Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis.
Crosstalk between bone marrow-derived myofibroblasts and gastric cancer cells regulates cancer stemness and promotes tumorigenesis.
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骨髓来源的肌成纤维细胞和胃癌细胞之间的串扰调节癌症干性并促进肿瘤发生。
DOI：
10.1038/onc.2016.76
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发表时间：
2016-10-13
期刊：
影响因子：
8
通讯作者：
Tu, S. P.
中科院分区：
文献类型：
--
作者：
Zhu, L.;Cheng, X.;Shi, J.;Lin, J.;Chen, G.;Jin, H.;Liu, A. B.;Pyo, H.;Ye, J.;Zhu, Y.;Wang, H.;Chen, H.;Fang, J.;Cai, L.;Wang, T. C.;Yang, C. S.;Tu, S. P.
骨髓来源的细胞在癌症的发生和发展中起重要作用。我们以前的研究表明，小鼠骨髓源性肌成纤维细胞（BMF）增强肿瘤生长。在这项研究中，我们研究了BMF的作用机制。我们发现BMF与胃癌细胞共同注射显著促进肿瘤发生。共培养的BMF或BMF条件培养基（BMF-CM）诱导球的形成，表达干细胞的签名，并表现出自我更新，上皮细胞向间质转化和肿瘤起始的功能。此外，球中的CD 44+组分能够在连续传代的异种移植物中启动肿瘤发生并重建肿瘤。在共培养体系中，骨髓基质细胞分泌高水平的白细胞介素6（IL-6）和肝细胞生长因子（HGF），而癌细胞分泌高水平的转化生长因子β1（TGF-β1）。BMF-CM和IL-6激活BMF产生mHGF，mHGF激活人癌细胞中的信号转导和转录激活因子3（STAT 3）并上调TGF-β1。反过来，癌细胞CM刺激BMF产生IL-6，而IL-6被抗TGF-β1中和抗体抑制。通过特异性抑制剂阻断HGF/Met、JAK 2/STAT 3和TGF-β1信号传导抑制BMF诱导的球体形成。STAT 3在癌细胞中的敲低也抑制BMF诱导的球体形成和肿瘤发生。胃癌组织中TGF-β1与IL-6、HGF在间质细胞中的表达呈正相关。我们的研究结果表明，BMF来源的IL-6/HGF和癌细胞来源的TGF-β1介导BMF与胃癌细胞之间的相互作用，从而调节癌的干性并促进肿瘤的发生。靶向抑制BMF与癌细胞的相互作用可能成为肿瘤治疗的新策略。
Bone marrow-derived cells play important roles in cancer development and progression. Our previous studies demonstrated that murine bone marrow-derived myofibroblasts (BMFs) enhanced tumor growth. In this study, we investigated the mechanisms of BMF actions. We found that co-injection of BMFs with gastric cancer cells markedly promoted tumorigenesis. Co-cultured BMFs or BMF-conditioned medium (BMF-CM) induced the formation of spheres, which expressed stem cell signatures and exhibited features of self-renewal, epithelial-to-mesenchymal transition and tumor initiation. Furthermore, CD44+ fractions in spheres were able to initiate tumorigenesis and reestablish tumors in serially passaged xenografts. In co-culture systems, BMFs secreted high levels of murine interleukin-6 (IL-6) and hepatocyte growth factor (HGF), while cancer cells produced high level of transformation growth factor-β1 (TGF-β1). BMF-CM and IL-6 activated BMFs to produce mHGF, which activated signal transducer and activator of transcription 3 (STAT3) and upregulated TGF-β1 in human cancer cells. In return, cancer cell-CM stimulated BMFs to produce IL-6, which was inhibited by anti-TGF-β1 neutralizing antibody. Blockade of HGF/Met, JAK2/STAT3 and TGF-β1 signaling by specific inhibitors inhibited BMF-induced sphere formation. STAT3 knockdown in cancer cells also inhibited BMF-induced sphere formation and tumorigenesis. Moreover, TGF-β1 overexpression in cancer cells was co-related with IL-6 and HGF overexpression in stromal cells in human gastric cancer tissues. Our results demonstrate that BMF-derived IL-6/HGF and cancer cell-derived TGF-β1 mediate the interactions between BMFs and gastric cancer cells, which regulate cancer stemness and promote tumorigenesis. Targeting inhibition of the interactions between BMFs and cancer cells may be a new strategy for cancer therapy.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
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作者：
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DOI：
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发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
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