Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer
Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer
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巨噬细胞通过 VLA4/VCAM1 途径介导的血管通透性决定卵巢癌腹水的发生
DOI：
10.1172/jci140315
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发表时间：
2021-02-01
影响因子：
15.9
通讯作者：
He, Huanhuan
中科院分区：
文献类型：
--
作者：
Zhang, Shibo;Xie, Bingfan;He, Huanhuan
腹水的发生与卵巢癌的晚期疾病和预后不良有关。血管通透性是腹水发生发展过程中的重要病理生理变化。以前，我们提供的证据表明，血管周围的M2样巨噬细胞通过与内皮细胞(ECs)直接接触来保护血管屏障。在此，我们探讨了卵巢癌发生的分子机制及其临床意义。我们发现，在与内皮细胞直接共培养后，M2巨噬细胞下调其VLA4，并降低内皮细胞中VCAM1的水平。另一方面，VLA4在巨噬细胞中的异位过表达或VCAM1在内皮细胞中的过度表达可引起高通透性。在机制上，VLA4或VCAM1下调导致RAC1和ROS水平降低，从而导致PYK2(p-PYK2)和VE-cadherin(p-VE-cad)磷酸化减少，从而增强细胞黏附。此外，靶向VLA4/VCAM1轴增强了血管的完整性，并减少了体内腹水的形成。最后，腹水分离的巨噬细胞上VLA4的表达决定了体外通透性。重要的是，VLA4抗体与贝伐单抗协同作用，进一步增强了血管屏障。综上所述，我们揭示M2巨噬细胞通过VCAM1/RAC1/ROS/p-PYK2/p-VE-cad级联途径调节血管屏障，为恶性腹水的治疗提供了特异性靶点。
The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.