Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects.
OBJECTIVE
To investigate the role of macrophages in tumor progression under sorafenib treatment and to explore whether combination of drugs that deplete macrophages improved the antitumor effect of sorafenib.


METHODS
Tumor growth, lung metastasis, and tumor angiogenesis were observed in HCCLM3-R and SMMC7721, two human hepatocellular carcinoma xenograft nude mouse models, when treated with sorafenib (30 mg/kg daily, n = 6 per group) or a vehicle as control. Macrophage infiltration was measured in the peripheral blood and in sorafenib-treated tumor by immunohistochemistry and flow cytometry with F4/80 antibody and CD11b antibody. The effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drug target macrophages, zoledronic acid (ZA) and clodrolip, was measured in the two models of hepatocellular carcinoma.


RESULTS
Although sorafenib significantly inhibited tumor growth and lung metastasis, it induced a significant increase in peripheral recruitment and intratumoral infiltration of F4/80- and CD11b-positive cells, which was accompanied with elevation of colony-stimulating factor-1, stromal-derived factor 1alpha, and vascular endothelial growth factor in the tumor and elevation of plasma colony-stimulating factor-1 and mouse vascular endothelial growth factor in peripheral blood, suggesting the role of macrophages in tumor progression under sorafenib treatment. Depletion of macrophages by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis, and lung metastasis compared with mice treated with sorafenib alone. ZA was more effective than clodrolip.


CONCLUSIONS
Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect.
Zhang
Wei
W
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China.
Zhu
Xiao-Dong
XD
Sun
Hui-Chuan
HC
Xiong
Yu-Quan
YQ
Zhuang
Peng-Yuan
PY
Xu
Hua-Xiang
HX
Kong
Ling-Qun
LQ
Wang
Lu
L
Wu
Wei-Zhong
WZ
Tang
Zhao-You
ZY
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004359:Drug Therapy, Combination; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008081:Liposomes / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D004164:Diphosphonates; D007093:Imidazoles; D008081:Liposomes; D010671:Phenylurea Compounds; D011725:Pyridines; D004002:Clodronic Acid; D009536:Niacinamide; D000077211:Zoledronic Acid; D000077157:Sorafenib