Hypoxia-inducible factor–dependent breast cancer–mesenchymal stem cell bidirectional signaling promotes metastasis
Pallavi Chaturvedi, Daniele M. Gilkes, Carmen Chak Lui Wong, Kshitiz, Weibo Luo, Huafeng Zhang, Hong Wei, Naoharu Takano, Luana Schito, Andre Levchenko, Gregg L. Semenza
Pallavi Chaturvedi, Daniele M. Gilkes, Carmen Chak Lui Wong, Kshitiz, Weibo Luo, Huafeng Zhang, Hong Wei, Naoharu Takano, Luana Schito, Andre Levchenko, Gregg L. Semenza
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Research Article

Hypoxia-inducible factor–dependent breast cancer–mesenchymal stem cell bidirectional signaling promotes metastasis

Abstract

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.

Authors

Pallavi Chaturvedi, Daniele M. Gilkes, Carmen Chak Lui Wong, Kshitiz, Weibo Luo, Huafeng Zhang, Hong Wei, Naoharu Takano, Luana Schito, Andre Levchenko, Gregg L. Semenza

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Figure 13

Bidirectional signaling between BCCs and MSCs.

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Bidirectional signaling between BCCs and MSCs. Hypoxia induces recruitme...
Hypoxia induces recruitment of bone marrow–derived MSCs to the primary tumor site. MSC-BCC interaction induces CXCL10, CCL5, and VEGFR1 expression in MSCs and CXCR3, CCR5, and PGF expression in BCCs. MSC→BCC interaction is mediated by CCL5→CCR5 and CXCL10→CXCR3 signaling. BCC→MSC interaction is mediated by PGF→VEGFR1 signaling, which induces CXCL10 expression in MSCs and thereby establishes a positive feedback loop between the 2 cell types. The PGF→VEGFR1 interaction is important for MSC homing, and CXCL10→CXCR3 and CCL5→CCR5 signaling promote BCC metastasis. The consequence of these interactions is the expression of genes that enhance invasion and the metastasis of BCCs to the lungs and LNs. The expression of CXCR3 and PGF (and probably CCR5) in BCCs as well as VEGFR1 (and perhaps CXCL10 and CCL5) in MSCs are regulated by HIFs.