Abstract
Abstract Background: Sorafenib prolonged survival in patients with unresectable hepatocellular carcinoma (HCC), but the effect is modest and tumor finally progressed even under continuous sorafenib therapy. The aim of this study is to investigate the mechanism of tumor progression under sorafenib treatment. Methods: Tumor growth, local invasion and lung metastasis were observed in MHCCLM3-R, a human HCC xenograft nude mouse model, when treated by sorafenib (30 mg/kg qd, n=6 per group) and vehicle as control. Macrophage infiltration was measured in the peripheral blood and macrophage in tumor after sorafenib treatment by immunohistochemistry and flow cytometry with F4/80 antibody, and the effect of macrophage depletion on tumor angiogenesis and metastasis after sorafenib treatment, using two drugs target macrophages, zoledronic acid (ZA) and clodrolip, in a mouse model of human hepatocellular carcinoma (HCC). Results: Sorafenib treatment significantly inhibited tumor growth and lung metastasis, but also induced significant increase in peripheral F4/80-positive cells and intratumoral macrophages infiltration, which was associated with elevation of colony stimulating factor-1, stromal-derived factor 1α and vascular endothelial growth factor in tumor and plasma VEGF of mouse origin in peripheral blood, suggesting the role of macrophage in tumor progression during sorafenib treatment. Depletion of macrophage by clodrolip or ZA in combination with sorafenib significantly inhibited tumor progression, tumor angiogenesis and lung metastasis compared to that of mice treated with sorafenib alone. ZA was more effective than clodrolip. Conclusions: Macrophage may have an important role in tumor progression under sorafenib treatment. Zoledronic acid is promising when combined with sorafenib to enhance its anti-tumor effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4145.
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