Signaling Pathways Underlying Bone Metastasis: Hypoxia Signaling in Bone Metastasis and Beyond
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Purpose of Review
This review provides an overview of the mechanisms induced by hypoxia that take place within primary tumors and within the bone microenvironment, and that promote bone metastasis.
In primary tumors, hypoxia stimulates metastasis by promoting vascularization, epithelial-mesenchymal transition, immunosuppression, and by inducing pre-metastatic lesions in distant tissues. In bones, local hypoxia maintains bone homeostasis and has been recently shown to promote tumor colonization, to reactivate dormant tumor cells, and strikingly, to promote systemic cancer growth and dissemination beyond the skeleton.
Hypoxia is recognized as a critical component of the tumor microenvironment that strongly affects tumor growth and metastasis. However, our knowledge of the mechanisms induced locally by hypoxia in the skeleton that promotes tumor dissemination in bones and beyond is only emerging. Recent studies identified LIFR and CXCL12 as important factors downstream of hypoxia signaling in the bone, but other molecules and mechanisms will be likely discovered in the future.
KeywordsBone metastasis Hypoxia HIF Tumor microenvironment CXCL12 LIFR
This manuscript was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Fondation ARC pour la Recherche Contre le Cancer (Project # R10081HS and C14007HS to S. Provot). The work performed by the authors cited here also received the support of the University of California San Francisco Academic Senate Committee on Research (Fund # 34935/500394 to S. Provot), and the Association le Cancer du Sein Parlons-en (Pink Ribbon award to S. Provot). C.S. Devignes was supported by the French Ministry of Research, and the Fondation ARC, and was recipient of the Société Française de Biologie des Tissus Minéralisés (SFBTM) award. The authors would like to acknowledge the investigators who generated the work highlighted in this review and to apologize for the published articles that were not cited due to space constraints.
Compliance with Ethical Standards
Conflict of Interest
Claire-Sophie Devignes, Yetki Aslan, and Sylvain Provot declare no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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