Integrin alpha 4 Induces Lymphangiogenesis and Metastasis via Upregulation of VEGF-C in Human Colon Cancer

Vascular endothelial growth factor-C (VEGF-C) is a key regulator in lymphangiogenesis, and is overexpressed in various malignancies. Integrin alpha 4 beta 1, a new member of the VEGF-C/VEGF receptor pathway, was found to be overexpressed in melanoma tumors. However, little is known regarding the potential role of integrin alpha 4 beta 1 in lymphangiogenesis and other solid tumors. The aim of this study was to investigate the expression patterns of integrin alpha 4 and VEGF-C in relation to lymphangiogenesis and clinicopathological parameters in human colon cancer. The expression of integrin alpha 4, VEGF-C, and VEGFR-3 was assessed in 71 human colon cancer tissues and 30 paracancerous normal tissues by immunohistochemical staining. Lymphatic microvessel density (LMVD) was measured after D2-40-labeling, and the correlations among different factors were statistically analyzed. The expression of integrin alpha 4, VEGF-C, VEGFR-3, and LMVD was higher in colon cancer tissues compared with the normal paracancerous colon tissues. There was a positive correlation between the expression of integrin alpha 4 and VEGF-C. Integrin alpha 4 and VEGF-C were significantly associated with the clinicopathological parameters (LMVD, Duke's stage, and lymph node metastasis). Kaplan-Meier analyses indicated that patients with high integrin alpha 4 or VEGF-C expression had significantly shorter overall survival and tumor-free survival time. Multivariate analyses suggested that integrin alpha 4 and VEGF-C may serve as independent prognostic factors for human colon cancer. Both integrin alpha 4 and VEGF-C are involved in lymphangiogenesis and lymphatic metastasis. Our results demonstrated that integrin alpha 4 is a novel prognostic indicator for human colon cancer. Anat Rec, 299:741-747, 2016.