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Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):E992-E1001. doi: 10.1073/pnas.1718009115. Epub 2018 Jan 16.

HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice.

Author information

1
INSERM U1132, Hôpital Lariboisière, 75010 Paris, France.
2
Department of Anatomy, University of California, San Francisco, CA 94143.
3
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300RC Leiden, The Netherlands.
4
Department of Anatomy, University of California, San Francisco, CA 94143; zena.werb@ucsf.edu sylvain.provot@inserm.fr.
5
INSERM U1132, Hôpital Lariboisière, 75010 Paris, France; zena.werb@ucsf.edu sylvain.provot@inserm.fr.

Abstract

Bone metastasis involves dynamic interplay between tumor cells and the local stromal environment. In bones, local hypoxia and activation of the hypoxia-inducible factor (HIF)-1α in osteoblasts are essential to maintain skeletal homeostasis. However, the role of osteoblast-specific HIF signaling in cancer metastasis is unknown. Here, we show that osteoprogenitor cells (OPCs) are located in hypoxic niches in the bone marrow and that activation of HIF signaling in these cells increases bone mass and favors breast cancer metastasis to bone locally. Remarkably, HIF signaling in osteoblast-lineage cells also promotes breast cancer growth and dissemination remotely, in the lungs and in other tissues distant from bones. Mechanistically, we found that activation of HIF signaling in OPCs increases blood levels of the chemokine C-X-C motif ligand 12 (CXCL12), which leads to a systemic increase of breast cancer cell proliferation and dissemination through direct activation of the CXCR4 receptor. Hence, our data reveal a previously unrecognized role of the hypoxic osteogenic niche in promoting tumorigenesis beyond the local bone microenvironment. They also support the concept that the skeleton is an important regulator of the systemic tumor environment.

KEYWORDS:

HIF; bone; breast cancer; hypoxia; metastasis

PMID:
29339479
PMCID:
PMC5798374
DOI:
10.1073/pnas.1718009115
[Indexed for MEDLINE]
Free PMC Article

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