The alpha2beta1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines.
Pancreatic cancer is characterised by a hallmark desmoplastic response that includes upregulated expression of the extracellular matrix, and type I collagen in particular. Recent studies indicate that pancreatic cancer cells stimulate type I collagen synthesis in adjacent stellate cells, and that this upregulated type I collagen expression promotes the malignant phenotype in tumour cells as defined by increased proliferation, resistance to chemically induced apoptosis, and increased tumorigenesis. The integrin specificity of this interaction between type I collagen and tumour cells was not identified, however. In the present study, we examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration, on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. Our results indicate, for the overwhelming majority of cell lines, that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilising function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, we demonstrate further that the malignant phenotype on type I collagen is mediated specifically by the alpha2beta1 integrin. These results identify alpha2beta1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.
Grzesiak
J J
JJ
Department of Surgery (112-E), University of California, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Bouvet
M
M
D000911:Antibodies, Monoclonal; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D024042:Collagen Type I / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D024042:Collagen Type I; D038982:Integrin alpha2beta1