Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146)

• Laminin-411 and, to a higher extent, laminin-421 promote migration of tumor cells.
• α6β1 and other integrins mediate tumor cell migration on laminins 411 and 421.
• MCAM (CD146) preferentially binds laminin-421.
• α6β1 integrin and MCAM bind the globular domain of laminins 411 and 421.
• MCAM selectively mediates migration of tumor cells on laminin-421.

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.