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PMID: 25681658 Published · ppublish English Journal Article Review

HIF targets in bone remodeling and metastatic disease.

Pharmacology & therapeutics ·Vol. 150 ·2015-06-00 ·Pages 169-77

Johnson RW, Schipani E, Giaccia AJ

Abstract

The bone marrow is a hypoxic microenvironment that is rich in growth factors and blood vessels and is readily colonized by tumor cells disseminated from numerous cancers including tumors of the breast, prostate, lung, and skin. The origin of metastatic growth promoting factors for tumor cells disseminated to the bone marrow is derived from multiple sources: the bone matrix, which is a reservoir for growth factors, and cells residing in the marrow and along bone surfaces, such as osteoblasts, osteoclasts, macrophages, and T cells, which secrete cytokines and chemokines. Low oxygen levels within the bone marrow induce hypoxia signaling pathways such as hypoxia inducible factor (HIF), which is regulated by oxygen requiring prolyl hydroxylases (PHDs) and von Hippel-Lindau (VHL) tumor suppressor. These hypoxia signaling pathways have profound effects on bone development and homeostasis. Likewise, hypoxic conditions observed in local breast and prostate tumors point to a role for hypoxia-inducible genes in metastasis to and colonization of the bone marrow. This review will explore the role of hypoxia-regulated factors in bone development and remodeling, and how these elements may contribute to solid tumor metastasis to the bone.

Keywords
Bone metastasis Bone microenvironment HIF Hypoxia PHD Remodeling
MeSH Terms
Antineoplastic Agents/pharmacology,therapeutic use Bone Development Bone Neoplasms/drug therapy,metabolism,pathology,secondary Bone Remodeling Cell Hypoxia Humans Hypoxia-Inducible Factor 1/metabolism Molecular Targeted Therapy Prolyl Hydroxylases/metabolism Tumor Microenvironment Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
Antineoplastic Agents Hypoxia-Inducible Factor 1 Prolyl Hydroxylases Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Johnson Rachelle W
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States.
Schipani Ernestina
Department of Orthopaedic Surgery, Medical School, University of Michigan, Ann Arbor, MI, United States; Department of Medicine and Endocrinology, Medical School, University of Michigan, Ann Arbor, MI, United States.
Giaccia Amato J
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States. Electronic address: giaccia@stanford.edu.
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Article Info
Journal
Pharmacology & therapeutics
Abbr.
Pharmacol Ther
ISSN
1879-016X
DOI
10.1016/j.pharmthera.2015.02.002
Email
giaccia@stanford.edu
Published
2015-06-00
Epub
2015-00-12
Pages
169-77
Language
English
Region
England
NLM ID
7905840
PMCID
PMC4414805
Subset
IM
Grants
NIAMS NIH HHS · R01 AR065403 · United States
External Links
PubMed source DOI: 10.1016/j.pharmthera.2015.02.002 PMC Full Text View journal details
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