We have previously demonstrated that pathophysiological shifts in the concentrations of extracellular Mg(2+) and Ca(2+) 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 Mg(2+) but not by Ca(2+). 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 Mg(2+) is present at concentrations that promote optimal adhesion and Ca(2+) is present at concentrations less than Mg(2+). On
vitronectin, Panc-1 cell migration is maximal with decreased Mg(2+) and increased Ca(2+), but the reverse is true for BxPC-3 cells. Both cell lines exhibited maximal proliferation with increased Mg(2+) and decreased Ca(2+), however. Together with evidence indicating that the in vivo local tumor microenvironment contains increased Mg(2+) and decreased Ca(2+), our studies demonstrate that such divalent
cation shifts could activate the
integrin-mediated malignant phenotype in
pancreatic cancer.