Monocyte chemoattractant protein‐1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas

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Abstract
Tumor angiogenesis requires the production of angiogenic factors by tumor and stromal cells. Macrophages are key effectors of angiogenesis and reported to contribute to tumor angiogenesis in several carcinomas. To investigate interactions between tumor cells and macrophages in angiogenesis, we examined macrophage infiltration, tumor vascularity and expression of monocyte chemoattractant protein (MCP)‐1, CC chemokine receptor 2 (CCR2) and vascular endothelial growth factor (VEGF) in 57 archival specimens from patients with esophageal dysplasia (n = 9) and squamous cell carcinomas (n = 48). Expression of MCP‐1 mRNA was also examined by reverse transcriptase‐polymerase chain reaction (RT‐PCR) in 7 esophageal carcinoma cell lines and fresh biopsy specimens from 14 patients. The number of infiltrating macrophages correlated closely with expression of VEGF by tumor cells and with neovascularization. Of the 7 cell lines, 4 (TE‐1, 3, 5 and 13) constitutively expressed MCP‐1 mRNA. In 9 (64.3%) of the 14 patients, MCP‐1 mRNA was expressed at high levels in tumor tissues as compared to normal mucosa. MCP‐1 immunoreactivity increased with the depth of tumor invasion (Tis 0%, T1 26.3%, T2, T3 42.1%). Moreover, macrophage and vessel counts were significantly higher in MCP‐1‐positive tumors than in MCP‐1‐negative tumors. Normal and dysplastic esophageal squamous epithelium showed no staining or faint cytoplasmic staining of MCP‐1. Expression of CCR2 immunoreactivity was detected in the cytoplasm of mononuclear cells but not of vascular endothelial cells. These results suggest that interactions between cancer cells and macrophages are important for tumor angiogenesis. MCP‐1 may play a role in progression of human esophageal carcinoma through its role in angiogenesis.