Elucidation of the osteoblastic bone metastasis mechanism in human prostate cancer

• Project/Area Number: 16590332
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: OCHIAI Atsushi Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 臨床腫瘍病理部, 部長 (60183034)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: prostate cancer / bone metastatic model / osteoclasts / apoptosis / osteoblastic bone metastasis / PSA / serine protease / IGF binding protein 5 / IGF-binding protein5 / 抗ヒトIGF特異阻害抗体 / プロテアーゼ

Research Abstract

We have established an animal model in which human adult bone fragments were xenotransplanted and human prostate cancer cells were inoculated into human bone. Using this animal model we have found that prostate specific antigen (PSA) works as a serine protease to activate various growth factors that are stored in bone matrix and stimulate osteoblasts and induce apoptosis of osteoclasts, resulting marked osteoblastc change at metastatic sites. In order to investigate detail mechanisms of PSA on osteoblastic changes, protease inhibitors were applied to inactivate PSA as a serine protease derived from human prostate cancer. Serine protease inhibitors treatment markedly reduced bone formation. These results indicate that serine protease activity of PSA plays an important role on bone formation in prostate cancer. In addition to the PSA effect of bone formation, PSA works as an activator of growth factors stored in bone matrix, such as insulin-like growth factor (IGF). We have tested whether PSA cleaved IGF binding protein 5 (IGFBP5) that makes a complex with IGF and is mainly stored in bone. PSA cleaved IGFBP5 in a dose dependent manner and activated IGF signaling. These data indicate that PSA produced by human prostate cancer activates bone stored growth factors such as IGF and TGFb and stimulates bone formation and cancer cell survival in bone microenvironment.

Research Products

• [Journal Article] Prostate-Specific Antigen Contributes to the Osteoblastic Phenotype via Apoptosis of Osteoclast Precursors : Potential role in Osteoblastic Bone Metastases of Prostate Cancer. (2006)
  • Author(s): Goya, M., Ochiai, A.et al.
  • Journal Title: The prostate In press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of Bone-Derived Insulin-like growth factors by a lignad specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse. (2006)
  • Author(s): Araki, K., Ochiai, A.et al.
  • Journal Title: Int J Cancer In prss
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prestate-Specific Antigen Contributes to the Osteoblastic Phenotype via Apoptosis of Osteoclast Precursors : Potential Role in Osteoblastic Bone Metastases of Prostate Cancer. (2006)
  • Author(s): Goya, M., Ochiai, A.et al.
  • Journal Title: The prostate In press
• [Journal Article] Inhibition of Bone-Derived Insulin-like growth factors by a lignad specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse. (2006)
  • Author(s): Araki, K., Ochiai, A.et al.
  • Journal Title: Int J Cancer In press
• [Journal Article] Blockage of paracrine supply of Insulin-like growth factors using neutralizing antibodies suppresses the liver metastasis of human colorectal cancers. (2005)
  • Author(s): Miyamoto, S., Ochiai, A.et al.
  • Journal Title: Clin Cancer Res. 11 Pages: 3494-3502
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. (2005)
  • Author(s): Nakamura, M., Ochiai, A.et al.
  • Journal Title: Biochem Biophys Res Commun 5・3 Pages: 1101-1106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In vivo and in vitro characterization of human fibroblast recruited selectively into human cancer stroma. (2005)
  • Author(s): Ishii, G., Ochiai, A., et al.
  • Journal Title: Stem cells (In press)
• [Journal Article] In vivo immunophenotype of bone-marrow-derived fibroblasts. (2005)
  • Author(s): Ishii, G., Ochiai, A., et al.
  • Journal Title: Int J Cancer (In press)
• [Journal Article] Engraftment of adult human lung tissue in non-obese diabetic/severe combined immunodeficient mice : a novel lung epithelial regeneration model. (2004)
  • Author(s): Yonou, H., Yokose, T., Yoshikawa, T., Kanomata, N., Kamijo, T., Hasebe, T., Nagai, K., Ito, H., Yamasaki, A., Hatano, T., Ogawa, Y., Emura, M., Ochiai, A.
  • Journal Title: Pathobiol. 71 Pages: 93-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Engraftment of adult human lung tissue in non- obese diabetic/severe combined immunodeficient mice : a novel lung epithelial rergeneration model. (2004)
  • Author(s): Yonou, H., Ochiai, A., et al.
  • Journal Title: Pathobiology 71 Pages: 93-102
• [Journal Article] Intraosseous growth of human prostate cancer in implanted adult human bone : Relationship of prostate cancer cells to osteoclasis in osteoblastic metastatic lesions. (2004)
  • Author(s): Yonou, H., Ochiai, A., et al.
  • Journal Title: Prostate 58 Pages: 406-413
• [Journal Article] Growth inhibiton of human prostate cancer cells in human adult bone implanted into non-obase diabetic-severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth fact (2004)
  • Author(s): Goya, M., Ochiai, A., et al.
  • Journal Title: Cancer Res. 64 Pages: 6252-6258