CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells

// Masayoshi Hosono 1, 2 , Yu-Ichiro Koma 1 , Nobuhisa Takase 1, 2 , Naoki Urakawa 1, 2 , Nobuhide Higashino 1, 2 , Kazuki Suemune 1 , Himiko Kodaira 1 , Mari Nishio 1 , Manabu Shigeoka 1 , Yoshihiro Kakeji 2 and Hiroshi Yokozaki 1 1 Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan 2 Division of Gastro-intestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan Correspondence to: Hiroshi Yokozaki, email: hyoko@med.kobe-u.ac.jp Keywords: CXCL8; esophageal squamous cell carcinoma; tumor-associated macrophage; tumor progression; tumor microenvironment Received: July 19, 2017      Accepted: October 28, 2017      Published: November 20, 2017 ABSTRACT Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 ( CXCL8 ) was up-regulated in the TAM-like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines’ migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells’ migration and invasion.