title: Monoclonal antibodies to human laminin α4 chain globular domain inhibit tumor cell adhesion and migration on laminins 411 and 421, and binding of α6β1 integrin and MCAM to α4-laminins.
abstract: α4-Laminins, such as laminins 411 and 421, are mesenchymal laminins expressed by vascular and lymphatic endothelial cells, leukocytes and other normal cell types. These laminins are recognized by α6β1 and α6β4 integrins and MCAM (CD146), and promote adhesion and migration of the cells. α4-Laminins are also expressed and secreted by some tumor cells and strongly promote tumor cell migration. Moreover, the abluminal side of blood and/or lymphatic vessels and the nerve perineurium, common tracks of tumor cell dissemination, express α4-laminins, and these laminin isoforms, when expressed in the stroma, may contribute to tumor invasion. In the present study, we examined ten mAbs to human laminin α4 chain for their reactivity with the isolated laminin α4 globular domain, their ability to inhibit tumor cell adhesion and migration on laminins 411 and 421, and their effect on the binding of α6β1 integrin and MCAM to both α4-laminins. Most of the mAbs reacted with the laminin α4 globular domain, but only two, mAbs FC10 and 084, significantly inhibited tumor cell adhesion and migration on laminin-411. When used in combination, these antibodies practically abolished the cell adhesion and migration on laminin-411 and significantly reduced the cellular responses on laminin-421. Accordingly, mAbs FC10 and 084 significantly inhibited the binding of purified α6β1 integrin and MCAM to laminins 411 and 421. These results indicate that mAbs to the laminin α4 globular domain are able to inhibit tumor cell adhesion and migration on laminins 411 and 421, and that α6β1 integrin and MCAM bind α4-laminins at very close sites on the globular domain. These reagents contribute to a better understanding of the biology of α4-laminins and may have a therapeutic potential in malignant and inflammatory diseases.
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Zenebech
authors.initials: Z
authors.lastname: Wondimu
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oikawa
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors.forename: Sulev
authors.initials: S
authors.lastname: Ingerpuu
authors.affiliation: Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland.
authors.forename: Ismo
authors.initials: I
authors.lastname: Virtanen
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: Manuel.Patarroyo@ki.se.
authors.forename: Manuel
authors.initials: M
authors.lastname: Patarroyo
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D051929:CD146 Antigen / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D007797:Laminin / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary
chemical_list: D000911:Antibodies, Monoclonal; D051929:CD146 Antigen; D039121:Integrin alpha6beta1; C501369:LAMA4 protein, human; D007797:Laminin; C497902:MCAM protein, human; C110308:laminin 8; C404084:laminin 9
keywords: Cell migration; Integrin; Laminin; Monoclonal antibody