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

Abstract

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.

Cancer as a tissue: The significance of cancer‐stromal interactions in the development, morphogenesis and progression of human upper digestive tract cancer

“…NCAM1 was up‐regulated in TAM‐like cells after exposure to the conditioned media of TE‐8, TE‐9 and TE‐15 ESCC cell lines (TAM9, TAM8 and TAM15, respectively) and co‐localized with F‐actin at a part of the lamellipodia suggesting its functional involvement in cell mobility . Moreover, NCAM1 was confirmed to be co‐localized with FGFR1 (Fig.…”

Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients

“…All of these genes have been validated as drivers of development of ESCC or other cancers. 12,13,15–27 …”

Fibroblast growth factor–mediated crosstalk in cancer etiology and treatment

“…Evidence also suggests that FGFs can alter the tumor environment to promote TAM accumulation. FGF2 secreted from esophageal cancer cells promotes macrophage migration and survival via an FGFR1/neural cell adhesion molecule signaling axis (Takase et al, ). Indeed, enhanced FGF2 in the stroma of esophageal squamous cell carcinoma patients correlated with a higher TAM infiltrate and poorer prognosis.…”