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Integrin β4 Signaling Promotes Mammary Tumor Cell Adhesion to Brain Microvascular Endothelium by Inducing ErbB2-Mediated Secretion of VEGF

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Abstract

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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Acknowledgment

This work was supported by NIH grants P20 CA118861, U54 CA137788, SC1 CA153325, R37 CA058976, R01 CA129023, as well as P30 CA08748. Mr. Jie Fan was partially supported by a scholarship from the China Scholarship Council. We thank Dr. Robert Majeska for his kind helps in language editing.

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This is no conflict of interests with any corporations and agencies.

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Authors and Affiliations

  1. Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, 10031, USA

    Jie Fan, Bin Cai, Min Zeng & Bingmei M. Fu

  2. Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China

    Jie Fan

  3. Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Yanyan Hao & Filippo G. Giancotti

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  1. Jie Fan
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Correspondence to Bingmei M. Fu.

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Associate Editor Cheng Dong oversaw the review of this article.

Filippo G. Giancotti and Bingmei M. Fu have contributed equally to this work.

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Fan, J., Cai, B., Zeng, M. et al. Integrin β4 Signaling Promotes Mammary Tumor Cell Adhesion to Brain Microvascular Endothelium by Inducing ErbB2-Mediated Secretion of VEGF. Ann Biomed Eng 39, 2223–2241 (2011). https://doi.org/10.1007/s10439-011-0321-6

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  • DOI: https://doi.org/10.1007/s10439-011-0321-6

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