Depletion of Tumor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects

Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China.
Clinical Cancer Research (Impact Factor: 8.72). 07/2010; 16(13):3420-30. DOI: 10.1158/1078-0432.CCR-09-2904
Source: PubMed


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.
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.
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.
Macrophages may have an important role in tumor progression under sorafenib treatment. ZA is promising when combined with sorafenib to enhance its antitumor effect.

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    • "It has been shown that TAM depletion reprograms the immunosuppressive tumor microenvironment and creates an antitumor immune microenvironment in breast cancer and liver cancer.23,32 TAMs may be a therapeutic target in other tumors, such as prostate cancer, renal cell carcinoma, and osteosarcoma.31,33,34 "
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    ABSTRACT: Tumor-associated macrophages play an important role in tumor growth and progression. These macrophages are heterogeneous with diverse functions, eg, M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth. In this study, we found that IFNγ and/or celecoxib (cyclooxygenase-2 inhibitor) treatment consistently inhibited tumor growth in a mouse lung cancer model. IFNγ alone and celecoxib alone increased the percentage of M1 macrophages but decreased the percentage of M2 macrophages in the tumors, and thus the M2/M1 macrophage ratio was reduced to 1.1 and 1.7 by IFNγ alone and celecoxib alone, respectively, compared to the M2/M1 macrophage ratio of 4.4 in the control group. A combination of IFNγ and celecoxib treatment reduced the M2/M1 macrophage ratio to 0.8. Furthermore, IFNγ and/or celecoxib treatment decreased expression of matrix metalloproteinase (MMP)-2, MMP-9, and VEGF, as well as the density of microvessels in the tumors, compared to the control group. This study provides the proof of principle that IFNγ and/or celecoxib treatment may inhibit lung-tumor growth through modulating the M2/M1 macrophage ratio in the tumor microenvironment, suggesting that IFNγ and celecoxib have potential to be further optimized into a new anticancer therapy.
    Drug Design, Development and Therapy 09/2014; 8:1527-38. DOI:10.2147/DDDT.S66302 · 3.03 Impact Factor
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    • "Until now, liposome-encapsulated Clodronate has documented its efficacy in vitro and in preclinical investigations for the transient suppression of macrophage functions [42], [43]. However, liposome technology shows some limitations linked to industrial applicability [48] and toxic effects in mice [22], [49]. Thus, a safe delivery system to selectively target bisphosphonates to macrophages is still needed and an alternative approach could be represented by the use of autologous engineered RBCs. "
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    PLoS ONE 06/2014; 9(6):e101260. DOI:10.1371/journal.pone.0101260 · 3.23 Impact Factor
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    • "The pro-angiogenic function of TAMs was also thoroughly investigated in animal cancer models. Accumulating evidences show that TAM depletion results in the decrease of tumor angiogenesis (31, 41), while TAM enhancement exhibits the opposing effect (42). For example, it has been shown that genetic depletion of macrophages in PyMT mammary tumor model delays the angiogenic switch, whereas restoring macrophage infiltration rescues the vessel phenotype (31). "
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