CCR7 enhances the angiogenic capacity of esophageal squamous carcinoma cells in vitro via activation of the NF-κB/VEGF signaling pathway.

High levels of angiogenesis are associated with poor prognosis and a highly invasive phenotype in esophageal squamous carcinoma. C-C chemokine receptor type 7 (CCR7) is overexpressed in multiple tumor types and has been suggested to act as an oncogene and pro-angiogenic factor. This study aimed to elucidate the effect of CCR7 on the angiogenic capacity of esophageal squamous carcinoma cells in vitro. Expression of CCR7 in esophageal squamous carcinoma cell lines and normal human esophageal epithelial cell line was examined by western blotting and quantitative real-time PCR. CCR7 was stably overexpressed or transiently knocked down in esophageal squamous carcinoma cell lines. Overexpressing CCR7 enhanced the capacity of esophageal squamous carcinoma cell conditioned media to induce human umbilical vein endothelial cells (HUVEC) proliferation and migration and neovascularization in the chicken chorioallantoic membrane (CAM) assay. While silencing CCR7 caused an opposite outcome. Moreover, we demonstrated that CCR7 activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling and regulated its targets, including vascular endothelial growth factor A (VEGF-A), VEGF-C, tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-6, IL-8 and transforming growth factor-beta (TGF-beta) expression. Additionally, CCR7 down-regulation reduced tumor volume and weight in xenograft mouse model, and significantly decreased NF-kappa B signaling pathway. This study suggests that CCR7 plays an important pro-angiogenic role in esophageal squamous carcinoma via a mechanism linked to activation of the NF-kappa B pathway; CCR7 may represent a potential target for anti-angiogenic therapy in esophageal squamous carcinoma.