Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas

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Abstract
The purpose of this study was to investigate the expression of vascular endothelial growth factor (VEGF) ‐C in human esophageal squamous cell carcinomas to elucidate its role in lymph node metastasis and tumor progression. The expression of VEGF‐C and flt‐4 genes was examined in 5 esophageal carcinoma cell lines, 12 fresh biopsy specimens and 48 archival surgical specimens of human esophageal carcinoma tissues by RT‐PCR and immunohistochemistry. Immunohistochemistry using antibodies against CD34 (endothelial cell specific) was also carried out and microvessels were quantified by counting vessels in a 200× field in the most vascular area of the tumor. Of the 5 human esophageal carcinoma cell lines, 4 constitutively expressed VEGF‐C mRNA. In 8 (66.7%) of 12 cases, VEGF‐C mRNA was detected in only tumor tissues but not in normal mucosa by RT‐PCR. There was a significant relationship between VEGF‐C and flt‐4 mRNA expression. Out of the 48 surgical specimens of esophageal carcinomas, 19 (39.6%) and 10 (20.8%) exhibited intense VEGF‐C immunoreactivity in the cytoplasm of many cancer cells and the stromal cells, respectively. In contrast, Flt‐4 was mainly expressed on the lymphatic endothelial cells. Normal and dysplastic esophageal squamous epithelium exhibited no or faint cytoplasmic staining of VEGF‐C. VEGF‐C expression correlated with depth of tumor invasion, tumor stage, venous invasion, lymphatic invasion and lymph node metastasis. Vessel count was significantly higher in the VEGF‐C positive tumors than in the negative tumors. These results overall suggest that VEGF‐C may play a role in tumor progression via lymphangiogenesis and angiogenesis in human esophageal carcinoma.