c-Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation

[[abstract]]Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long-term survival whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via lymphatic system and may overhead distant metastasis. c-Myc overexpression is involved in tumorigenesis. The role of c-Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c-Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c-Myc overexpression. c-Myc transcriptionally upregulates VEGFC expression and secretion of pNET cells through direct binding to E-box of VEGFC promoter and enhanced VEGF receptor 3 phosphorylation and tube formation of LECs. c-Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment of mTOR inhibitor with c-Myc inhibitor or VEGFC neutralizing chimera protein reduced lymph node metastasis of the mice with c-Myc overexpression. mTOR inhibitor acts on lymphangiogenesis via reducing VEGFC expression in pNET cells and inhibiting tube formation of LECs. In conclusion, mTOR and c-Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET