Divalent cations modulate the integrin-mediated malignant phenotype in pancreatic cancer cells

We have previously demonstrated that pathophysiological shifts in the concentrations of extracellular Mg2+ and Ca2+ activate the alpha(2)beta(1) integrin-mediated malignant phenotype on type I collagen in pancreatic cancer cells, as evidenced by increased adhesion, migration and proliferation. In the present study, we examined the integrin and divalent cation specificity of pancreatic cancer cell interactions with other physiologically relevant extracellular matrix proteins, including fibronectin, type IV collagen, laminin and vitronectin. Our results indicate that, like alpha(2)beta(1) integrin-mediated interactions with type I collagen, beta(1) integrin-mediated adhesion to fibronectin, type IV collagen and laminin are promoted by Mg2+ but not by Ca2+. On vitronectin, cells attach via alpha(v)beta(5) and beta(1) integrins, and in the presence of either divalent cation. We also demonstrate that, like type I collagen, pancreatic cancer cell migration and proliferation on fibronectin, laminin and type IV collagen is maximal when Mg2+ is present at concentrations that promote optimal adhesion and Ca2+ is present at concentrations less than Mg2+. On vitronectin, Panc-1 cell migration is maximal with decreased Mg2+ and increased Ca2+, but the reverse is true for BxPC-3 cells. Both cell lines exhibited maximal proliferation with increased Mg2+ and decreased Ca2+, however. Together with evidence indicating that the in vivo local tumor microenvironment contains increased Mg2+ and decreased Ca2+, our studies demonstrate that such divalent cation shifts could activate the integrin-mediated malignant phenotype in pancreatic cancer. (Cancer Sci 2008; 99: 1553-1563)