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

ABSTRACT: 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.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.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.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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC4506598 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Xu Youzhi Y Lu Wenjie W Yang Peng P Peng Wen W Wang Chunting C Li Manli M Li Yan Y Li Guobo G Meng Nana N Lin Hongjun H Kan Lixin L Wang Siying S Yang Shengyong S Yu Luoting L Zhao YingLan Y

BMC cancer 20150718

<h4>Background</h4>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.<h4>Method</h4>We investigated the effect of YL529 on tumor-associated lymphangiogenesis ...[more]

PMID: 26187637

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Project description:BackgroundSentinel lymph node metastasis is a common and early event in the metastatic process of head and neck squamous cell carcinoma (HNSCC) and is the most powerful prognostic factor for survival of HNSCC patients. 3-O-acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from seeds of Vigna sinensis K., has been reported to have potent anti-angiogenesis and anti-tumor activities. However, its effects on tumor-related lymphangiogenesis and lymph node metastasis are not yet understood.MethodsThe in vitro inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis were investigated via in vitro experiments using mouse oral squamous cell carcinoma (SCCVII) cells and human lymphatic microvascular endothelial cells (HLMECs). The in vivo inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis and sentinel lymph node metastasis were investigated in an oral cancer sentinel lymph node (OCSLN) animal model.Results3AOA inhibited tumor-induced lymphangiogenesis and sentinel lymph node metastasis in an OCSLN animal model, and reduced expression of VEGF-A, a lymphangiogenic factor in hypoxia mimetic agent CoCl2-treated SCCVII cells. 3AOA inhibited proliferation, tube formation, and migration of VEGF-A-treated HLMECs. The lymphatic vessel formation that was stimulated in vivo in a by VEGF-A Matrigel plug was reduced by 3AOA. 3AOA suppressed phosphorylation of vascular endothelial growth factor (VEGFR) -1 and - 2 receptors that was stimulated by VEGF-A. In addition, 3AOA suppressed phosphorylation of the lymphangiogenesis-related downstream signaling factors PI3K, FAK, AKT, and ERK1/2. 3AOA inhibited tumor growth, tumor-induced lymphangiogenesis, and sentinel lymph node metastasis in a VEGF-A-induced OCSLN animal model that was established using VEGF-A overexpressing SCCVII cells.Conclusion3AOA inhibits VEGF-A-induced lymphangiogenesis and sentinel lymph node metastasis both in vitro and in vivo. The anti-lymphangiogenic effects of 3AOA are probably mediated via suppression of VEGF-A/VEGFR-1 and VEGFR-2 signaling in HLMECs, and can be a useful anti-tumor agent to restrict the metastatic spread of oral cancer.

Dataset Information

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

Publications

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

Similar Datasets

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