Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma
Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma
复制标题
多巴胺通过重编程大鼠 C6 神经胶质瘤 M2 极化巨噬细胞诱导生长抑制和血管正常化
DOI：
10.1016/j.taap.2015.03.021
复制
发表时间：
2015-07-15
影响因子：
3.8
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Qin, Tian;Wang, Chenlong;Yang, Jing
多巴胺（DA）是一种具有抗血管生成活性的单胺儿茶酚胺类神经递质，可稳定结肠癌、前列腺癌和卵巢癌的肿瘤血管，从而提高化疗疗效。在这里，在大鼠C6胶质瘤模型中，我们研究了DA的血管正常化作用及其作用机制。DA（25，50 mg/kg）抑制肿瘤生长，而DA的前体（左旋多巴）延长大鼠原位C6胶质瘤荷瘤生存时间。DA改善了肿瘤灌注，从第3天起具有显著效果，并且在第5天至第7天具有更高的水平。此外，DA降低了肿瘤组织中的微血管密度和缺氧诱导因子Ice的表达，同时增加了周细胞的覆盖率。相反，多巴胺受体2（DR 2）（依替氯必利）而不是DR 1（butaclamol）拮抗剂废除DA诱导的肿瘤消退和血管正常化。此外，DA改善了替莫唑胺治疗的递送和疗效。重要的是，DA增加了代表性的M1标志物（iNOS，CXCL 9等），同时降低M2标志物（CD 206、CD 206酶-1等）。氯屈膦酸盐或唑来膦酸对巨噬细胞的消耗减弱了DA的作用。值得注意的是，DA处理诱导RAW264.7细胞和小鼠腹腔巨噬细胞的M2至M1极化，并增强周细胞样细胞（10 T1/2）的迁移，这被依替氯必利或DR 2-siRNA逆转。这种变化伴随着VEGF/VEGFR 2信号转导的下调。总之，DA通过重编程M2极化的巨噬细胞诱导生长抑制和血管正常化。因此，通过DA靶向肿瘤微血管系统代表了治疗人类胶质瘤的有希望的策略。(C)2015 Elsevier Inc. All rights reserved.
Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-Ice expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. (C) 2015 Elsevier Inc. All rights reserved.