Abstract 505: 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 have demonstrated that HIFs mediate paracrine signaling between breast cancer cells (BCCs) and mesenchymal stem cells (MSCs) that facilitate metastasis. In an orthotopic implantation model, MSCs were recruited to primary breast tumors and promoted BCC metastasis to lymph nodes and lungs in a HIF-dependent manner. In vitro gene analysis of co-culture of MSCs with BCCs showed induced expression of the chemokine CXCL10 in MSCs and its cognate receptor CXCR3 in BCCs, which was augmented by hypoxia. Further we showed that CXCR3 expression was blocked in co-cultures treated with neutralizing antibody against CXCL10. Conversely, CXCL10 expression was blocked in MSCs co-cultured with BCCs that did not express CXCR3 or HIFs. MSC co-culture did not enhance the metastasis of CXCR3-deficient or HIF-deficient BCCs. Co-culture of MSCs with BCCs augmented HIF activity in BCCs. BCCs and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGF1, respectively, in a HIF-dependent manner. The expression of CXCL10 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. Citation Format: Pallavi Chaturvedi, Daniele Gilkes, Gregg Semenza. Hypoxia inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 505. doi:10.1158/1538-7445.AM2013-505