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PMID: 23318994 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 123 ·No. 1 ·2013-01-00 ·Pages 189-205

Chaturvedi P, Gilkes DM, Wong CC, Kshitiz, Luo W, Zhang H, Wei H, Takano N, Schito L, Levchenko A, Semenza GL

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.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/genetics,metabolism Breast Neoplasms/genetics,metabolism,pathology Cell Line, Tumor Chemokine CXCL10/biosynthesis,genetics Female Humans Lung Neoplasms/genetics,metabolism,pathology,secondary Mesenchymal Stem Cells/metabolism,pathology Mice Mice, SCID Neoplasm Metastasis Neoplasm Proteins/genetics,metabolism Neoplasm Transplantation Receptors, CXCR3/biosynthesis,genetics Signal Transduction Transplantation, Heterologous
Chemicals
Basic Helix-Loop-Helix Transcription Factors CXCL10 protein, human CXCR3 protein, human Chemokine CXCL10 Neoplasm Proteins Receptors, CXCR3
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Chaturvedi Pallavi
Vascular Program, Johns Hopkins Institute for Cell Engineering, 733 North Broadway, Baltimore, Maryland 21205, USA.
Gilkes Daniele M
Wong Carmen Chak Lui
Kshitiz
Luo Weibo
Zhang Huafeng
Wei Hong
Takano Naoharu
Schito Luana
Levchenko Andre
Semenza Gregg L
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI64993
Published
2013-01-00
Epub
2012-00-17
Pages
189-205
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3533298
Subset
IM
Grants
NCRR NIH HHS · P40 RR017447 · United States
NCI NIH HHS · U54 CA143868 · United States
NCI NIH HHS · U54-CA143868 · United States
NCRR NIH HHS · P40-RR017447 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1172/JCI64993 PMC Full Text View journal details
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