Abstract
BackgroundCancer-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).MethodsWe 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.ResultsHistologically 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.ConclusionsOur 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.
Highlights
Histological Classification of Cancer-associated fibroblasts (CAF) is Correlated with Prognosis in esophageal squamous cell carcinoma (ESCC)
The immature CAF phenotypes were significantly associated with increased microvessel density (MVD) (p,0.001) and enhanced infiltration of tumor associated macrophage (TAM) (p = 0.003) compared to the mature stromal phenotype
Both increased MVD and infiltration of TAM are correlated with poor prognosis of ESCC (Figure S1)
Summary
Cancer-associated fibroblasts (CAFs) are activated fibroblasts in the cancer stroma and are at the leading edge of many solid tumors, including breast, colon, and melanoma.[1,2,3,4,5] CAFs are the most prominent cell type within the tumor stroma of many cancers and an important player in the cancer-microenvironment which consists of a dynamic mixture of fibroblasts, monocytes/ macrophages, endothelial cells, lymphocytes, and granulocytes.[2,6] CAFs drive tumor progression by directly stimulating tumor cell proliferation through the secretion of various growth factors and cytokines such as hepatocyte growth factor, transforming growth factor-b, stromal cell-derived factor 1, and interleukin-6 as well as by remodeling the cancer microenvironment through deposition of extracellular matrix and recruitment of other players such as various inflammatory cells and endothelial cells.[1,2,3] activated CAFs contribute to cancer progression by inducing angiogenesis.[1,2,3] During cancer progression, CAFs contribute to invasive growth of cancer by secreting several proteases such as matrix metalloproteinase or cathepsins and inducing the epithelial to mesenchymal transition (EMT) [1,2,3]. fibroblasts are widely distributed and recognizable due to their fusiform or spindle-like shape, fibroblasts remain poorly defined in molecular terms and there is no known specific and reliable molecular fibroblast markers.[4]. There are several wellestablished indicators of CAF such as smooth muscle actin (SMA), fibroblast stimulating protein-1 (FSP-1), platelet-derived growth factor a (PDGFRa), and PDGFRb.[4] none of them are both exclusive to CAFs and present in all CAFs.[4] Instead, each of these CAF markers is estimated to represent a certain and different phenotype of CAFs. In addition, fibroblasts are highly heterogeneous and fibroblasts from different anatomical sites have considerably different expression profile [7]. Some reports have indicated the correlation between the expression of CAF markers and adverse prognosis in several cancers. No reports have studied CAF phenotype and its clinical relevance in esophageal squamous cell carcinoma (ESCC)
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