Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031.
Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education School of Biological Science and Medical Engineering, Beihang University, Beijing 100191, China.
Ann Biomed Eng. 2011 Aug;39(8):2223-2241. doi: 10.1007/s10439-011-0321-6. Epub 2011 May 10.
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.
先前的研究表明，β4 整合素通过与 ErbB2 结合并放大其信号转导能力，促进乳腺肿瘤的侵袭和转移。然而，β4 整合素发挥这些作用的效应途径和细胞功能尚不完全清楚。为了研究β4 信号是否在乳腺肿瘤细胞黏附至微血管内皮细胞过程中发挥作用，我们检测了表达野生型（WT）或信号缺陷型（1355T）β4 的 ErbB2 转化的乳腺肿瘤细胞。我们发现，与 1355T 细胞相比，WT 细胞在体外黏附至脑微血管内皮细胞的程度显著更大。有趣的是，整合素β4 信号对黏附至内皮细胞或基底膜本身没有直接影响。相反，它增强了肿瘤细胞中 ErbB2 依赖性 VEGF 的表达。VEGF 反过来破坏内皮细胞单层的紧密连接和黏附连接，使基底膜暴露，并增加肿瘤细胞与内皮细胞细胞间连接的黏附。肿瘤细胞上的 ErbB2 或内皮细胞上的 VEGFR-2 的抑制作用可抑制乳腺肿瘤细胞黏附至微血管内皮细胞。我们的结果表明，β4 信号调节乳腺肿瘤细胞中 VEGF 的表达，从而增强其对微血管内皮细胞的黏附。
