Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, Shanghai, P.R. China.
Clin Cancer Res. 2010 Jul 1;16(13):3420-30. doi: 10.1158/1078-0432.CCR-09-2904. Epub 2010 Jun 22.
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.
研究巨噬细胞在索拉非尼治疗下肿瘤进展中的作用，并探讨耗竭巨噬细胞的药物联合是否能增强索拉非尼的抗肿瘤作用。
在 HCCLM3-R 和 SMMC7721 两种人肝癌异种移植裸鼠模型中，观察索拉非尼（30mg/kg，每日 1 次，每组 6 只）或载体对照治疗时的肿瘤生长、肺转移和肿瘤血管生成。用 F4/80 抗体和 CD11b 抗体通过免疫组织化学和流式细胞术检测外周血和索拉非尼处理肿瘤中的巨噬细胞浸润。用唑来膦酸（ZA）和氯膦酸两种药物靶点巨噬细胞，在两种肝癌模型中观察索拉非尼治疗后巨噬细胞耗竭对肿瘤血管生成和转移的影响。
虽然索拉非尼显著抑制肿瘤生长和肺转移，但它诱导外周募集和肿瘤内 F4/80 和 CD11b 阳性细胞的浸润显著增加，同时伴有肿瘤中集落刺激因子-1、基质衍生因子 1alpha 和血管内皮生长因子的升高以及外周血中集落刺激因子-1 和小鼠血管内皮生长因子的升高，表明巨噬细胞在索拉非尼治疗下肿瘤进展中的作用。与单独用索拉非尼治疗的小鼠相比，用氯膦酸或 ZA 联合索拉非尼耗竭巨噬细胞显著抑制肿瘤进展、肿瘤血管生成和肺转移。ZA 比氯膦酸更有效。
巨噬细胞在索拉非尼治疗下肿瘤进展中可能具有重要作用。ZA 与索拉非尼联合使用增强其抗肿瘤作用有很大的潜力。
