title: The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration.
abstract: The most abundant cells in the extensive desmoplastic stroma of pancreatic adenocarcinomas are the pancreatic stellate cells, which interact with the carcinoma cells and strongly influence the progression of the cancer. Tumor stroma interactions induced by IL-1α/IL-1R1 signaling have been shown to be involved in pancreatic cancer cell migration. TGFβ and its receptors are overexpressed in pancreatic adenocarcinomas. We aimed at exploring TGFβ and IL-1α signaling and cross-talk in the stellate cell cancer cell interactions regulating pancreatic adenocarcinoma cell migration.
  
  
  
  Human pancreatic stellate cells were isolated from surgically resected pancreatic adenocarcinomas and cultured in the presence of TGFβ or pancreatic adenocarcinoma cell lines. The effects of TGFβ were blocked by inhibitors or amplified by silencing the endogenous inhibitor of SMAD signaling, SMAD7. Pancreatic stellate cell responses to IL-1α or to IL-1α-expressing pancreatic adenocarcinoma cells (BxPC-3) were characterized by their ability to stimulate migration of cancer cells in a 2D migration model.
  
  
  
  In pancreatic stellate cells, IL-1R1 expression was found to be down-regulated by TGFβ and blocking of TGFβ signaling re-established the expression. Endogenous inhibition of TGFβ signaling by SMAD7 was found to correlate with the levels of IL-1R1, indicating a regulatory role of SMAD7 in IL-1R1 expression. Pancreatic stellate cells cultured in the presence of IL-1α or in co-cultures with BxPC-3 cells enhanced the migration of cancer cells. This effect was blocked after treatment of the pancreatic stellate cells with TGFβ. Silencing of stellate cell expression of SMAD7 was found to suppress the levels of IL-1R1 and reduce the stimulatory effects of IL-1α, thus inhibiting the capacity of pancreatic stellate cells to induce cancer cell migration.
  
  
  
  TGFβ signaling suppressed IL-1α mediated pancreatic stellate cell induced carcinoma cell migration. Depletion of SMAD7 upregulated the effects of TGFβ and reduced the expression of IL-1R1, leading to inhibition of IL-1α induced stellate cell enhancement of carcinoma cell migration. SMAD7 might represent a target for inhibition of IL-1α induced tumor stroma interactions.
authors.affiliation: Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. vegard.tjomsland@medisin.uio.no.|Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. vegard.tjomsland@medisin.uio.no.
authors.forename: Vegard
authors.initials: V
authors.lastname: Tjomsland
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Dagny
authors.initials: D
authors.lastname: Sandnes
authors.affiliation: Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Ewa
authors.initials: E
authors.lastname: Pomianowska
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Smiljana Torbica
authors.initials: ST
authors.lastname: Cizmovic
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Monica
authors.initials: M
authors.lastname: Aasrum
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Oral Biology, University of Oslo, Oslo, Norway.|Department of Pediatric Dentistry and Behavioral Science, Faculty of Dentistry, University of Oslo, Oslo, Norway.
authors.forename: Ingvild Johnsen
authors.initials: IJ
authors.lastname: Brusevold
authors.affiliation: Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Christoffersen
authors.affiliation: Department of Hepato-pancreato-biliary Surgery, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Ivar P
authors.initials: IP
authors.lastname: Gladhaug
mesh_terms: D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000166:cytology* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C508584:IL1A protein, human; C508590:IL1R1 protein, human; D053582:Interleukin-1alpha; D053573:Receptors, Interleukin-1 Type I; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta
keywords: IL-1α; Pancreatic adenocarcinoma; Pancreatic stellate cells; TGFβ; Tumor stroma