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Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia.

Kuchimaru T, Hoshino T, Aikawa T, Yasuda H, Kobayashi T, Kadonosono T, Kizaka-Kondoh S - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.

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Murine osteosarcoma LM8 cells develop osteoblastic bone metastasis. (a) Representative time course bioluminescence (BL) images after intracardiac (i.c.) transplantation of LM8/luc. (b) Ex vivo imaging of LM8/luc tumor-bearing hind limb shown in (a) (14 days after LM8/luc injection). LM8/luc metastasis signal is indicated by an arrowhead. Scale bar = 5 mm. (c) Hematoxylin–eosin staining of hind limb bone with LM8 metastasis (T) of (b). Scale bar = 100 μm. (d) Multimodal imaging. Images were obtained 14 days after i.c. transplantation of LM8/luc. The dashed line indicates imaging section of the transverse image. Micro CT, micro X-ray computed tomography. (e) Aberrant bone formation due to osteoblastic bone metastasis in the femur and tibia. Micro X-ray CT images were obtained 21 days after i.c. injection of LM8 (upper panels). Scale bar = 1 mm. The lower panels indicate that von Kossa staining of the same metastasis-free (Meta−) and bone metastatic (Meta+) femurs as the upper panels. Scale bar = 500 μm.
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fig01: Murine osteosarcoma LM8 cells develop osteoblastic bone metastasis. (a) Representative time course bioluminescence (BL) images after intracardiac (i.c.) transplantation of LM8/luc. (b) Ex vivo imaging of LM8/luc tumor-bearing hind limb shown in (a) (14 days after LM8/luc injection). LM8/luc metastasis signal is indicated by an arrowhead. Scale bar = 5 mm. (c) Hematoxylin–eosin staining of hind limb bone with LM8 metastasis (T) of (b). Scale bar = 100 μm. (d) Multimodal imaging. Images were obtained 14 days after i.c. transplantation of LM8/luc. The dashed line indicates imaging section of the transverse image. Micro CT, micro X-ray computed tomography. (e) Aberrant bone formation due to osteoblastic bone metastasis in the femur and tibia. Micro X-ray CT images were obtained 21 days after i.c. injection of LM8 (upper panels). Scale bar = 1 mm. The lower panels indicate that von Kossa staining of the same metastasis-free (Meta−) and bone metastatic (Meta+) femurs as the upper panels. Scale bar = 500 μm.

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).


Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia.

Kuchimaru T, Hoshino T, Aikawa T, Yasuda H, Kobayashi T, Kadonosono T, Kizaka-Kondoh S - Cancer Sci. (2014)

Murine osteosarcoma LM8 cells develop osteoblastic bone metastasis. (a) Representative time course bioluminescence (BL) images after intracardiac (i.c.) transplantation of LM8/luc. (b) Ex vivo imaging of LM8/luc tumor-bearing hind limb shown in (a) (14 days after LM8/luc injection). LM8/luc metastasis signal is indicated by an arrowhead. Scale bar = 5 mm. (c) Hematoxylin–eosin staining of hind limb bone with LM8 metastasis (T) of (b). Scale bar = 100 μm. (d) Multimodal imaging. Images were obtained 14 days after i.c. transplantation of LM8/luc. The dashed line indicates imaging section of the transverse image. Micro CT, micro X-ray computed tomography. (e) Aberrant bone formation due to osteoblastic bone metastasis in the femur and tibia. Micro X-ray CT images were obtained 21 days after i.c. injection of LM8 (upper panels). Scale bar = 1 mm. The lower panels indicate that von Kossa staining of the same metastasis-free (Meta−) and bone metastatic (Meta+) femurs as the upper panels. Scale bar = 500 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig01: Murine osteosarcoma LM8 cells develop osteoblastic bone metastasis. (a) Representative time course bioluminescence (BL) images after intracardiac (i.c.) transplantation of LM8/luc. (b) Ex vivo imaging of LM8/luc tumor-bearing hind limb shown in (a) (14 days after LM8/luc injection). LM8/luc metastasis signal is indicated by an arrowhead. Scale bar = 5 mm. (c) Hematoxylin–eosin staining of hind limb bone with LM8 metastasis (T) of (b). Scale bar = 100 μm. (d) Multimodal imaging. Images were obtained 14 days after i.c. transplantation of LM8/luc. The dashed line indicates imaging section of the transverse image. Micro CT, micro X-ray computed tomography. (e) Aberrant bone formation due to osteoblastic bone metastasis in the femur and tibia. Micro X-ray CT images were obtained 21 days after i.c. injection of LM8 (upper panels). Scale bar = 1 mm. The lower panels indicate that von Kossa staining of the same metastasis-free (Meta−) and bone metastatic (Meta+) femurs as the upper panels. Scale bar = 500 μm.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus