Takase N, Koma Y, Urakawa N, Nishio M, Arai N, Akiyama H, Shigeoka M, Kakeji Y, Yokozaki H.
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.
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.
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / pathology
Cell Line, Tumor
Culture Media, Conditioned / metabolism
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / pathology
Esophageal Squamous Cell Carcinoma
Fibroblast Growth Factor 2 / metabolism*
Macrophages / metabolism*
Macrophages / pathology
Neural Cell Adhesion Molecules / genetics
Neural Cell Adhesion Molecules / metabolism*
Phosphatidylinositol 3-Kinase / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
Stromal Cells / metabolism*
Stromal Cells / pathology
|Human and Animal Cells