The role of alpha 6 integrin and its ligand, laminin, in prostate cancer.

Abstract

Laminin is a major component of basal lamina and binds to the cell largely through a6 integrin receptors. The continued production of laminin by a tumor cell could confer an advantage to further invasion. The endogenous production of laminin by human prostate tumor cell lines OU145 (tumorigenic) and LNCaP (non-tumorigenic) was analyzed and related to their tumorigenic potential. Both produced classical laminin and S-laminin. OU145 laminin chain ratio (A:B1:B2:S) was (1.8):(1.0):(2.5):(1.0) compared to LNCaP cells, which was (1.0):(0):(10.0):(2.5). LNCaP cells retained most of their laminin production and their secreted forms were hypoglycosylated. LNCaP cells bound little laminin to their surface. In contrast, tumorigenic OU145 cells secreted most of their laminin in mature forms which bound to their surface. These features of LNCaP cells could contribute to their low adhesiveness and non-tumorigenic phenotype. Cell adhesion to' the extracellular matrix is mediated largely by integrins and is an important component to accomplish invasion. Prostate tumor cell lines were analyzed for their integrin content and function and related to their tumorigenic potential. OU145 cells contained α6, α3, α5, av integrins. Except for α3, LNCaP cells expressed all integrins with a lower molecular weight. LNCaP cells attached to ECM substrates to a lesser extent than DU145 cells. LNCaP cell deficient production of integrins and low attachment could affect their tumorigenic potential. In contrast DU145 cells express normal integrins and laminin and are tumorigenic. The α6 integrin (laminin receptor) persists during prostate tumor progression. To examine the role of a6 integrin in invasion, DU145 cells were sorted to select high (DU-H) and low (DU-L) a6 integrin expressors. DU-H cells contained α6β1 and α6β4 heterodimers compared to DU-L that only contained a low levels of α6β4. DU-H cells were three times more mobile on laminin as compared to the low expressors. Adhesion and migration were inhibited with anti-α6 antibody. Cells were injected intraperitoneally into SCID mice to test their invasive potential. DU-H showed greater invasion than DU-L, with increased expression of α6 integrins at the invasion areas. These data suggest that α6 integrin expression may be advantageous for invading cells.