bFGF Promotes Migration and Induces Cancer-Associated Fibroblast Differentiation of Mouse Bone Mesenchymal Stem Cells to Promote Tumor Growth
bFGF Promotes Migration and Induces Cancer-Associated Fibroblast Differentiation of Mouse Bone Mesenchymal Stem Cells to Promote Tumor Growth
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bFGF 促进小鼠骨间充质干细胞迁移并诱导癌症相关成纤维细胞分化，从而促进肿瘤生长
DOI：
10.1089/scd.2016.0217
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发表时间：
2016
影响因子：
4
通讯作者：
Wu Xiong Zhi
中科院分区：
文献类型：
--
作者：
Yang Xue;Hao Jian;Mao Yu;Jin Zi Qi;Cao Rui;Zhu Cui Hong;Liu Xiao Hui;Liu Chang;Ding Xiu Li;Wang Xiao Dong;Chen Dan;Wu Xiong Zhi
肿瘤招募骨髓间充质干细胞（BMSC）定位于肿瘤部位，这诱导它们转化为促进肿瘤进展的癌症相关成纤维细胞（CAF）。然而，这一过程在分子水平上知之甚少。在本研究中，我们发现4 T1乳腺癌细胞促进BMSCs迁移，bFGF中和抗体抑制肿瘤条件培养基诱导的BMSCs迁移。此外，外源性bFGF在体外以剂量依赖的方式促进BMSCs的迁移。BMSCs在条件培养液和异种移植瘤模型中均能促进4 T1肿瘤细胞的增殖。戏剧性地，BMSCs表达CAF标记物并在肿瘤微环境中产生胶原，并且这种转变被bFGF抗体阻断。此外，外源性bFGF诱导BMSCs向CAF分化。bFGF诱导BMSC转分化过程中Erk 1/2和Smad 3的磷酸化增加，Erk抑制剂PD 98059可阻断bFGF诱导的Erk和Smad 3磷酸化，提示Erk/Smad 3信号通路参与bFGF诱导BMSC转分化。总的来说，我们的研究结果表明，bFGF信号在BMSC招募和转分化成CAFs以及随后的促肿瘤效应中起着不可或缺的作用，通过bFGF抑制靶向肿瘤基质可能是抑制肿瘤进展的一种有前途的策略。
Tumors recruit bone mesenchymal stem cells (BMSCs) to localize to tumor sites, which induces their conversion into cancer-associated fibroblasts (CAFs) that facilitate tumor progression. However, this process is poorly understood on the molecular level. In this study, we found that 4T1 breast cancer cells promoted the migration of BMSCs, and bFGF neutralizing antibody inhibited the migration of BMSCs induced by a tumor-conditioned medium. In addition, exogenous bFGF enhanced the migration of BMSCs in a dose-dependent manner in vitro. Furthermore, BMSCs promoted the proliferation of 4T1 tumor cells under BMSC-conditioned medium and in tumor xenograft model. Dramatically, BMSCs expressed CAF markers and produced collagen in the tumor microenvironment, and this transition was blocked by bFGF antibody. In addition, exogenous bFGF induced CAF differentiation of BMSCs. And bFGF increased phosphorylation of Erk1/2 and Smad3 in BMSCs and Erk inhibitor PD98059 was shown to block bFGF-induced Erk and Smad3 phosphorylation, suggesting that Erk/Smad3 signaling pathway involved in BMSC transdifferentiation induced by bFGF. Collectively, our results indicate that bFGF signaling plays indispensable roles in BMSC recruitment and transdifferentiation into CAFs and the consequent protumor effects, and targeting tumor stroma through bFGF inhibition maybe a promising strategy to suppress tumor progression.