Usefulness of insulin-like growth factor as a therapeutic target against the liver metastasis of colon cancer

• Project/Area Number: 18590678
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: MIYAMOTO Shinichi Kyoto University, Graduate School of Medicine, Department of Gastroenterology & Hepatology, Assistant Professor (90378761)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,470,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: molecular target therapy / insulin-like growth factor / neutralizing antibody / familial adenomatous polyposis / 肝転移

Research Abstract

Using neutralizing antibody against insulin-like growth factor (IGF), we have been demonstrated the usefulness of IGF as a therapeutic target in the bone metastasis of prostate cancer and multiple myeloma and in the liver metastasis of colon cancer. In addition to the mouse IGF-II neutralizing antibody (KM1468) which we published in the literature, mouse IGF- I neutralizing antibody was successfully developed. However, preliminary experimental results strongly suggested that high dose of each neutralizing antibody resulted in the rebound phenomenon of its corresponding ligand in the serum level. This fact clearly showed the necessity of low dose administration of neutralizing antibody in the in-vivo experimental model. Next, we had paid attention to the familial adenomatous polyposis (FAP) which had been shown to be caused by the mutations in the tumor suppressor adenomatous polyposis coli (APC) gene. FAP model mouse (APC+/- mouse) spontaneously develops a large number of pre-malignant tumors mainly in the small intestine. By mating the APC+/- mouse with matrix netalloprotease-7 known as an IGF activating factor knock-out mouse or IGF- II conditional (intestine-specific) knock-out mouse, the number of polyp in the small intestine was significantly decreased. Based on these previous reports, we tried to demonstrate the usefulness of IGF as a therapeutic target in the FAP using two neutralizing antibodies. In the two lineage of APC-E mice, KM3168 significantly reduced the number of small intestinal polyp only in the low dose, whereas KM1468 had the same effect in a dose dependent manner. Combination administration in the effective dose of each antibody had the synergistic effect. The source of IGF- I was mostly liver (endocrine), whereas that of IGF- II was intestinal polyp (autocrine) and adjacent normal small intestine (paracrine). Our findings suggest that IGFs in the tumor microenvironment may be the promising therapeutic target for suppressing intestinal tumorigenesis.

Research Products

• [Journal Article] Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. (2007)
  • Author(s): Miyamoto S, Nakamura M, Yano K, Ishii G, Hasebe T, Endoh Y, Sangai T, Maeda H, Shi-Chuang Z, Chiba T, Ochiai A.
  • Journal Title: Cancer Sci 98 Pages: 685-691
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix (2007)
  • Author(s): Miyamoto, S, Nakamura, M, Yano, K, Ishii, G, Hasebe, T, Endoh, Y, Sangai, T, Maeda, H, Shi-Chuang, Z, Chiba, T, Ochiai, A
  • Journal Title: Cancer Sci 98 Pages: 685-91
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II viaproteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix. (2007)
  • Author(s): Miyamoto S, Nakamura M, Ochiai A, et. al.
  • Journal Title: Cancer Sci 98 Pages: 685-691
  • Peer Reviewed
• [Journal Article] Prostate-specific antigen induces apoptosis of osteoclast precursors: potential role in osteoblastic bone metastases of prostate cancer. (2006)
  • Author(s): Goya M, Ishii G, Miyamoto S, Hasebe T, Nagai K, Yonou H, Hatano T, Ogawa Y, Ochiai A.
  • Journal Title: Prostate 66 Pages: 1573-84
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prostate-specific antigen induces apoptosis of osteoclast precursors : potential role in osteoblastic bone metastases of prostate cancer (2006)
  • Author(s): Goya, M, Ishii, G, Miyamoto, S, Hasebe, T, Nagai, K, Yonou, H, Hatano, T, Ogawa, Y, Ochiai, A
  • Journal Title: Prostate 66 Pages: 1573-84
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prostate-specific antigen induces apoptosis of osteoclast precursors : potential role in osteoblastic bone metastases of prostate cancer. (2006)
  • Author(s): Goya M, Ishii G, Miyamoto S, Hasebe T, Nagai K, Yonou H, Hatano T, Ogawa Y, Ochiai A.
  • Journal Title: Prostate 66 Pages: 1573-1584