INTEGRINS AND THEIR EXTRACELLULAR-MATRIX LIGANDS IN GASTRIC-CANCER

Extracellular matrix (ECM) proteins and their specific cellular recept ors, play an important role in the regulation of epithelial morphogene sis and differentiation. Alterations in their expression and function have been found in a number of malignant tumours and these changes may help to explain their dedifferentiation and altered behaviour. In thi s study we have investigated expression and distribution of the epithe lial beta 1 integrins (alpha 2 beta 1, alpha 3 beta 1 and alpha 6 beta 1) and their ECM ligands (fibronectin, tenascin and laminin) in norma l and neoplastic tissue. An up-regulation of two isoforms of fibronect in, and tenascin was seen in tumour associated matrix compared to norm al stroma. Loss or down regulation of alpha integrin chains was seen m ore frequently in poorly differentiated carcinomas (alpha 2 p=0.002; a lpha 3 p=0.013; alpha 6 p=0.0012) irrespective of tumour type (diffuse or intestinal) than in well/moderately differentiated tumours. Cell a dhesion assays revealed that the ability of gastric carcinoma cell lin es to bind matrix glycoproteins correlated to their degree of differen tiation. Furthermore, poorly differentiated cell lines showed a down-r egulation of alpha 2 and alpha 6 integrin expression. These data indic ate that architectural and cytological differentiation in gastric carc inoma relates to altered patterns of expression of matrix glycoprotein s and their receptors. The traditional Lauren classification seems to reflect these differences in cell-matrix interactions. Differing patte rns of expression of those molecules involved in cell-matrix interacti ons may prove to be a more objective and biologically more relevant me ans of classifying gastric cancer.