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

Claire Sophie Devignes, Yetki Aslan, Audrey Brenot, Audrey Devillers, Koen Schepers, Stéphanie Fabre, Jonathan Chou, Amy Jo Casbon, Zena Werb, Sylvain Provot

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)E992-E1001
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number5
DOIs
StatePublished - Jan 30 2018

Keywords

  • Bone
  • Breast cancer
  • HIF
  • Hypoxia
  • Metastasis

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