提供了强有力的理由。
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