NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumor-associated macrophages and cancer cells
NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumor-associated macrophages and cancer cells
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DOI：
10.1016/j.canlet.2016.06.009
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发表时间：
2016-09-28
期刊：
影响因子：
9.7
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
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作者：
Takase, Nobuhisa;Koma, Yu-ichiro;Yokozaki, Hiroshi
肿瘤相关巨噬细胞（TAM）在包括食管鳞状细胞癌（ESCC）在内的各种癌症的血管生成和肿瘤免疫抑制中起重要作用。为了阐明TAM在食管鳞癌中的作用，我们利用cDNA微阵列技术比较了人外周血单核细胞来源的巨噬细胞样细胞（Macrophage_Ls）和TE系列人食管鳞癌细胞系（TECM）条件培养液刺激的巨噬细胞样细胞（Macrophage_Ls）（TAM_Ls）的基因表达谱。在TAM_Ls的高表达基因中，我们重点研究了神经细胞粘附分子（NCAM）。TAM_Ls中的NCAM敲低揭示了通过抑制PI 3 K-Akt和成纤维细胞生长因子受体I（FGFR 1）信号传导而显著降低的迁移和存活。TECM刺激可上调巨噬细胞中FGFR 1的表达。重组人成纤维细胞生长因子-2（rhFGF-2）通过FGFR 1信号通路促进TAM_Ls和TE-细胞的迁移和存活。我们对70例手术切除的ESCC样本的免疫组化分析显示，基质细胞（包括巨噬细胞）中FGF-2的上调与更具侵袭性的表型和大量浸润的M2巨噬细胞相关。这些发现可能表明NCAM和FGF-2介导的FGFRI信号在ESCC的肿瘤微环境中的新作用。(C)2016作者出版社：Elsevier爱尔兰Ltd.
Tumor-associated macrophages (TAMs) have important roles in the angiogenesis and tumor immuno-suppression of various cancers, including esophageal squamous cell carcinomas (ESCCs). To elucidate the roles of TAMs in ESCCs, we compared the gene expression profiles between human peripheral blood monocyte-derived macrophage-like cells (Macrophage_Ls) and Macrophage_Ls stimulated with conditioned medium of the TE series human ESCC cell line (TECM) (TAM_Ls) using cDNA microarray analysis. Among the highly expressed genes in TAM_Ls, we focused on neural cell adhesion molecule (NCAM). NCAM knockdown in TAM_Ls revealed a significant decrease of migration and survival via a suppression of PI3K-Akt and fibroblast growth factor receptor I (FGFR1) signaling. Stimulation by TECM up-regulated the level of FGFR1 in Macrophage_Ls. Recombinant human fibroblast growth factor-2 (rhFGF-2) promoted the migration and survival of TAM_Ls and TE-cells through FGFR1 signaling. Our immunohistochemical analysis of 70 surgically resected ESCC samples revealed that the up-regulated FGF-2 in stromal cells, including macrophages, was associated with more aggressive phenotypes and a high number of infiltrating M2 macrophages. These findings may indicate a novel role of NCAM- and FGF-2-mediated FGFRI signaling in the tumor microenvironment of ESCCs. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.