Vascular Program, Johns Hopkins Institute for Cell Engineering, 733 North Broadway, Baltimore, Maryland 21205, USA.
J Clin Invest. 2013 Jan;123(1):189-205. doi: 10.1172/JCI64993. Epub 2012 Dec 17.
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 stem 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.
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 (HIFs) 促进转移。我们证明 HIFs 介导乳腺癌细胞 (BCCs) 和间充质干细胞 (MSCs) 之间的旁分泌信号，以促进转移。在小鼠原位植入模型中，MSCs 被招募到原发性乳腺癌肿瘤中，并以 HIF 依赖的方式促进 BCC 转移到 LNs 和肺部。MSCs 与 BCC 的共培养增强了 BCC 中的 HIF 活性。此外，共培养诱导了 MSCs 中趋化因子 CXCL10 和 BCC 中同源受体 CXCR3 的表达，而缺氧则增强了这种表达。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，在与不表达 CXCR3 或 HIF 的 BCC 共培养的 MSC 中，阻断了 CXCL10 的表达。MSC 共培养并未增强 HIF 缺陷型 BCC 的转移。BCC 和 MSC 分别以 HIF 依赖的方式表达胎盘生长因子 (PGF) 和其同源受体 VEGFR1，而 MSC 中 CXCL10 的表达依赖于 BCC 中 PGF 的表达。PGF 促进了 BCC 的转移，也促进了 MSCs 向肿瘤的归巢。因此，HIFs 介导了 BCC 和 MSCs 之间复杂的双向旁分泌信号，刺激了乳腺癌的转移。
