Liposomal honokiol inhibits VEGF‐D‐induced lymphangiogenesis and metastasis in xenograft tumor model

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.

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…In solid tumors, VCAM-1-targeted liposomes can prevent endothelial cell activation and function through TNF-a binding [134] and any agent with a high affinity to a peculiar MMP type or integrin ligand-conjugated PEG-liposomes loaded with doxorubicin can target both tumor angiogenesis and tumor cells [135,136]. Positively charged liposomal nanoparticles might also be used to deliver plaxitel to endothelial cells [137], deliver pro-inflammatory mediators to macrophages [138] and deliver Honokiol, an inhibitor of VEGF-induced autophosphorylation of VEGF receptor 2, to lymphocytes [139]. Interestingly, the targeted delivery of siRNA through CD44 targeting hyaluronic acid based selfassembling nanosystems, an approach still investigated in solid tumors, might also be effective in AML as LSCs are more dependent on CD44 than HSCs [140].…”

Molecular targeting of liposomal nanoparticles to tumor microenvironment

“…99 Exploration exhibited that VEGF-C and VEGF-D enhanced lymphangiogenesis, the metastatic spread of malignant cells to lymph nodes. 100,101 Honokiol is a potential antiangiogenic and antitumor medicine that acts by blocking VEGF-induced autophosphorylation of VEGF receptor 2. To investigate related lymph node metastasis and antitumor activity, liposomal honokiol was injected intraperitoneally in a mouse model of xenografted Lewis lung carcinoma cells overexpressing VEGF-D. Liposomal honokiol markedly reduced metastasis to the lymph nodes when compared with the control group.…”

Lymphangiogenesis, Lymphatic Endothelial Cells and Lymphatic Metastasis in Head and Neck Cancer — A Review of Mechanisms

“…Previous studies have shown that lymphangiogenesis was closely associated with an increased risk of lymph node metastasis. If lymphangiogenesis-related properties of LECs were inhibited, the risk of lymphatic dissemination was significantly reduced (Wen et al, 2009). Therefore, cancer-induced lymphangiogenesis is essential for the invasion and secondary lymphatic metastasis.…”