title: Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling.
abstract: OBJECTIVE
  Generation of a reactive stroma environment occurs in many human cancers and is likely to promote tumorigenesis. However, reactive stroma in human prostate cancer has not been defined. We examined stromal cell phenotype and expression of extracellular matrix components in an effort to define the reactive stroma environment and to determine its ontogeny during prostate cancer progression.
  
  
  METHODS
  Normal prostate, prostatic intraepithelial neoplasia (PIN), and prostate cancer were examined by immunohistochemistry. Tissue samples included radical prostatectomy specimens, frozen biopsy specimens, and a prostate cancer tissue microarray. A human prostate stromal cell line was used to determine whether transforming growth factor beta1 (TGF-beta1) regulates reactive stroma.
  
  
  RESULTS
  Compared with normal prostate tissue, reactive stroma in Gleason 3 prostate cancer showed increased vimentin staining and decreased calponin staining (P < 0.001). Double-label immunohistochemistry revealed that reactive stromal cells were vimentin and smooth muscle alpha-actin positive, indicating the myofibroblast phenotype. In addition, reactive stroma cells exhibited elevated collagen I synthesis and expression of tenascin and fibroblast activation protein. Increased vimentin expression and collagen I synthesis were first observed in activated periacinar fibroblasts adjacent to PIN. Similar to previous observations in prostate cancer, TGF-beta1-staining intensity was elevated in PIN. In vitro, TGF-beta1 stimulated human prostatic fibroblasts to switch to the myofibroblast phenotype and to express tenascin.
  
  
  CONCLUSIONS
  The stromal microenvironment in human prostate cancer is altered compared with normal stroma and exhibits features of a wound repair stroma. Reactive stroma is composed of myofibroblasts and fibroblasts stimulated to express extracellular matrix components. Reactive stroma appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular stroma. These studies and others suggest that TGF-beta1 is a candidate regulator of reactive stroma during prostate cancer progression.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Tuxhorn
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Ayala
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Smith
authors.forename: Truong D
authors.initials: TD
authors.lastname: Dang
authors.forename: David R
authors.initials: DR
authors.lastname: Rowley
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D001706:Biopsy; D002135:Calcium-Binding Proteins / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000032:analysis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011468:Prostatectomy; D019048:Prostatic Intraepithelial Neoplasia / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology; D019063:Tenascin / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000032:analysis; D014945:Wound Healing; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D019063:Tenascin; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D000096985:Calponins; C508960:TGFB1 protein, human