Ha Sang Yun, Yeo So-Young, Xuan Yan-hiua, Kim Seok-Hyung
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.
PLoS One. 2014 Jun 19;9(6):e99955. doi: 10.1371/journal.pone.0099955. eCollection 2014.
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).
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.
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.
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.
癌症相关成纤维细胞（CAF）是癌基质中被激活的成纤维细胞，在癌症进展中起重要作用。一些报告指出，CAF标志物的表达与几种癌症的不良预后之间存在相关性。然而，尚无关于食管鳞状细胞癌（ESCC）中CAF表型及其临床相关性的报道。
我们基于116例ESCC组织样本中5种CAF标志物的组织学和免疫组化表达，研究了ESCC的CAF表型。这5种标志物分别为成纤维细胞活化蛋白（FAP）、平滑肌肌动蛋白（SMA）、成纤维细胞特异性蛋白-1（FSP1）、血小板衍生生长因子受体（PDGFRα）和PDGFRβ。此外，我们还研究了CAF表型与临床相关性以及其他癌症微环境相关因素之间的关系。
组织学上不成熟的CAF表型与预后不良相关（p<0.001），并与微血管密度增加、肿瘤相关巨噬细胞增多以及上皮-间质转化有关。CAF标志物在靠近肿瘤细胞的基质成纤维细胞中特异性表达，且在每个病例中5种CAF标志物的表达模式高度异质性。在5种CAF标志物中，SMA、FSP1和PDGFRα是ESCC的不良预后指标。不成熟CAF的ESCC中阳性CAF标志物的数量多于成熟CAF的ESCC。
我们的结果表明，CAF表型的组织学分类是ESCC中可靠且重要的预后预测指标。CAF标志物有可能成为ESCC的诊断和治疗靶点。
