Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion.
Transforming growth factor-beta signaling-deficient fibroblasts enhance hepatocyte growth factor signaling in mammary carcinoma cells to promote scattering and invasion.
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DOI：
10.1158/1541-7786.mcr-07-2203
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Moses HL
中科院分区：
文献类型：
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作者：
Cheng N;Chytil A;Shyr Y;Joly A;Moses HL
成纤维细胞是肿瘤微环境的主要细胞成分，部分通过分泌细胞外基质蛋白、生长因子和血管生成因子来调节肿瘤细胞行为。在之前的研究中，成纤维细胞中 II 型 TGF-β 受体 (Tgfbr2FspKO) 的条件性缺失被证明可促进成纤维细胞中乳腺肿瘤的转移：小鼠上皮细胞共移植研究，与 HGF 表达增加相关。在此，我们推进研究结果表明，Tgfbr2FspKO 成纤维细胞增强 HGF/c-Met 和 HGF/Ron 信号传导，从而促进乳腺癌细胞的分散和侵袭。通过siRNA沉默和药物抑制剂阻断c-Met和Ron可显着减少Tgfbr2FspKO成纤维细胞引起的乳腺癌细胞分散和侵袭。此外，c-Met 和 Ron 的中和抗体显着抑制 HGF 诱导的细胞分散和侵袭，这与 Stat3 和 p42/44MAPK 磷酸化减少相关。通过药理抑制和 siRNA 沉默对 Stat3 和 MAPK 信号通路的研究揭示了这两种通路之间的协同相互作用，可调节 HGF 诱导的乳腺肿瘤细胞的侵袭、分散和运动。此外，虽然发现 c-Met 可调节 Stat3 和 MAPK 信号通路，但 Ron 被发现可调节乳腺癌细胞中的 Stat3，但不能调节 MAPK 信号通路。这些研究证明了成纤维细胞中 TGF-β 信号传导的肿瘤抑制作用，部分是通过抑制乳腺成纤维细胞和上皮细胞之间的 HGF 信号传导来实现的。这些研究描述了 HGF 和 TGF-β 信号在介导肿瘤中的复杂功能作用：乳腺肿瘤细胞分散和侵袭期间的基质相互作用，对转移过程具有重要意义。
Fibroblasts are major cellular components of the tumor microenvironment, regulating tumor cell behavior in part through secretion of extracellular matrix proteins, growth factors and angiogenic factors. In previous studies, conditional deletion of the type II TGF-β receptor in fibroblasts (Tgfbr2FspKO) was shown to promote mammary tumor metastasis in fibroblast: epithelial cell co-transplantation studies in mice, correlating with increased expression of HGF. Here, we advance our findings to show that Tgfbr2FspKO fibroblasts enhance HGF/c-Met and HGF/Ron signaling to promote scattering and invasion of mammary carcinoma cells. Blockade of c-Met and Ron by siRNA silencing and pharmacologic inhibitors significantly reduced mammary carcinoma cell scattering and invasion caused by Tgfbr2FspKO fibroblasts. Moreover, neutralizing antibodies to c-Met and Ron significantly inhibited HGF-induced cell scattering and invasion correlating with reduced Stat3 and p42/44MAPK phosphorylation. Investigation of the Stat3 and MAPK signaling pathways by pharmacologic inhibition and siRNA silencing revealed a cooperative interaction between the two pathways to regulate HGF- induced invasion, scattering and motility of mammary tumor cells. Furthermore, while c-Met was found to regulate both the Stat3 and MAPK signaling pathways, Ron was found to regulate Stat3, but not MAPK signaling in mammary carcinoma cells. These studies demonstrate a tumor suppressive role for TGF-β signaling in fibroblasts, in part by suppressing HGF signaling between mammary fibroblasts and epithelial cells. These studies characterize complex functional roles for HGF and TGF-β signaling in mediating tumor: stromal interactions during mammary tumor cell scattering and invasion, with important implications in the metastatic process.