Laminin isoforms and their integrin receptors in glioma cell migration and invasiveness: Evidence for a role of α5-laminin(s) and α3β1 integrin

Glioma cell infiltration of brain tissue often occurs along the basement membrane (BM) of blood vessels. In the present study we have investigated the role of laminins, major structural components of BMs and strong promoters of cell migration. Immunohistochemical studies of glioma tumor tissue demonstrated expression of α2-, α3-, α4- and α5-, but not α1-, laminins by the tumor vasculature. In functional assays, α3 (Lm-332/laminin-5)- and α5 (Lm-511/laminin-10)-laminins strongly promoted migration of all glioma cell lines tested. α1-Laminin (Lm-111/laminin-1) displayed lower activity, whereas α2 (Lm-211/laminin-2)- and α4 (Lm-411/laminin-8)-laminins were practically inactive. Global integrin phenotyping identified α3β1 as the most abundant integrin in all the glioma cell lines, and this laminin-binding integrin exclusively or largely mediate the cell migration. Moreover, pretreatment of U251 glioma cells with blocking antibodies to α3β1 integrin followed by intracerebral injection into nude mice inhibited invasion of the tumor cells into the brain tissue. The cell lines secreted Lm-211, Lm-411 and Lm-511, at different ratios. The results indicate that glioma cells secrete α2-, α4- and α5-laminins and that α3- and α5-laminins, found in brain vasculature, selectively promote glioma cell migration. They identify α3β1 as the predominant integrin and laminin receptor in glioma cells, and as a brain invasion-mediating integrin.