Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer.
Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer.
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DOI：
10.1158/0008-5472.can-14-3373
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Moughon DL;He H;Schokrpur S;Jiang ZK;Yaqoob M;David J;Lin C;Iruela-Arispe ML;Dorigo O;Wu L
恶性腹水是上皮性卵巢癌（EOC）晚期的常见并发症，极大地降低了患者的生活质量。恶性腹水是血管功能障碍的已知后果，但目前批准的治疗方法不能有效防止积液。在这项研究中，我们研究了另一种策略，即靶向巨噬细胞功能，以逆转恶性腹水的血管病理学，使用来自人类患者的液体和EOC的免疫活性小鼠模型（ID8），该模型通过发展进行性血管解体和渗漏最终导致大量腹水来反映人类疾病。我们证明人类患者腹水中的巨噬细胞含量和 ID8 模型与血管通透性直接相关。为了进一步证实巨噬细胞在恶性腹水发病机制中的作用，我们使用集落刺激因子 1 受体激酶抑制剂 (GW2580) 阻断 ID8 小鼠中的巨噬细胞功能。在疾病晚期施用 GW2580 可减少促肿瘤 (M2) 巨噬细胞的浸润，并显着减少腹水量。此外，紊乱的腹膜脉管系统变得正常化，并且来自 GW2580 处理的腹水的血清可以防止内皮渗透性。因此，我们的研究结果表明，巨噬细胞靶向治疗可能是一种有前途的策略，可以安全有效地控制 EOC 恶性腹水。
Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages’ role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.