CHARACTERIZATION OF INTEGRIN CHAINS IN NORMAL AND NEOPLASTIC HUMAN PANCREAS

Integrins are a complex family of non-covalently linked heterodimeric glycoproteins which function as cell adhesion molecules, interacting with extracellular matrix molecules such as laminin, fibronectin, vitronectin, and collagen, and also having a role in intercellular adhesion. Each integrin subfamily is characterized by a common beta-chain associated with variable alpha-chains. We have examined, using immunohistological methods, the expression of the VLA (very late activation) family comprising beta-1 in association with alpha-1-6, and also alpha-6 in association with beta-4, the LFA beta-chain beta-2, and the vitronectin receptor, in association with beta-1 or beta-5 and as the complex alpha-v-beta-3. Cryostat sections of normal pancreas, pancreatic adenocarcinomas, and ampullary tumours were studied together with six pancreatic carcinoma cell lines. Normal pancreas showed expression of beta-1 in all parenchyma. Alpha-2 and alpha-6 had a similar distribution whereas alpha-3 expression was confined to ducts, including the very smallest radicles. Staining along the basement membranes of ducts was seen with beta-4 and the anti-vitronectin alpha-v chain receptor antibody 13C2. Islet cells failed to stain with any antibody. No staining of epithelial components was seen with antibodies to alpha-1, alpha-4, alpha-5, or to the alpha-v-beta-3 form of the vitronectin receptor (beta-3 and alpha-v-beta-3 using the antibody 23C6). Pancreatic adenocarcinomas and ampullary tumours showed expression of alpha-2, alpha-3, alpha-6, beta-1, beta-4, and the vitronectin receptor (alpha-v associated with beta-1 or beta-5). Well differentiated cell lines (BXPC-3 and Capan-2) showed an identical phenotype, but less well differentiated lines showed variable loss of one or more integrin chains. The functional role of integrins was quantitated by adhesion assays in which we could assess the ability of pancreatic carcinoma cells to stick to the extracellular matrix substrates fibronectin, collagen, and laminin but not to fibrinogen or BSA. Binding of well differentiated cell lines to fibronectin and collagen was, in part, inhibited by exogenous RGD peptide. The distribution of integrins in normal and neoplastic cells and their functional properties were also shown to correlate well with the spatial distribution of laminin, fibronectin, and type IV collagen as shown by immunohistology in normal and neoplastic pancreas.