Fibroblast Growth Factor Receptor 2–Positive Fibroblasts Provide a Suitable Microenvironment for Tumor Development and Progression in Esophageal Carcinoma

Abstract

Purpose: Tumor fibroblasts (TF) have been suggested to play an essential role in the complex process of tumor-stroma interactions and tumorigenesis. The aim of the present study was to investigate the specific role of TF in the esophageal cancer microenvironment. Experimental Design: An Affymetrix expression microarray was used to compare gene expression profiles between six pairs of TFs and normal fibroblasts from esophageal squamous cell carcinoma (ESCC). Differentially expressed genes were identified, and a subset was evaluated by quantitative real-time PCR and immunohistochemistry. Results: About 43% (126 of 292) of known deregulated genes in TFs were associated with cell proliferation, extracellular matrix remodeling, and immune response. Up-regulation of fibroblast growth factor receptor 2 (FGFR2), which showed the most significant change, was detected in all six tested TFs compared with their paired normal fibroblasts. A further study found that FGFR2-positive fibroblasts were only observed inside the tumor tissues and not in tumor-surrounding stromal tissues, suggesting that FGFR2 could be used as a TF-specific marker in ESCC. Moreover, the conditioned medium from TFs was found to be able to promote ESCC tumor cell growth, migration, and invasion in vitro. Conclusions: Our study provides new candidate genes for the esophageal cancer microenvironment. Based on our results, we hypothesize that FGFR2(+)-TFs might provide cancer cells with a suitable microenvironment via secretion of proteins that could promote cancer development and progression through stimulation of cancer cell proliferation, induction of angiogenesis, inhibition of cell adhesion, enhancement of cell mobility, and promotion of the epithelial-mesenchymal transition.

Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts

“…These results are in agreement with the finding that CAF isolated from ESCC tissue have an increased CCL5 gene expression compared with normal fibroblasts (44). It was shown for co-cultures with MDA-MB-231 breast cancer cells or ovarian cancer cells that these cells can induce Ccl5 mRNA expression in mesenchymal stromal cells and normal fibroblasts, respectively (21,49).…”

“…Mechanistically, KYSE-410 cells may induce fibroblasts to produce autostimulatory Wnt proteins, such as Wnt2, upon direct cell-cell contact. Indeed, CAF isolated from ESCC tissue show increased Wnt2 and Wnt5a expression compared with normal fibroblasts (44). The reduced amount of ␣SMA in co-cultures with Has2 knockdown SF underlines the role of HA in myofibroblast differentiation.…”

“…There is evidence that CAF can affect cancer cells more potently than normal fibroblasts (42)(43)(44). Consequently, mRNA expression of EMT markers as well as proliferation and migration were also measured in co-cultures with KYSE-410 cells and CAF.…”

Primary Cell Culture Systems for Human Thyroid Studies

“…These four genes were: cadherin 1 (CDH1), also known as E-cadherin; S100 calcium binding protein A4 (S100A4), also known as fibroblast-specific protein 1 (FSP1); fibronectin 1 (FN1); and collagen, type I, alpha 1 (COL1A1) (13)(14)(15)(16)(17). It was observed that CDH1 and S100A4 showed decreased expression, similar to most thyroid markers from day 8 to day 43 in the primary cultures.…”

Growth Factors, Signal Transduction Pathways, and Tumor Suppressor Genes in Esophageal Cancer

“…Stromal fibroblasts are also involved in tumor progression through degradation of extracellular matrix, secretion of growth factors, and regulation of epithelial cell behavior. It has also been shown that FGF receptor 2-positive fibroblasts provide a suitable microenvironment for tumor development and progression through stimulation of cancer cell proliferation, induction of angiogenesis, cell mobility, inhibition of cell adhesion, and promotion of epithelial-mesenchymal transition [75].…”