TY - JOUR
T1 - HIF signaling in osteoblast-lineage cells promotes systemic breast cancer growth and metastasis in mice
AU - Devignes, Claire Sophie
AU - Aslan, Yetki
AU - Brenot, Audrey
AU - Devillers, Audrey
AU - Schepers, Koen
AU - Fabre, Stéphanie
AU - Chou, Jonathan
AU - Casbon, Amy Jo
AU - Werb, Zena
AU - Provot, Sylvain
N1 - Funding Information:
We thank all the investigators who generated and made available the floxed/transgenic mice used in these studies: V. Haase (Vhlh floxed), R. Johnson (Hif-1 floxed), and A. McMahon (Osx-Cre::GFP); Stanford Photonics for providing the Onyx/M dark box system for in vivo luminescence imaging; J. Ghysdael for providing shCxcr4 lentiviruses; E. Jaffee for providing NT2.5 cells; A. Ostertag for advice on statistical analyses; and M. Cohen-Solal for advice on bone histomorphometry. This study was initiated through the support of the University of California, San Francisco Academic Senate Committee on Research Fund 34935/500394 (to S.P.) and was supported by NIH Grants R01 CA057621, R01 CA180039, and U01 CA199315 (to Z.W.), by INSERM, by the Fondation pour la Recherche Contre le Cancer (ARC) as part of the ATIP-AVENIR Program Project Grants R10081HS and C14007HS (to S.P.), and by an Association le Cancer du Sein Parlons-en Pink Ribbon Award (to S.P.). C.-S.D. was supported by the French Ministry of Research and the Fondation ARC and was the recipient of the French Society for Miner-alized Tissue Biology Award. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.
Funding Information:
and M. Cohen-Solal for advice on bone histomorphometry. This study was initiated through the support of the University of California, San Francisco Academic Senate Committee on Research Fund 34935/500394 (to S.P.) and was supported by NIH Grants R01 CA057621, R01 CA180039, and U01 CA199315 (to Z.W.), by INSERM, by the Fondation pour la Recherche Contre le Cancer (ARC) as part of the ATIP-AVENIR Program Project Grants R10081HS and C14007HS (to S.P.), and by an Association le Cancer du Sein Parlons-en Pink Ribbon Award (to S.P.). C.-S.D. was supported by the French Ministry of Research and the Fondation ARC and was the recipient of the French Society for Mineralized Tissue Biology Award. The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.
PY - 2018/1/30
Y1 - 2018/1/30
N2 - 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.
AB - 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.
KW - Bone
KW - Breast cancer
KW - HIF
KW - Hypoxia
KW - Metastasis
UR - http://www.scopus.com/inward/record.url?scp=85041214403&partnerID=8YFLogxK
U2 - 10.1073/pnas.1718009115
DO - 10.1073/pnas.1718009115
M3 - Article
C2 - 29339479
AN - SCOPUS:85041214403
SN - 0027-8424
VL - 115
SP - E992-E1001
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -