A small molecular agent YL529 inhibits VEGF-D-induced lymphangiogenesis and metastasis in preclinical tumor models in addition to its known antitumor activities

作者：Xu, Youzhi; Lu, Wenjie; Yang, Peng; Peng, Wen; Wang, Chunting; Li, Manli; Li, Yan; Li, Guobo; Meng, Nana; Lin, Hongjun; Kan, Lixin; Wang, Siying; Yang, Shengyong; Yu, Luoting^*; Zhao, YingLan

来源：BMC Cancer, 2015, 15(1): 525.

DOI：10.1186/s12885-015-1451-2

• YL529
• Lymphangiogenesis
• Metastasis
• VEGF-D
• VEGFR-3

Background: The lymph node metastasis is a key early step of the tumor metastatic process. VEGFD-mediated tumor lymphangiogenesis plays a key role, since down-regulation of p-VEGFR-3 could block the lymph node metastasis. YL529 has been reported to possess potent anti-angiogenesis and antitumor activities; however, its roles in tumor-associated lymphangiogenesis and lymphatic metastasis remain unclear.
Method: We investigated the effect of YL529 on tumor-associated lymphangiogenesis and lymph node metastasis using in vitro lymph node metastasis models and in vivo subcutaneous tumor models in C57 BL/6 mice.
Result: We found that YL529 inhibited VEGF-D-induced survival, proliferation and tube-formation of Human Lymphatic Endothelial Cells. Furthermore, in established in vitro and in vivo lymph node metastasis models using VEGF-D-LL/2 cells, YL529 significantly inhibited the tumor-associated lymphangiogenesis and metastasis. At molecular level, YL529 down- regulated p-VEGFR-3, p-JNK and Bax while up-regulated Bcl-2.
Conclusion: YL529 provided the therapeutic benefits by both direct effects on tumor cells and inhibiting lymphangiogenesis and metastasis via the VEGFR-3 signaling pathway, which may have significant direct clinical implications.

• 单位
  安徽医科大学; 贵州省人民医院; 四川大学; 生物治疗国家重点实验室