Experimental Translational Research Using siRNA to Target Vascular Genesis in Inhibition of Mammary Cancer Metastasis

Cancer cells spread through the body by different mechanisms, such as direct invasion of surrounding tissue, dispersion of cells via the blood vascular system (i.e., hematogenous metastasis), and/or dissemination by means of the lymphatic system (i.e., lymphatic metastasis). Lymph node metastasis is one of the most important adverse prognostic factors in breast carcinoma [2]. An adequate blood supply is required to sustain the uncontrolled cell proliferation characteristic of malignant tumors, and tumorigenesis and metastasis have both been associated with angiogenesis [3]. Thus, members of the vascular endothelial growth factor (VEGF) family, which promote the formation of new blood and lymphatic vessels in tumor tissues and enable the spread of tumor cells [4], have come under particular scrutiny. Within the VEGF family, VEGF-A is also known to exert a crucial role in tumor angiogenesis [3], while both VEGF-C and VEGF-D have been reported to induce lymphangiogenesis via activation of the VEGF receptor-3 (VEGFR3) expressed on lymphatic endothelial cells [5,6]. In animal models, VEGF-C and VEGF-D have also been shown to enhance lymphangiogenesis and associated lymphatic metastasis [7-13], while clinical studies have demonstrated overexpression of either VEGF-C or VEGF-D associated with lymph node metastasis and poor prognosis in breast cancer patients [14-17].