Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF.
Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF.
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DOI：
10.1007/s10439-011-0321-6
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发表时间：
2011-08
影响因子：
3.8
通讯作者：
Fu, Bingmei M.
中科院分区：
文献类型：
--
作者：
Fan, Jie;Cai, Bin;Zeng, Min;Hao, Yanyan;Giancotti, Filippo G.;Fu, Bingmei M.
关键词：
已有研究表明，β4整合素通过与ErbB 2结合并增强其信号传导能力，促进乳腺肿瘤的侵袭和转移。然而，β4整联蛋白发挥这些作用的效应途径和细胞功能尚未完全了解。为了检查β4信号在乳腺肿瘤细胞粘附至微血管内皮期间是否起作用，我们检查了表达野生型（WT）或信号缺陷型β4（1355 T）的ErbB 2转化的乳腺肿瘤细胞。我们报告说，WT细胞粘附在体外脑微血管内皮细胞在显着更大的程度上相比，1355 T细胞。有趣的是，整联蛋白β4信号传导对内皮细胞或基底膜的粘附没有直接影响。相反，它增强肿瘤细胞的ErbB 2依赖性VEGF表达。VEGF进而破坏内皮细胞单层的紧密和粘附连接，使下面的基底膜暴露并增加肿瘤细胞与内皮细胞间连接的粘附。抑制肿瘤细胞上的ErbB 2或内皮细胞上的VEGFR-2可抑制乳腺肿瘤细胞与微血管内皮的粘附。我们的研究结果表明，β4信号调节乳腺肿瘤细胞的VEGF表达，从而增强它们与微血管内皮的粘附。
Prior studies have indicated that the β4 integrin promotes mammary tumor invasion and metastasis by combining with ErbB2 and amplifying its signaling capacity. However, the effector pathways and cellular functions by which the β4 integrin exerts these effects are incompletely understood. To examine if β4 signaling plays a role during mammary tumor cell adhesion to microvascular endothelium, we have examined ErbB2-transformed mammary tumor cells expressing either a wild-type (WT) or a signaling-defective form of β4 (1355T). We report that WT cells adhere to brain microvascular endothelium in vitro to a significantly larger extent as compared to 1355T cells. Interestingly, integrin β4 signaling does not exert a direct effect on adhesion to the endothelium or the underlying basement membrane. Rather, it enhances ErbB2-dependent expression of VEGF by tumor cells. VEGF in turn disrupts the tight and adherens junctions of endothelial monolayers, enabling the exposure of underlying basement membrane and increasing the adhesion of tumor cells to the intercellular junctions of endothelium. Inhibition of ErbB2 on tumor cells or the VEGFR-2 on endothelial cells suppresses mammary tumor cell adhesion to microvascular endothelium. Our results indicate that β4 signaling regulates VEGF expression by the mammary tumor cells thereby enhancing their adhesion to microvascular endothelium.
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