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α4-laminins, such as laminins 411 and 421, are mesenchymal laminins expressed by blood and lymphatic vessels and some tumor cells. Laminin-411 promotes migration of leukocytes and endothelial cells, but the effect of this laminin and laminin-421 on tumor cells is poorly understood. In the present study, we demonstrate that laminin-411 and, to a greater extent, laminin-421 significantly promote migration of tumor cells originated from melanomas, gliomas and different carcinomas via α6β1 integrin. In solid-phase binding assays, both laminins similarly bound α6β1 integrin but only laminin-421, among several laminin isoforms, readily bound MCAM (CD146), a cell-surface adhesion molecule strongly associated with tumor progression. Accordingly, a function-blocking mAb to MCAM inhibited tumor cell migration on laminin-421 but not on laminins 411 or 521. In tumor tissues, melanoma cells co-expressed MCAM, laminin α4, β1, β2 and γ1 chains, and integrin α6 and β1 chains. The present data highlight the novel role of α4-laminins in tumor cell migration and identify laminin-421 as a primary ligand for MCAM and a putative mediator of tumor invasion and metastasis.

Melanoma cells express and interact with laminins (LMs) and other basement membrane components during invasion and metastasis. In the present study we have investigated the production and migration-promoting activity of laminin isoforms in melanoma. Immunohistochemistry of melanoma specimens and immunoprecipitation/western blotting of melanoma cell lines indicated expression of laminin-111/121, laminin-211, laminin-411/421, and laminin-511/521. Laminin-332 was not detected. In functional assays, laminin-111, laminin-332, and laminin-511, but not laminin-211 and laminin-411, strongly promoted haptotactic cell migration either constitutively or following stimulation with insulin-like growth factors. Both placenta and recombinant laminin-511 preparations were highly active, and the isolated recombinant IVa domain of LMα5 also promoted cell migration. Function-blocking antibodies in cell migration assays revealed α6β1 integrin as the major receptor for laminin-111, and both α3β1 and α6β1 integrins for laminin-332 and laminin-511. In contrast, isolated LMα5 IVa domain-promoted melanoma cell migration was largely mediated via αVβ3 integrin and inhibited by RGD peptides. Given the ubiquitous expression of α5 laminins in melanoma cells and in melanoma-target tissues/anatomical structures, as well as the strong migration-promoting activity of these laminin isoforms, the α5 laminins emerge as putative primary extracellular matrix mediators of melanoma invasion and metastasis via α3β1 and other integrin receptors.

The aims of this study were to investigate the proliferative activity and the localization of adhesion molecules in human healthy and inflamed portions of gingiva. Gingival biopsies were taken under informed consent from 33 patients undergoing gingivectomy at the Dental Hospital of Iwate Medical University. Adhesion molecules such as E-cadherin (of adherens junction-related molecules), desmoglein (of desmosomal cadherins), integrin α6 and integrin, β4 (of hemidesmosome-related molecules) were studied immunohistochemically to analyze the patterns of expression in the gingival epithelia. Desmoglein was detected intercellularly in the spinous layer of the lining epithelia, but not in the junctional epithelium (JE). Integrin α6 was confined to the basement membranes facing the connective tissue of all parts of the gingival epithelia. Integrin β4 was found in the basal layer of the epithelia, and it was markedly found in all layers of the JE. The expression patterns of adhesion molecules in the pocket epithelium (PE) were similar to those in the JE. The proliferative activity was analyzed by the bromodeoxyuridine (BrdU) labeling method and immunohistochemical staining for Ki-67. BrdU-positive cells were found in the basal layer of the sulcular (SE) and oral epithelia (OE), but not in the JE, and were particularly localized in the suprabasal layer at the bottom of the SE. Meanwhile, proliferative activity was found in the PE with the progression of ueriodontitis.