Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.
Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.
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DOI：
10.1158/2159-8290.cd-15-0012
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发表时间：
2015-09
期刊：
影响因子：
28.2
通讯作者：
Condeelis JS
中科院分区：
文献类型：
--
作者：
Harney AS;Arwert EN;Entenberg D;Wang Y;Guo P;Qian BZ;Oktay MH;Pollard JW;Jones JG;Condeelis JS
肿瘤细胞的扩散是转移的重要步骤。巨噬细胞、Mena过表达肿瘤细胞和内皮细胞之间的直接接触[转移的肿瘤微环境（TMEM）]与乳腺癌患者的转移相关。在这里，我们表明，使用活体高分辨率双光子显微镜，短暂的血管通透性和肿瘤细胞内渗同时发生，并专门在TMEM。肿瘤血管系统的高渗透性被描述为空间和时间异质性。使用实时成像，我们观察到血管渗透性是短暂的，仅限于TMEM，并且是肿瘤细胞传播所需的。来自Tie2Hi TMEM巨噬细胞的VEGFA信号传导导致血管连接的局部丧失、短暂的血管通透性和肿瘤细胞内渗，证明了TMEM在原发性乳腺肿瘤中的作用。这些数据提供了对乳腺癌中肿瘤细胞内渗和血管通透性机制的深入了解，解释了TMEM密度作为患者远处转移复发的预测因子的价值。
Dissemination of tumor cells is an essential step in metastasis. Direct contact between a macrophage, Mena over-expressing tumor cell and endothelial cell [Tumor MicroEnvironment of Metastasis (TMEM)], correlates with metastasis in breast cancer patients. Here we show, using intravital high-resolution two-photon microscopy, that transient vascular permeability and tumor cell intravasation occur simultaneously and exclusively at TMEM. The hyperpermeable nature of tumor vasculature is described as spatially and temporally heterogeneous. Using real-time imaging we observed that vascular permeability is transient, restricted to TMEM, and required for tumor cell dissemination. VEGFA signaling from Tie2Hi TMEM macrophages causes local loss of vascular junctions, transient vascular permeability and tumor cell intravasation, demonstrating a role for TMEM within the primary mammary tumor. These data provide insight into the mechanism of tumor cell intravasation and vascular permeability in breast cancer, explaining the value of TMEM density as a predictor of distant metastatic recurrence in patients.