Pancreatic cancer is characterized by a transforming growth factor β1 (TGFβ1)-mediated desmoplastic response that includes the aberrant expression of the extracellular matrix (ECM). Studies indicate that type I collagen in particular, is highly upregulated in pancreatic cancer in vivo. Recent studies also demonstrate in vitro and in vivo, 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 the tumor cells as defined by increased proliferation, resistance to chemically-induced apoptosis and increased tumorigenesis. In the present study, we examined Capan-1, CFPAC, FG, Colo-357, AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 pancreatic cancer cell lines for relative integrin expression, adhesion, proliferation and migration on types I and IV collagen, fibronectin, laminin, and vitronectin in 2-D assay systems, as well as adhesion and proliferation on 3-D type I collagen/glycosaminoglycan matrices. Our results indicate that type I collagen promotes the strongest adhesion, proliferation, and migration in the majority of the cell lines tested. Only MiaPaCa-2 cells, which do not express the α1 or α2 collagen-binding integrin subunits, do not adhere, migrate, or proliferate on types I or IV collagen in 2-D. Our results also indicate strong adhesion and proliferation on 3-D type I collagen/chondroitin-6-sulfate scaffolds for all cell lines except MiaPaCa-2. When these 3-D matrices are coated with fibronectin, however, MiaPaCa-2 cells adhere and proliferate. Utilizing function-blocking monoclonal antibodies directed against specific integrin subunits as well as affinity chromatography and immunoprecipitation experiments, we also demonstrate that adhesion, migration, and proliferation of pancreatic cancer cell lines on type I collagen in both the 2-D and 3-D systems is mediated specifically by the α2β1 integrin. Additionally, our results identify the α1β1 integrin as a type IV collagen and laminin-binding integrin in pancreatic cancer cell lines. These results are the first demonstration of a physiologically relevant 3-D in vitro platform for the study of pancreatic cancer, and identify α2β1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]