Liposomal honokiol inhibits VEGF-D-induced lymphangiogenesis and metastasis in xenograft tumor model
Authors: Yong-Sheng Wang
You Lu
Li-Juan Chen
Ming-Hai Tang
Xia Zhao
Ping Chen
Jing Wen
Xian-Cheng Chen
Jiong Li
Xing-Jiang Xie
Xi Ming Shao
A-fu Fu
Yu-Quan Wei
Guang-Li Yang
Journal: International Journal of Cancer (2009)
Discipline: CLINICAL MEDICINE
Keywords: lymph nodes metastasis; tumor lymphangiogenesis; VEGFR-3 signaling pathway; honokiol; antiangiogenesis
Affiliations: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

Abstract:  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. 

Retracted: No

PubPeer comments:
 2020 correction. https: doi.org 10.1002 ijc.33195 Through image integrity analysis it has come to the attention of the editors of the International Journal of Cancer that in Figure 3d and 3g of this article parts of the images are identical, meaning that they originate from the same immunohistochemistry experiment. The authors are unable to retrieve the original data due to the time that has elapsed. Given that the experiments presented in this manuscript have been performed in 2007 or earlier and experimental and logistic conditions are very different now, the editors consider that a reu2010performance of the experiments would not be appropriate. The authors agree with this statement and believe that the concerns do not affect the data interpretation and overall conclusion of the paper. ,