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

Research output: Contribution to journalArticle

155 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)189-205
Number of pages17
JournalJournal of Clinical Investigation
Volume123
Issue number1
DOIs
StatePublished - Jan 2 2013

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Neoplastic Stem Cells
Mesenchymal Stromal Cells
Breast Neoplasms
Neoplasm Metastasis
Coculture Techniques
Paracrine Communication
Intercellular Signaling Peptides and Proteins
Hypoxia
CXCR3 Receptors
Chemokine CXCL10
Cell Hypoxia
Stromal Cells
Neutralizing Antibodies
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 123, No. 1, 02.01.2013, p. 189-205.

Research output: Contribution to journalArticle

Chaturvedi, P, Gilkes, DM, Wong, CCL, Kshitiz, , Luo, W, Zhang, H, Wei, H, Takano, N, Schito, L, Levchenko, A & Semenza, GL 2013, 'Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis', Journal of Clinical Investigation, vol. 123, no. 1, pp. 189-205. https://doi.org/10.1172/JCI64993
Chaturvedi, Pallavi ; Gilkes, Daniele M. ; Wong, Carmen Chak Lui ; Kshitiz, ; Luo, Weibo ; Zhang, Huafeng ; Wei, Hong ; Takano, Naoharu ; Schito, Luana ; Levchenko, Andre ; Semenza, Gregg L. / Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 1. pp. 189-205.
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