title: Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF.
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.
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031.
authors.forename: Bin
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031.
authors.forename: Min
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
authors.affiliation: Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031.
authors.forename: Bingmei M
authors.initials: BM
authors.lastname: Fu
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply; D002448:Cell Adhesion / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D039663:Integrin beta4; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008833:Microcirculation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D039663:Integrin beta4; D018719:Erb-b2 Receptor Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C524056:Erbb2 protein, mouse