Takase Nobuhisa, Koma Yu-Ichiro, Urakawa Naoki, Nishio Mari, Arai Noriaki, Akiyama Hiroaki, Shigeoka Manabu, Kakeji Yoshihiro, Yokozaki Hiroshi
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Cancer Lett. 2016 Sep 28;380(1):47-58. doi: 10.1016/j.canlet.2016.06.009. Epub 2016 Jun 15.
Tumor-associated macrophages (TAMs) have important roles in the angiogenesis and tumor immunosuppression 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 1 (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 FGFR1 signaling in the tumor microenvironment of ESCCs.
肿瘤相关巨噬细胞（TAM）在包括食管鳞状细胞癌（ESCC）在内的多种癌症的血管生成和肿瘤免疫抑制中发挥着重要作用。为了阐明TAM在ESCC中的作用，我们使用cDNA微阵列分析比较了人外周血单核细胞衍生的巨噬细胞样细胞（巨噬细胞_Ls）与用TE系列人ESCC细胞系的条件培养基（TECM）刺激的巨噬细胞_Ls（TAM_Ls）之间的基因表达谱。在TAM_Ls中高表达的基因中，我们重点关注神经细胞粘附分子（NCAM）。TAM_Ls中的NCAM敲低通过抑制PI3K-Akt和成纤维细胞生长因子受体1（FGFR1）信号传导，显著降低了迁移和存活率。TECM刺激上调了巨噬细胞_Ls中FGFR1的水平。重组人成纤维细胞生长因子-2（rhFGF-2）通过FGFR1信号传导促进了TAM_Ls和TE细胞的迁移和存活。我们对70例手术切除的ESCC样本进行的免疫组织化学分析显示，包括巨噬细胞在内的基质细胞中FGF-2的上调与更具侵袭性的表型和大量浸润的M2巨噬细胞有关。这些发现可能表明NCAM和FGF-2介导的FGFR1信号在ESCC肿瘤微环境中具有新的作用。
