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Cloning of the molecules associated with bone metastases of cancers and its characterization

Research Project

Project/Area Number 11557136
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Functional basic dentistry
Research InstitutionOsaka University

Principal Investigator

YONEDA Toshiyuki  Osaka University Graduate School of Dentistry, Professor, 大学院・歯学研究科, 教授 (80142313)

Co-Investigator(Kenkyū-buntansha) NISHIMURA Riko  Osaka University Graduate School of Dentistry, Associate Professor, 大学院・歯学研究科, 助教授 (60294112)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥11,100,000 (Direct Cost: ¥11,100,000)
KeywordsCancer / Bone metastases / TGF-beta / Soft tissues metastases / Bone resorption / Smad / DDR1 / Bisphosohonate / TGF-β / IGF-1 / TGF / 遠隔転移 / 乳癌 / 前立腺癌 / レポーターアッセイ
Research Abstract

(1) Role of TGF-beta and IGF-1 in bone metastases of breast cancers
In bone tissues/there are large amount of Transforming growth factor-beta (TGF-beta) and Insulin-like growth factor-1 (IGF-1), it is, therefore, likely that these two major growth factors play some roles in bone remodeling in physiological or pathological conditions. It is well know that breast cancers resorb the bone after metastasizing into bone. To examine the role of IGF-1 in bone metastases, we established the breast cancer cell line MDA231 overexpressing dominant-negative IGF-1 receptor, and assessed its bone-metastatic effects using animal model. We found that the cell line showed much less bone metastatic activity compared with parental MDA231 cells. We next evaluated the effects of TGF-beta on MDA231 cells. TGF-beta had little effects on the growth of MDA231 cells but markedly enhanced the production of PTHrP which is one of the important factor in bone metastases by cancers. In addtion, TGF-beta activates the Smad signaling through Smad2, Smad3 and Smad4. Finally, we found the breast cancer cell line that is deficient in Smad4 showed no ability to metastasize into bone. These finding suggest that important roles of TGF-beta and IGF-1 in bone metastases by breast cancers.
(2) The effects of bisphosphonate on soft-tissue metastases of breast cancers
It is well know that bisphosphonate is a powerful inhibitor for osteoclasts and useful to treat the bone metastasized cancers. However, little is know the effects on soft tissue metastases of breast cancers. To address this, we established the system in which we can evaluate the bone metastases as well as soft tissues metastases. Using this system, we found that bisphosphonate blocked the bone metastases but stimulated the metastases into soft tissues such as lung and liver. It is likely that bisphosphonate has distinct effects on bone and soft tissues.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (51 results)

All Other

All Publications (51 results)

  • [Publications] Ji X et al.: "Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A"J Bone Miner Met. 18. 132-139 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y Takaoka et al.: "The pancreas : A storehouse of protein anabolic factors and bone/calcium metabolism-regulating factors"J Bone Miner Met. 18. 2-8 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toshiyuki Yaneda et al.: "Cellular and molecular basis of preferential metastasis of breast cancer to bone"J Orthop. Sci.. 5. 75-81 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Michigami T et al.: "Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 andα4β1 integrin enhances production of osteoclast-stimulating activity in culture"Blood. 96. 1953-1960 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Marzia M et al.: "Decreased c-Src expression enhances osteoblast differentiation and bone formation"J Cell Biol.. 151. 311-320 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Lai CF et al.: "Transforming Growth Factor-beta Up-regulates the beta 5 Integrin subunit Expression via Sp1 and Smad Signaling"J Biol. Chem.. 275. 36400-36406 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoneda T et al.: "Actions of bisphosphonate on bone metastasis in animal models of breast cancer"Cencer. 88. 2979-2988 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoneda T et al.: "A Bone-seeking Clone Exhibits Different Biological Properties from the MDA-MB-231 Parental Human Breast Cancer Cells and a Brain-seeking Clone in Vivo and In Vitro"J Bone Miner Res.. 16. 1486-1495 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoneda T, et al.: "Use of bisphosphonates for the treatment of bone metastasis in experimental animal models"Cancer Treat Rev. 25. 293-300 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Boyce BF, et al.: "Factors regulating the growth of metastatic cancer in bone"Endocr Relat Cancer. 34. 333-337 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Lai CF, et al.: "Transforming growth factor-beta up-regulates the beta 5 integrin subunit expression via Sp1 and Smad signaling"J. Biol Chem. 275. 36400-6 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yi B, et al.: "Tumor-derived PDGF-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer"Cancer Res. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Mundy GR, et al.: "Preclinical studies with zoledronic acid and other bisphosphonates: Impact on the bone microenvironment"Semin Oncol. 28 (2, suppl 6). 35-44 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Cruz JC, et al.: "Ibandronate decreases bone disease development and osteoclast stimulatory activity in an in vivo model of human myeloma"Exp Hematol. 29. 441-447 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Jackson JG, et al.: "Regulation of breast cancer cell motilitv bv insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines"Oncogene. 20. 7318-25 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ji X, et al.: "Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A"J Bone Miner Metab. 18. 132-139 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takaoka Y, et al.: "The pancreas: A storehouse of protein anabolic factors and bone/calcium metabolism-regulating factors"J Bone Miner Metb. 18. 2-8 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoneda T: "Cellular and molecular basis of preferential metastasis of breast cancer to bone"J Orthop Sci. 5. 75-81 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoneda T, et al.: "Actions of bisphosphonate on bone metastasis in animal models of breast cancer"Cancer. 88. 2979-2988 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Jackson JG, et al.: "Elevated levels of p66 Shc are found in breast cancer cell lines and primary tumors with high metastatic potential"Clin Cancer Res. 6. 1135-1139 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Michigami T, et al.: "Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1 integrin enhances production or osteoclast-stimulating activity in culture"Blood. 96. 1953-1960 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Marzia M, et al.: "Decreased c-src expression enhances osteoblast differentiation and bone formation"J Cell Biol. 151. 311-320 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oyajobi BO, et al.: "Therapeutic efficacy of a soluble RANK-IgG Fc (RANK.Fc) fusion protein in suppressing bone resorption and hypercalcemia in a model or numeral nypercalcemia of malignancy"Cancer Res. 61. 2572-2578 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiraga T, et al.: "The bisphosphonate ibandronate promotes apoptosis in MDA-231 human breast cancer cells in bone metastases"Cancer Res. 61. 4418-4424 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] YonedaT, et al.: "A bone-seeking subclone exhibits different properties from the parental MDA-MB-231 human breast cancer cells and a brain-seeking subclone in vivo and in vitro"J Bone Miner Res. 16. 1486-1495 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ji X et al.: "Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A"J Bone Miner Met. 18. 132-139 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y Takaoka et al.: "The pancreas : A storehouse of protein anabolic factors and bone/calcium metabolism-regulating factors"J Bone Miner Met. 18. 2-8 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toshiyuki Yoneda et al.: "Cellular and molecular basis of preferential metastasis of breast cancer to bone"J Orthop Sci. 5. 75-81 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toshiyuki Yoneda et al.: "Use of bisphosphonates for the treatment of bone metastasis in experimental animal models"Cancer Treat Rev. 25. 293-299 (1999)

    • Related Report
      2001 Annual Research Report
  • [Publications] Michigami T et al.: "Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 andα4β1 integrin enhances production of osteoclast-stimulating activity in culture"Blood. 96. 1953-1960 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Marzia M et al.: "Decreased c-Src expression enhances osteoblast differentiation and bone formation"J Cell Biol. 151. 311-320 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Lai CF et al.: "Transforming Growth Factor-beta Up-regulates the beta 5 Integrin Subunit Expression via Sp1 and Smad Signaling"J Biol Chem. 275. 36400-36406 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoneda T et al.: "Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma"Cancer. 88. 2979-2988 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoneda T et al.: "A Bone-Seeking Clone Exhibits Different Biological Properties from the MDA-MB-231 Parental Human Breast Cancer Cells and a Brain-seeking Clone in Vivo and In Vitro"J Bone Miner Res. 16. 1486-1495 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ji X et al: "Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A"J Bone Miner Met. 18. 132-139 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y Takaoka et al: "The pancreas : A storehouse of protein anabolic factors and bone/calcium metabolism-regulating factors."J Bone Miner Met. 18. 2-8 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Toshiyuki Yoneda et al: "Cellular and molecular basis of preferential metastasis of breast cancer to bone."J Orthop Sci. 5. 75-81 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Toshiyuki Yoneda et al: "Use of bisphosphonates for the treatment of bone metastasis in experimental animal models"Cancer Treat Rev. 25. 293-299 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Michigami T et al: "Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 andα4β1 integrin enhances production of osteoclast-stimulating activity in culture"Blood. 96. 1953-60 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Marzia M et al: "Decreased c-Src expression enhances osteoblast differentiation and bone formation"J Cell Biol. 151. 311-20 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Lai CF et al: "Transforming Growth Factor-beta Up-regulates the beta 5 Integrin Subunit Expression via Sp1 and Smad Signaling."J Biol Chem. 275. 36400-36406 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoneda T et al: "Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma."Cancer. 88. 2979-88 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoneda T et al: "A Bone-Seeking Clone Exhibits Different Biological Properties from the MDA-MB-231 Parental Human Breast Cancer Cells and a Brain-seeking Clone in Vivo and in Vitro"J Bone Miner Res. (印刷中). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ji X: "Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A"J Bone Miner Net. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Y Takaoka: "The pancreas: A storehouse of protein anabolic factors and bone/calcium metabolism-regulating factors"J Bone Miner Met. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Toshiyuki Yoneda: "Cellular and molecular basis of preferential metastasis of breast cancer to bone"J Orthop Sci. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Toshiyuki Yoneda: "Use of bisphosphonates for the treatment of bone metastasis in experimental animal models"Cancer Treat Rev. (印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西村理行: "SmadファミリーによるTGF-βスーパーファミリーのシグナルの制御"ホルモンと臨床. 47・1. 79-88 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 米田俊之: "ビスホスホネートの癌への新展開"Clinical Calcium. 9・11. 30-35 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 米田俊之: "癌骨転移の分子細胞生物学"Clinical Calcium. 9・4. 22-27 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 米田俊之: "骨転移動物実験モデルの作成とその臨床応用"関節外科. 19・3. 25-29 (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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