Roles of VEGF-C and Smad4 in the Lymphangiogenesis, Lymphatic Metastasis, and Prognosis in Colon Cancer

We combined two different signal pathways on transforming growth factor beta 1 (TGF-beta 1)-Smad and vascular endothelial growth factor C (VEGF-C)/VEGF receptors for exploring changes in pathway members and their influence on lymphangiogenesis and clinicopathological features. Expression of TGF-beta 1, TGF-beta RII, Smad4, VEGF-C, and VEGFR-3 was immunohistochemically evaluated in 147 colon cancer patients who were followed up for 5 years. Lymphatic vessel density in colon cancer tissues was significantly higher than in normal colonic tissues. Smad4 expression negatively correlated with lymphatic vessel count and VEGF-C expression. VEGF-C expression positively correlated with lymphatic vessel count. Analysis using the Kaplan-Meier method indicated that patients with VEGF-C-positive tumors had significantly shorter overall survival and tumor-free survival time than those with VEGF-C-negative tumors. Patients with Smad4-negative tumors had significantly shorter overall survival and tumor-free survival time than those with Smad4-positive tumors. Both Smad4 and VEGF-C are involved in lymphangiogenesis and lymphatic metastasis. Smad4 and VEGF-C expression may be clinically useful indicators for prognostic evaluation in colon cancer patients.