Study of roles of bone microenvironment and immune system in establishment and progression of bone metastasis

• Project/Area Number: 17591594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Josai International University
• Principal Investigator: ONO Katsuhiro 城西国際大, 薬学部, 助教授 (00398554)
• Co-Investigator(Kenkyū-buntansha): KAMIYA Sadahiro KAMIYA,Sadahiro, 助手 (10398555) ; AMIZUKA Norio Niigata University, Center for Transdisciplinary Research, Professor, 超域研究機構, 教授 (30242431) ; YOSHIMOTO Takayuki Tokyo Medical University, Intractable Immune System Disease Research Center, Associate Professor, 医学部, 助教授 (80202406) ; WADA Seiki WADA,Seiki, 教授 (10301467)
• Project Period (FY): 2005
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: mammary cancer / bone metastasis / hepatocyte growth factor

Research Abstract

Some cancers frequently affect the skeleton, and the bone microenvironment supports growth of certain cancer. After tumors metastasize to bone, they stimulate osteoclastogenesis and expand in the bone tissue. Hepatocyte growth factor (HGF) promotes tumor growth, invasion and metastasis. HGF is mainly produced by cells of mesenchymal origin, and osteoblasts/osteocytes and bone marrow stromal cells originate from mesenchymal cells. However, it is not clear what effect HGF has on bone metastasis. In the present study, we investigated the roles of HGF in bone metastasis using the mouse mammary cancer cell line BALB/c-MC. Cancer cells injected into hearts of mice metastasized to bone in their hind limbs. HGF immunoreactivity was detected in the stroma surrounding the tumor, and blood vessels expressing CD31 (a marker of endothelial cells) were observed in the HGF-positive area. To identify the cells producing HGF, we measured concentrations of HGF in culture media. HGF concentration was ele vated in osteoblast cultures (3.13 ± 0.25 ng/ml), whereas HGF was undetectable (<0.4 ng/ml) in BALB/c-MC or bone marrow cell cultures. Addition of HGF to BALB/c-MC cultures caused doubling of the cell number. Western blot revealed expression of c-Met/HGF receptor in BALB/c-MC. In the Matrigel invasion chamber assay, addition of HGF to the bottom well increased the rate at which BALB/c-MC invaded the bottom through the membrane. When osteoblasts were cultured in the bottom well, the number of BALB/c-MC cells that invaded the bottom increased 3.7-fold, compared to assays without osteoblasts. Addition of NK4, an inhibitor of HGF, abolished the enhancement of the invasive potential of BALB/c-MC by osteoblasts. These findings suggest that HGF produced by osteoblasts induces migration of cancer from sinusoidal capillaries to bone marrow and stimulates growth of cancer in the bone microenvironment. Thus, it appears that osteoblasts promote bone metastasis of some cancers via HGF-c-Met signaling.

Research Products

• [Journal Article] Involvement of hepatocyte growth factor in the development of bone metastasis of a mouse mammary cancer cell line,BALB/c-MC. (2006)
  • Author(s): Ono K., Kamiya S, Akatsu T, Nakamura C, Li M, Amizuka N, Matsumoto K, Nakamura T, Kugai N, Wada S
  • Journal Title: Bone 39(1) Pages: 27-34
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of hepatocyte growth factor in the development of bone metastasis of a mouse mammary cancer cell line, BALB/c-MC. (2006)
  • Author(s): Ono K, Kamiya S, Akatsu T, Nakamura C, Li M, Amizuka N, Matsumoto K, Nakamura T, Kugai N, Wada S.
  • Journal Title: Bone 39 Pages: 27-34
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of hepatocyte growth factor in the development of bone metastasis of a mouse mammary cancer cell line, BALB/c-MC. (2006)
  • Author(s): Ono K, Kamiya S, Akatsu T, Nakamura C, Li M, Amizuka N, Matsumoto K, Nakamura T, Kugai N, Wada S.
  • Journal Title: Bone E-Pub Feb2,2006