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: A cell line derived from Dunn murine osteosarcoma, LM8 was established as a highly lung metastatic subline by in vivo selection through pulmonary metastasis.26 Furthermore, LM8 formed osteoblastic lesions in the bone marrow after intratibial injection.27 These facts motivated us to assess bone metastasis formation following intracardiac (i.c.) injection of LM8. We isolated an LM8 subclone (LM8/luc), which stably expresses a firefly luciferase and preferentially metastasizing to the bone. Bioluminescence signals were typically obtained around the hind limbs of nude mice within 1 week of i.c. injection of LM8/luc (Fig.1a). We confirmed LM8/luc metastasis in the bone marrow by ex vivo imaging and histological analysis of hind limb bones (Fig.1b,c). The multimodal imaging of LM8/luc bone metastasis revealed the precise location of bone metastasis in the femur and ilium (Figs1d,S1) and aberrant bone formation at the metastatic sites 21 days after LM8/luc transplantation (Figs1e,S2).
Affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.