Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma.
OBJECTIVE
To investigate the role of macrophage colony-stimulating factor (M-CSF) in patients with hepatocellular carcinoma (HCC) after surgery.


METHODS
Expression of M-CSF, distribution of M2 macrophages (MΦs), and angiogenesis were assessed in the liver, including tumors and peritumoral liver tissues. The prognostic power of these factors was assessed. Mouse isolated hepatic MΦs or monocytes were cultured with media containing M-CSF. The concentration of vascular endothelial growth factor (VEGF) in media was assessed. Furthermore, the role of the M-CSF-matured hepatic MΦs on proliferation of the vascular endothelial cell (VEC) was investigated.


RESULTS
A strong correlation between the expressions of M-CSF and CD163 was observed in the peritumoral area. Also, groups with high density of M-CSF, CD163 or CD31 showed a significantly shorter time to recurrence (TTR) than low density groups. Multivariate analysis revealed the expression of M-CSF or hepatic M2MΦs in the peritumoral area as the most crucial factor responsible for shorter TTR. Moreover, the expression of M-CSF and hepatic M2MΦs in the peritumoral area had better predictable power of overall survival. Values of VEGF in culture media were significantly greater in the hepatic MΦs compared with the monocytes. Proliferation of the VEC was greatest in the cells co-cultured with hepatic MΦs when M-CSF was present in media.


CONCLUSIONS
M-CSF increases hepatocarcinogenesis, most likely by enhancing an angiogenic factor derived from hepatic MΦ and could be a useful target for therapy against HCC.
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Hiroshi
H
Kono
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Hideki
H
Fujii
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Shinji
S
Furuya
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Michio
M
Hara
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Kazuyoshi
K
Hirayama
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Yoshihiro
Y
Akazawa
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Yuuki
Y
Nakata
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Masato
M
Tsuchiya
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Naohiro
N
Hosomura
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun, First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
Chao
C
Sun
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism; D049109:Cell Proliferation; D018572:Disease-Free Survival; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000378:metabolism; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000098902:CD163 Antigen
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D000098902:CD163 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016173:Macrophage Colony-Stimulating Factor
Angiogenesis; M2 macrophage; Monocyte; Vascular endothelial cell; Vascular endothelial growth factor