The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma

PLoS One. 2014 Jun 19;9(6):e99955. doi: 10.1371/journal.pone.0099955. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics*
  • Actins / metabolism
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Endopeptidases
  • Epithelial-Mesenchymal Transition / genetics
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / mortality
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gelatinases / genetics
  • Gelatinases / metabolism
  • Gene Expression
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Phenotype
  • Prognosis
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • S100 Calcium-Binding Protein A4
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Survival Analysis
  • Tissue Array Analysis
  • Tumor Microenvironment / genetics*

Substances

  • ACTA2 protein, human
  • Actins
  • Biomarkers, Tumor
  • Calcium-Binding Proteins
  • Membrane Proteins
  • S100 Calcium-Binding Protein A4
  • S100A4 protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta
  • Endopeptidases
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases

Grants and funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI11C17620000), and Samsung Biomedical Research Institute grant SS1B30131. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.