2004 Fiscal Year Final Research Report Summary
Roles of prostaglandin E on osteolysis due to cancer metastasis.
| Project/Area Number |
15590070
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | National University Corporation Tokyo University of Agriculture and Technology (2004)
Tokyo University of Pharmacy and Life Science (2003) |
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Principal Investigator |
MIYAURA Chisato National University Corporation Tokyo University of Agriculture and Technology, Institute of Symbiotic Science and Technology, Professor, 大学院・共生科学技術研究部, 教授 (20138382)
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| Project Period (FY) |
2003 – 2004
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| Keywords | cancer / bone / metastasis / bone resorption / prostaglandin E / melanoma / mouse |
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| Research Abstract |
Bone metastasis of cancer induces osteolysis with increased bone resorption, but the mechanism of bone loss in metastatic region is not fully understood. We have reported that the injection of human breast cancer cells into nude mice causes severe osteolysis accompanied with elevated expression of the receptor activator of NF-κB ligand(RANKL) and matrix metalloproteinase-13(MMP-13) in bone with metastasis. In this study, we made a new model of osteolytic bone metastasis by injection of mouse malignant melanoma B16 cells into C57BL/6 mice and also performed the cocultures of B16 cells and osteoblasts in vitro. When mice were injected with B16 cells from the left heart ventricle, metastatic regions were detected in femurs and tibiae. Bone mineral density in femur with metastasis was significantly decreased. When osteoblasts were cocultured with fixed-B16 cells, the expression of RANKL and MMP-13 was elevated in osteoblasts after the contact with B16 cells. The addition of SB203580, a selective inhibitor of p38 MAP kinase, to the cocultures suppressed the induction of MMP-13 in osteoblasts. Adding fixed-B16 cells to the cocultures of bone marrow cells and osteoblasts induced osteoclast formation without exogenous bone-resorbing factor. Therefore, cell-to-cell contact with cancer cells induces the expression of RANKL and MMP-13 via p38 MAP kinase pathway in host osteoblasts to lead the metastatic region to severe osteolysis. In additon, the treatment of EP4 antagonist suppressed bone resorption due to bone metastasis, suggesting that EP4 is one of the candidates for the treatment of bone metastasis of cancer.
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