HIF targets in bone remodeling and metastatic disease.

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.