Liposomal honokiol inhibits VEGF-D-induced lymphangiogenesis and metastasis in xenograft tumor model.
Lymph nodes metastasis of tumor could be a crucial early step in the metastatic process. Induction of tumor lymphangiogenesis by vascular endothelial growth factor-D may play an important role in promoting tumor metastasis to regional lymph nodes and these processes can be inhibited by inactivation of the VEGFR-3 signaling pathway. Honokiol has been reported to possess potent antiangiogenesis and antitumor properties in several cell lines and xenograft tumor models. However, its role in tumor-associated lymphangiogenesis and lymphatic metastasis remains unclear. Here, we established lymph node metastasis models by injecting overexpressing VEGF-D Lewis lung carcinoma cells into C57BL/6 mice to explore the effect of honokiol on tumor-associated lymphangiogenesis and related lymph node metastasis. The underlying mechanisms were systematically investigated in vitro and in vivo. In in vivo study, liposomal honokiol significantly inhibited the tumor-associated lymphangiogenesis and metastasis in Lewis lung carcinoma model. A remarkable delay of tumor growth and prolonged life span were also observed. In in vitro study, honokiol inhibited VEGF-D-induced survival, proliferation and tube-formation of both human umbilical vein endothelial cells (HUVECs) and lymphatic vascular endothelial cells (HLECs). Western blotting analysis showed that liposomal honokiol-inhibited Akt and MAPK phosphorylation in 2 endothelial cells, and downregulated expressions of VEGFR-2 of human vascular endothelial cells and VEGFR-3 of lymphatic endothelial cells. Thus, we identified for the first time that honokiol provided therapeutic benefit not only by direct effects on tumor cells and antiangiogenesis but also by inhibiting lymphangiogenesis and metastasis via the VEGFR-3 pathway. The present findings may be of importance to investigate the molecular mechanisms underlying the spread of cancer via the lymphatics and explore the therapeutical strategy of honokiol on antilymphangiogenesis and antimetastasis.
Wen
Jing
J
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Fu
A-fu
AF
Chen
Li-Juan
LJ
Xie
Xing-Jiang
XJ
Yang
Guang-Li
GL
Chen
Xian-Cheng
XC
Wang
Yong-Sheng
YS
Li
Jiong
J
Chen
Ping
P
Tang
Ming-Hai
MH
Shao
Xi Ming
XM
Lu
You
Y
Zhao
Xia
X
Wei
Yu-Quan
YQ
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D017705:Lignans / Q000008:administration & dosage* / Q000494:pharmacology; D008081:Liposomes; D042583:Lymphangiogenesis / Q000187:drug effects*; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors* / Q000502:physiology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D017705:Lignans; D008081:Liposomes; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols