Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.
Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway.
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DOI：
10.1038/onc.2016.421
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发表时间：
2017-05-11
期刊：
影响因子：
8
通讯作者：
Condeelis J
中科院分区：
文献类型：
--
作者：
Leung E;Xue A;Wang Y;Rougerie P;Sharma VP;Eddy R;Cox D;Condeelis J
在转移到远处的过程中，肿瘤细胞迁移到血管。在体内，乳腺肿瘤细胞利用一种称为流动的特殊迁移模式，在这种模式下，肿瘤细胞的线性组装响应于趋化信号，定向迁移到含有纤维连接蛋白-I型胶原I的细胞外基质(ECM)纤维上的血管。我们通过将肿瘤细胞、巨噬细胞和内皮细胞共沉积在2.5 μm厚的ECM涂层微图案基板上，成功地重建了体外肿瘤细胞流动。我们发现，当肿瘤细胞和巨噬细胞一起被放置在微图案底物上时，不会显示出仅在一个方向上的持续定向迁移(持续方向性)，而是表现出随机的双向行走。在体外，当包裹着人脐静脉内皮细胞的珠子被放置在微图案化的“ECM纤维”的一端时，在体外建立了体内肿瘤细胞的持续方向性。我们证明，这些内皮细胞供应肝细胞生长因子(HGF)，这是导致持续方向性的趋化梯度所需的。使用这个体外重组的流式系统，我们发现定向流式是依赖的，并且最有效地被阻断，通过抑制内皮细胞和肿瘤细胞之间的HGF/C-Met信号通路。利用体内侵袭试验和肿瘤细胞流动的活体多光子成像，在体外重组系统中进行的涉及C-Met信号的关键观察在乳腺肿瘤中得到了证实。这些结果确立了HGF/C-Met作为体内血管导向的肿瘤细胞迁移的中心组织信号，并突出了C-Met抑制剂在阻断体内肿瘤细胞流动和转移以及用于人体试验方面的前景。
During metastasis to distant sites, tumor cells migrate to blood vessels. In vivo, breast tumor cells utilize a specialized mode of migration known as streaming, where a linear assembly of tumor cells migrate directionally towards blood vessels on fibronectin-collagen I-containing extracellular matrix (ECM) fibers in response to chemotactic signals. We have successfully reconstructed tumor cell streaming in vitro by co-plating tumors cells, macrophages and endothelial cells on 2.5 μm thick ECM-coated micro-patterned substrates. We found that tumor cells and macrophages, when plated together on the micro-patterned substrates, do not demonstrate sustained directional migration in only one direction (sustained directionality) but show random bi-directional walking. Sustained directionality of tumor cells as seen in vivo was established in vitro when beads coated with human umbilical vein endothelial cells were placed at one end of the micro-patterned ‘ECM fibers' within the assay. We demonstrated that these endothelial cells supply the hepatocyte growth factor (HGF) required for the chemotactic gradient responsible for sustained directionality. Using this in vitro reconstituted streaming system, we found that directional streaming is dependent on, and most effectively blocked, by inhibiting the HGF/C-Met signaling pathway between endothelial cells and tumor cells. Key observations made with the in vitro reconstituted system implicating C-Met signaling were confirmed in vivo in mammary tumors using the in vivo invasion assay and intravital multiphoton imaging of tumor cell streaming. These results establish HGF/C-Met as a central organizing signal in blood vessel-directed tumor cell migration in vivo and highlight a promising role for C-Met inhibitors in blocking tumor cell streaming and metastasis in vivo, and for use in human trials.