Lymphangiogenesis is essential for tumor metastasis via lymphatic system. c-Myc overexpression has been found in many cancers and is involved in tumorigenesis. However, whether c-Myc participates in lymphangiogenesis of pancreatic neuroendocrine tumor (pNET) microenvironment is unclear. We have found that high expression of c-Myc was commonly observed in pNETs previously. In this study, we found that VEGFC expression was increased in human and mouse pNET cell lines with c-Myc overexpression. Mechanistically, c-Myc transcriptionally upregulated VEGFC expression through direct binding to E-box of VEGFC promoter and enhanced VEGFR3 phosphorylation and tube formation of lymphatic endothelial cells. In mouse model, mice bearing pNET cells with c-Myc overexpression had more lymph node metastasis. Combine treatment of mTOR inhibitor, RAD001, with c-Myc inhibitor, 10058-F4, or VEGFC neutralizing chimera protein, VEGFR3/Fc, reduced lymph node metastasis of the mice. Taken together, we demonstrated that c-Myc enhances lymph node metastases via upregulating VEGFC/VEGFR3 axis. Simultaneously targeting mTOR and c-Myc or VEGFC may attenuate c-Myc induced lymphangiogenesis of pNET.
