title: The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma.
abstract: BACKGROUND
  Cancer-associated fibroblasts (CAF) are activated fibroblasts in the cancer stroma and play an important role in cancer progression. Some reports have indicated the correlation between the expression of CAF markers and adverse prognosis in several cancers. However, no reports have studied CAF phenotype and its clinical relevance in esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  We investigated CAF phenotype of ESCC based on histology and immunohistochemical expressions of five CAF markers such as fibroblast activation protein (FAP), smooth muscle actin (SMA), fibroblast-specific protein-1 (FSP1), platelet-derived growth factor receptor (PDGFRα), and PDGFRβ in 116 ESCC tissue samples. Besides, we also examined the correlation of the CAF phenotype with clinical relevance as well as other cancer-microenvironment related factors.
  
  
  RESULTS
  Histologically immature CAF phenotype was correlated with poor prognosis (p<0.001) and associated with increased microvessel density, increased tumor associated macrophages, and epithelial to mesenchymal transition. CAF markers were characteristically expressed in stromal fibroblast close to tumor cells and the expression pattern of 5 CAF markers was highly heterogeneous in every individual cases. Of five CAF markers, SMA, FSP1, and PDGFRα were unfavorable prognostic indicators of ESCC. The number of positive CAF markers was greater in ESCC with immature CAFs than in those with mature ones.
  
  
  CONCLUSIONS
  Our results demonstrate that histologic classification of CAF phenotype is a reliable and significant prognostic predictor in ESCC. CAF markers have the potential to be diagnostic and therapeutic targets in ESCC.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Ha
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Yeo
authors.affiliation: Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji, China; Department of Pathology, Yanbian University School of Medicine, Yanji, China.
authors.forename: Yan-hiua
authors.initials: YH
authors.lastname: Xuan
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D010450:Endopeptidases; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000235:genetics*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000199:Actins; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D000071999:S100 Calcium-Binding Protein A4; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C541116:ACTA2 protein, human; C077591:S100A4 protein, human