title: Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity.
abstract: OBJECTIVE
  Pancreatic cancer creates desmoplasia by stimulating stellate cells (PSCs), thereby influencing tumor aggressiveness. The aim of this study was to analyze the impact of the PSC-specific matrix protein periostin on tumor responses to radiochemotherapy.
  
  
  METHODS
  PSCs and cancer cells in primary and metastatic lesions of patients treated with or without neoadjuvant radiochemotherapy were evaluated by immunohistochemistry. Periostin messenger-RNA levels determined by quantitative reverse-transcription polymerase chain reaction were correlated to patient survival. Interactions between PSCs and cancer cells and the effects of periostin in modulating cellular responses under conditions of hypoxia, starvation, and radiochemotherapy were assessed by immunoblotting and by growth, clonogenicity, and invasion assays.
  
  
  RESULTS
  Periostin messenger-RNA levels were elevated 42-fold in cancer, and patients with increased expression had a tendency toward shorter survival (19 vs 12 months; P = .14). Stromal cells were the only source of periostin in the pancreas and in metastatic sites. Cancer cell supernatants stimulated periostin secretion from PSCs. Recombinant periostin increased alpha-smooth muscle actin, periostin, collagen-1, fibronectin, and transforming growth factor-beta1 expression while decreasing PSC invasiveness. These effects were reversed by silencing periostin expression and secretion by small interfering RNA transfection. In cancer cells, periostin stimulated growth and conferred resistance to starvation and hypoxia. In addition, the periostin downstream target collagen-1 significantly increased chemoresistance.
  
  
  CONCLUSIONS
  Once stimulated by cancer cells, PSCs remain active via an autocrine periostin loop even under radiotherapy and produce excessive extracellular matrix proteins, creating a tumor-supportive microenvironment. Increased periostin expression may therefore reflect a more aggressive tumor phenotype.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Andre
authors.initials: A
authors.lastname: Gorbachevski
authors.forename: Carolin
authors.initials: C
authors.lastname: Reiser
authors.forename: Tomas
authors.initials: T
authors.lastname: Mitkus
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003720:Densitometry; D018450:Disease Progression; D005353:Fibronectins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D005355:Fibrosis / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000473:pathology; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
chemical_list: D000199:Actins; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D024042:Collagen Type I; D005353:Fibronectins; C512835:POSTN protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1