Angiogenic factors play a major role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)- D is a ligand for VEGF receptor-3 (VEGFR-3/Flt-4), which mainly expressed on the lymphatic endothelium. Recent experimental studies have shown that VEGF-D induces tumor lymphangiogenesis and promote metastatic spread of tumor cells via lymphatic vessels. However, the contribution of VEGFD to lymph node metastasis in human colorectal cancer is less understood. We therefore examined VEGF-D and VEGFR-3 expression in patients with colorectal cancer. Sections of formalin-fixed and paraffin-embedded specimens from 76 colorectal cancers were immunohistochemically stained for VEGF-D and VEGFR-3. Staining for VEGF-D was positive in the cytoplasm of tumor cells in 43 of 76 examined tumors (56.6%). Staining for VEGFR-3 was positive in endothelial cells in 38 (50.0%) tumors. Univariate analysis showed that both VEGF-D and VEGFR-3 expressions correlated significantly with lymph node metastasis, histological type and depth of tumor invasion. However, logistic regression analysis indicated that VEGF-D expression, but not that of VEGFR-3, was an independent predictor for lymph node metastasis. Our data suggest that VEGF-D plays an important role in lymph node metastasis in colorectal cancer
