Activation of the α 2 β 1 integrin‐mediated malignant phenotype on type I collagen in pancreatic cancer cells by shifts in the concentrations of extracellular Mg 2+ and Ca 2+

The authors have previously demonstrated that α 2 β 1 integrin‐mediated pancreatic cancer cell adhesion to Type I collagen is Mg 2+ ‐dependent, inhibited by Ca 2+ , and that this integrin, purified from cell lysates using Type I‐collagen‐sepharose in Mg 2+ , can be eluted with Ca 2+ . In the present study, the authors examined the divalent cation‐dependency of α 2 β 1 integrin‐mediated pancreatic cancer cell adhesion, migration and proliferation on Type I collagen, an extracellular matrix protein shown to be highly up‐regulated, and to promote the malignant phenotype in vitro and in vivo . The results indicate that cells attach to Type I collagen maximally when Mg 2+ is greater than 1 mM, and that addition of increasing concentrations of Ca 2+ reduces this adhesion. These effects are reversible, in that previous cell attachment in Mg 2+ can be reversed by adding Ca 2+ , and vice versa . They also demonstrate that pancreatic cancer cells migrate and proliferate on Type I collagen in Mg 2+ alone, but maximally when Mg 2+ is present at concentrations that promote maximal cell adhesion and Ca 2+ is present at concentrations less than Mg 2+ . Cell adhesion and proliferation assays, as well as affinity chromatography on Type I collagen using anti‐integrin function‐blocking monoclonal antibodies indicate that the effects of these divalent cation shifts are mediated specifically by the α 2 β 1 integrin. As pancreatic juice contains over 1,200‐fold more Mg 2+ than Ca 2+ and solid tumors are characterized by increased magnesium load, these data indicate that such pathophysiological divalent cation shifts could be involved in the activation of the α 2 β 1 integrin‐mediated malignant phenotype on Type I collagen in the pancreatic cancer. © 2008 Wiley‐Liss, Inc.