Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia.
Bottom Line: We found that treatment with receptor activator of factor-κB ligand (RANKL) increased osteoblastic bone metastasis when given at the same time as intracardiac injection of cancer cells, but failed to increase metastasis when given 4 days after cancer cell injection, suggesting that RANKL-induced bone resorption facilitates growth of cancer cells colonized in the bone.We show that insulin-like growth factor-1 released from the bone during bone resorption and hypoxia-inducible factor activity in cancer cells cooperatively promoted survival and proliferation of cancer cells in bone marrow.These results suggest a mechanism that bone resorption and hypoxic stress in the bone microenvironment cooperatively play an important role in establishing osteoblastic metastasis.
Affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.Show MeSH
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Mentions: In osteoblastic bone metastasis, activated osteoblasts are thought to release growth factors leading to the proliferation of cancer cells, however, these growth factors have not yet been identified.9 In this work, we suggest that IGF-1 is the most reasonable candidate because IGF-1 promoted LM8 colonization at the metastatic sites, and because the IGF/IGFR signaling pathway, such as Igf1r expression and IGFR phosphorylation, was strongly activated in LM8 cells under hypoxic conditions (Fig.4c,d). We also showed that HIF was strongly activated in metastasized LM8 in the physiologically hypoxic bone microenvironment (Fig.3e), and that IGF-1 enhanced HIF expression and activity under hypoxic conditions (Fig.4e,f). These findings are consistent with previous studies showing that activation of HIF enhances cancer cell homing and metastatic progression in the bone marrow.16,17,28,29 Together with previous reports that IGF-1 activates HIF in various cancer cells,31,32 the cross-talk between IGF/IGFR signaling and hypoxia would be a key event that promotes osteoblastic bone metastasis (Fig.5), and is a potential target for effective therapy for bone metastasis.
Affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.