| Project/Area Number |
21590442
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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 |
Experimental pathology
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| Research Institution | Nagoya City University |
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Principal Investigator |
FUTAKUCHI Mitsuru 名古屋市立大学, 大学院・医学研究科, 准教授 (60275120)
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| Co-Investigator(Renkei-kenkyūsha) |
FUKAMACHI Katsumi 名古屋市立大学, 大学院・医学研究科, 助教 (90381798)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 腫瘍 / 骨転移 / sRANKL / TGFβ / 乳癌 / 腫瘍間質相互作用 / 骨微小環境 / 腫瘍・間質相互作用 |
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| Research Abstract |
Understanding how cancer cells induce bone metastases is essential for the identification of new therapies to control bone metastasis. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G to be proteases that are up-regulated at the tumor bone(TB)-interface. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of receptor activator of nuclear factor-KB ligand(RANKL), generating active soluble version(sRANKL) that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G seems to be osteoclasts. Furthermore, we showed that in vivo inhibition of cathepsin G reduces mammary tumor. induced osteolysis.
Next we examined the preventive effects of a competitive inhibitor of sRANKL, osteoprotegrin fusion protein(OCIF) was administered to mice before osteolysis induction by implantation of mammary tumor cells(pre), after osteolysis induction(post) or during the entire experimental period(whole). Tumor growth at the TB-interface was significantly suppressed in the pre as well as the post and whole treatment groups of OCIF. The extent of bone destruction was significantly reduced in the pre, post and whole treatment groups. In addition, significantly fewer osteoclasts wereobserved in the OCIF treatment groups regardless of treatment period.
Together, our data indicate that inhibition of cathepsin G activity at the TB interface could be therapeutic targets, and sRANKL which is generated by cathepsin G is a potentially target for prevention as well as treatment of breast cancer bone metastasis.
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