This study investigates the role of vascular endothelial growth factor-C (VEGF-C) in tumor metastasis. VEGF-C is a recently identified lymphangiogenic factor, and its expression in primary tumors correlates with the dissemination of tumor cells to regional lymph nodes. However, the direct role of VEGF-C in tumor lymphangiogenesis and metastasis has not been established. The authors generated transgenic mice with VEGF-C expression driven by the rat insulin promoter (Rip) in β-cells of the endocrine pancreas. These mice developed extensive lymphatic networks around the islets of Langerhans, which were not present in wild-type mice. When these transgenic mice were crossed with Rip1Tag2 mice, which develop pancreatic β-cell tumors that are neither lymphangiogenic nor metastatic, the resulting double-transgenic mice formed tumors surrounded by well-developed lymphatics. These tumors frequently contained masses of tumor cells and frequently developed pancreatic lymph node metastases. The findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumor cell dissemination and the formation of lymph node metastases. This study provides the first direct evidence for a causal role of VEGF-C-mediated lymphangiogenesis in tumor metastasis and offers a relevant animal model to further investigate the mechanisms of lymphangiogenesis and lymphatic tumor metastasis.This study investigates the role of vascular endothelial growth factor-C (VEGF-C) in tumor metastasis. VEGF-C is a recently identified lymphangiogenic factor, and its expression in primary tumors correlates with the dissemination of tumor cells to regional lymph nodes. However, the direct role of VEGF-C in tumor lymphangiogenesis and metastasis has not been established. The authors generated transgenic mice with VEGF-C expression driven by the rat insulin promoter (Rip) in β-cells of the endocrine pancreas. These mice developed extensive lymphatic networks around the islets of Langerhans, which were not present in wild-type mice. When these transgenic mice were crossed with Rip1Tag2 mice, which develop pancreatic β-cell tumors that are neither lymphangiogenic nor metastatic, the resulting double-transgenic mice formed tumors surrounded by well-developed lymphatics. These tumors frequently contained masses of tumor cells and frequently developed pancreatic lymph node metastases. The findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumor cell dissemination and the formation of lymph node metastases. This study provides the first direct evidence for a causal role of VEGF-C-mediated lymphangiogenesis in tumor metastasis and offers a relevant animal model to further investigate the mechanisms of lymphangiogenesis and lymphatic tumor metastasis.