Retrospective Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2016; 22(39): 8779-8789
Published online Oct 21, 2016. doi: 10.3748/wjg.v22.i39.8779
Macrophage colony-stimulating factor expressed in non-cancer tissues provides predictive powers for recurrence in hepatocellular carcinoma
Hiroshi Kono, Hideki Fujii, Shinji Furuya, Michio Hara, Kazuyoshi Hirayama, Yoshihiro Akazawa, Yuuki Nakata, Masato Tsuchiya, Naohiro Hosomura, Chao Sun
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
Author contributions: Kono H conducted this experiment; Fujii H organized this experiment; Furuya S collected samples; Hara M collected samples; Hirayama K analyzed the data; Akazawa Y analyzed the data; Nakata Y analyzed the data; Tsuchiya M collected samples; Hosomura N and Sun C collected samples.
Institutional review board statement: This study was reviewed and approved by the University of Yamanashi, Faculty of Medicine IRB (Prof Zentaro Yamagata).
Informed consent statement: All involved persons (subjects or legally authorized representatives) gave their informed consent (written or verbal, as appropriate) prior to study inclusion.
Conflict-of-interest statement: There are no conflicts-of-interest on this study.
Data sharing statement: Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hiroshi Kono, MD, PhD, First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. hkouno@yamanashi.ac.jp
Telephone: +81-55-2737390 Fax: +81-55-2736751
Received: November 10, 2015
Peer-review started: November 11, 2015
First decision: December 21, 2015
Revised: January 22, 2016
Accepted: March 18, 2016
Article in press: March 18, 2016
Published online: October 21, 2016
Processing time: 344 Days and 22.9 Hours
Abstract
AIM

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.

CONCLUSION

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.

Keywords: M2 macrophage; Vascular endothelial growth factor; Vascular endothelial cell; Monocyte; Angiogenesis

Core tip: This study was designed to investigate the role of macrophage colony-stimulating factor (M-CSF) in patients with hepatocellular carcinoma (HCC) after resection. 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. The expression of M-CSF and hepatic M2MΦs in the peritumoral area had better power for the prediction of overall survival. Thus, M-CSF could be a useful target for therapy against HCC.