title: Profile of MMP and TIMP Expression in Human Pancreatic Stellate Cells: Regulation by IL-1α and TGFβ and Implications for Migration of Pancreatic Cancer Cells.
abstract: Pancreatic ductal adenocarcinoma is characterized by a prominent fibroinflammatory stroma with both tumor-promoting and tumor-suppressive functions. The pancreatic stellate cell (PSC) is the major cellular stromal component and the main producer of extracellular matrix proteins, including collagens, which are degraded by metalloproteinases (MMPs). PSCs interact with cancer cells through various factors, including transforming growth factor (TGF)β and interleukin (IL)-1α. The role of TGFβ in the dual nature of tumor stroma, i.e., protumorigenic or tumor suppressive, is not clear. We aimed to investigate the roles of TGFβ and IL-1α in the regulation of MMP profiles in PSCs and the subsequent effects on cancer cell migration. Human PSCs isolated from surgically resected specimens were cultured in the presence of pancreatic cancer cell lines, as well as IL-1α or TGFβ. MMP production and activities in PSCs were quantified by gene array transcripts, mRNA measurements, fluorescence resonance energy transfer-based activity assay, and zymography. PSC-conditioned media and pancreatic cancer cells were included in a collagen matrix cell migration model. We found that production of IL-1α by pancreatic cancer cells induced alterations in MMP and tissue inhibitors of matrix metalloproteinase (TIMP) profiles and activities in PSCs, upregulated expression and activation of MMP1 and MMP3, and enhanced migration of pancreatic cancer cells in the collagen matrix model. TGFβ counteracted the effects of IL-1α on PSCs, reestablished PSC MMP and TIMP profiles and activities, and inhibited migration of cancer cells. This suggests that tumor TGFβ has a role as a suppressor of stromal promotion of tumor progression through alterations in PSC MMP profiles with subsequent inhibition of pancreatic cancer cell migration.
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: vegard.tjomsland@medisin.uio.no.
authors.forename: Vegard
authors.initials: V
authors.lastname: Tjomsland
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Eva
authors.initials: E
authors.lastname: Pomianowska
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Monica
authors.initials: M
authors.lastname: Aasrum
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Dagny
authors.initials: D
authors.lastname: Sandnes
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Caroline Sophie
authors.initials: CS
authors.lastname: Verbeke
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Ivar Prydz
authors.initials: IP
authors.lastname: Gladhaug
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation / Q000187:drug effects; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D010183:Pancreatic Ducts / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; C088390:TIMP3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1