Activation of the alpha2beta1 integrin-mediated malignant phenotype on type I collagen in pancreatic cancer cells by shifts in the concentrations of extracellular Mg2+ and Ca2+.
The authors have previously demonstrated that alpha(2)beta(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 alpha(2)beta(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 alpha(2)beta(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 alpha(2)beta(1) integrin-mediated malignant phenotype on Type I collagen in the pancreatic cancer.
Grzesiak
John J
JJ
Department of Surgery, VA San Diego Healthcare System and the University of California, San Diego, CA, USA.
Bouvet
Michael
M
D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D002846:Chromatography, Affinity; D024042:Collagen Type I / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D014407:Tumor Cells, Cultured
D024042:Collagen Type I; D038982:Integrin alpha2beta1; D008274:Magnesium; D002118:Calcium