The Prognostic Significance of Cancer-Associated Fibroblasts in Esophageal Squamous Cell Carcinoma

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.

## 背景
癌相关成纤维细胞（Cancer-associated fibroblasts, CAF）是癌间质中的活化成纤维细胞，在癌症进展过程中发挥关键作用。已有多项研究报道，多种癌症的CAF标志物表达水平与不良预后存在相关性，但目前尚无针对食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）的CAF表型及其临床相关性的研究。

## 方法
本研究针对116例ESCC组织样本，通过组织学检测与免疫组化分析，对5种CAF标志物的表达情况进行评估，包括成纤维细胞活化蛋白（fibroblast activation protein, FAP）、平滑肌肌动蛋白（smooth muscle actin, SMA）、成纤维细胞特异性蛋白-1（fibroblast-specific protein-1, FSP1）、血小板衍生生长因子受体α（platelet-derived growth factor receptor α, PDGFRα）及PDGFRβ，以此探究ESCC的CAF表型。此外，本研究还分析了CAF表型与临床相关性及其他肿瘤微环境相关因素的关联。

## 结果
组织学分类下的未成熟CAF表型与不良预后显著相关（p<0.001），同时与微血管密度升高、肿瘤相关巨噬细胞增多及上皮间质转化（epithelial to mesenchymal transition）存在关联。CAF标志物特异性表达于肿瘤细胞邻近的间质成纤维细胞中，且5种CAF标志物的表达模式在每例个体样本中均呈现高度异质性。在5种CAF标志物中，SMA、FSP1及PDGFRα是ESCC的不良预后指标。未成熟CAFs的ESCC样本中，阳性CAF标志物的数量多于成熟CAFs对应的样本。

## 结论
本研究结果证实，CAF表型的组织学分类是ESCC可靠且具有重要临床价值的预后预测因子。CAF标志物有望成为ESCC的诊断与治疗靶点。