Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis
Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis
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DOI：
10.1172/jci64993
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发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
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作者：
Chaturvedi, Pallavi;Gilkes, Daniele M.;Semenza, Gregg L.
转移涉及癌症和基质细胞之间的关键相互作用。肿瘤内缺氧通过激活缺氧诱导因子（HIF）促进转移。我们证明HIF介导乳腺癌细胞（BCC）和间充质干细胞（MSC）之间的旁分泌信号，以促进转移。在小鼠原位移植模型中，MSC被招募到原发性乳腺肿瘤，并以HIF依赖性方式促进BCC转移到LN和肺。骨髓间充质干细胞与基底细胞共培养可增强基底细胞中HIF活性。此外，共培养诱导MSC中趋化因子CXCL10和BCC中同源受体CXCR3的表达，这是由缺氧增强。在用针对CXCL10的中和抗体处理的共培养物中，CXCR3表达被阻断。相反，在共培养的MSC中，CXCL10表达被阻断。与不表达CXCR3或HIF的BCC一起。MSC共培养并没有增强HIF缺陷型基底细胞癌的转移。BCCs和MSCs分别以HIF依赖的方式表达胎盘生长因子（PGF）及其同源受体VEGFR1，MSCs表达CXCL10依赖于BCCs表达PGF。PGF促进BCCs的转移，也促进MSC向肿瘤的归巢。因此，HIF介导BCCs和MSC之间复杂的双向旁分泌信号传导，刺激乳腺癌转移。
Metastasis involves critical interactions between cancer and stromal cells. Intratumoral hypoxia promotes metastasis through activation of hypoxia-inducible factors (HIFs). We demonstrate that HIFs mediate paracrine signaling between breast cancer cells (BCCs) and mesenchymal stein cells (MSCs) to promote metastasis. In a mouse orthotopic implantation model, MSCs were recruited to primary breast tumors and promoted BCC metastasis to LNs and lungs in a HIF-dependent manner. Coculture of MSCs with BCCs augmented HIF activity in BCCs. Additionally, coculture induced expression of the chemokine CXCL10 in MSCs and the cognate receptor CXCR3 in BCCs, which was augmented by hypoxia. CXCR3 expression was blocked in cocultures treated with neutralizing antibody against CXCL10. Conversely, CXCL10 expression was blocked in MSCs cocultured. with BCCs that did not express CXCR3 or HIFs. MSC coculture did not enhance the metastasis of HIF-deficient BCCs. BCCs and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGFR1, respectively, in a HIF-dependent manner, and CXCL10 expression by MSCs was dependent on PGF expression by BCCs. PGF promoted metastasis of BCCs and also facilitated homing of MSCs to tumors. Thus, HIFs mediate complex and bidirectional paracrine signaling between BCCs and MSCs that stimulates breast cancer metastasis.