Hypoxic Microenvironment and Metastatic Bone Disease

Abstract

Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible factors, which play critical roles in the key stages of metastatic dissemination including angiogenesis, epithelial-mesenchymal transition, invasion, maintenance of cancer stem cells, tumor cell dormancy, release of extracellular vesicles, and generation of pre-metastatic niches. Hypoxia also affects bone cells, such as osteoblasts and osteoclasts, and immune cells, which also act to support the development and progression of bone metastases. Paradoxically, hypoxia and related signaling molecules are recognized as high-priority therapeutic targets and many candidate drugs are currently under preclinical and clinical investigation. The present review focuses on our current knowledge of the potential roles of hypoxia in cancer metastasis to bone by considering the interaction between metastatic cancer cells and the bone microenvironment. Current therapeutic approaches targeting hypoxia are also described.

Keywords: bone metastasis; hypoxia; hypoxia-inducible factors.

Figure 1

Hypoxic signaling in the bone-metastatic cascade. The figure summarizes hypoxia-induced and hypoxia inducible factor (HIF)-target genes involved in the key stages of the bone-metastatic cascade. Upregulated genes are shown in red and downregulated genes are in blue. Images adapted from Servier Medical Art (https://smart.servier.com/).