Vitamin D Binding Protein-Macrophage Activating Factor Inhibits HCC in SCID Mice

Nonaka, Koichi; Onizuka, Shinya; Ishibashi, Hiromi; Uto, Yoshihiro; Hori, Hitoshi; Nakayama, Toshiyuki; Matsuura, Nariaki; Kanematsu, Takashi; Fujioka, Hikaru

doi:10.1016/j.jss.2010.07.057

« Previous Next »Journal of Surgical Research
Volume 172, Issue 1 , Pages 116-122, January 2012

Vitamin D Binding Protein-Macrophage Activating Factor Inhibits HCC in SCID Mice

Koichi Nonaka, M.D.
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
- To whom correspondence and reprint requests should be addressed at Clinical Research Center and Department of Surgery, National Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8652, Japan.
Shinya Onizuka, M.D., Ph.D.
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Hiromi Ishibashi, M.D., Ph.D.
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
Yoshihiro Uto, Ph.D.
- Department of Life System, Institute of Technology and Science, University of Tokushima Graduate School, Tokushima, Japan
Hitoshi Hori, Ph.D.
- Department of Life System, Institute of Technology and Science, University of Tokushima Graduate School, Tokushima, Japan
Toshiyuki Nakayama, M.D., Ph.D.
- Department of Pathology, Atomic Bomb Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Nariaki Matsuura, M.D., Ph.D.
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan
Takashi Kanematsu, M.D., Ph.D.
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Hikaru Fujioka, M.D., Ph.D.
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan

Received 12 June 2010; accepted 28 July 2010. published online 01 September 2010.

Background

A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP-maf) is able to inhibit the growth of HCC.

Methods

The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d.

Results

DBP-maf showed anti-proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 ± 18mm³, untreated group: 1691.5 ± 546.9mm³, P = 0.0077). Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group.

Conclusion

DBP-maf has at least two novel functions, namely, an anti-angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC.

Key Words: DBP-maf, HCC, anti-angiogenesis, macrophage, SCID mouse