Department of Genetic Engineering and Graduate School of Biotechnology, Kyung Hee University, Yongin, 446-701, South Korea.
BMC Cancer. 2018 Jul 5;18(1):714. doi: 10.1186/s12885-018-4630-0.
Sentinel 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.
The 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.
3AOA 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 CoCl-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.
3AOA 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.
前哨淋巴结转移是头颈部鳞状细胞癌（HNSCC）转移过程中的常见和早期事件，是影响 HNSCC 患者生存的最有力的预后因素。3-O-乙酰齐墩果酸（3AOA）是从豇豆种子中分离得到的一种五环三萜化合物，已被报道具有很强的抗血管生成和抗肿瘤活性。然而，其对肿瘤相关淋巴管生成和淋巴结转移的影响尚不清楚。
通过体外实验，使用小鼠口腔鳞状细胞癌（SCCVII）细胞和人淋巴管微血管内皮细胞（HLMEC），研究 3AOA 对 VEGF-A 诱导的淋巴管生成的体外抑制作用。在口腔癌前哨淋巴结（OCSLN）动物模型中，研究 3AOA 对 VEGF-A 诱导的淋巴管生成和前哨淋巴结转移的体内抑制作用。
3AOA 抑制了 OCSLN 动物模型中的肿瘤诱导的淋巴管生成和前哨淋巴结转移，并降低了缺氧模拟剂 CoCl 处理的 SCCVII 细胞中淋巴管生成因子 VEGF-A 的表达。3AOA 抑制了 VEGF-A 处理的 HLMEC 的增殖、管形成和迁移。体内 VEGF-A 在 Matrigel 塞中刺激的淋巴管形成减少。3AOA 抑制了 VEGF-A 刺激的血管内皮生长因子（VEGFR）-1 和 -2 受体的磷酸化。此外，3AOA 抑制了与淋巴管生成相关的下游信号因子 PI3K、FAK、AKT 和 ERK1/2 的磷酸化。3AOA 抑制了 VEGF-A 过表达 SCCVII 细胞诱导的 OCSLN 动物模型中的肿瘤生长、肿瘤诱导的淋巴管生成和前哨淋巴结转移。
3AOA 抑制了体内外 VEGF-A 诱导的淋巴管生成和前哨淋巴结转移。3AOA 的抗淋巴管生成作用可能是通过抑制 HLMEC 中的 VEGF-A/VEGFR-1 和 VEGFR-2 信号传导来介导的，可作为一种有用的抗肿瘤药物，限制口腔癌的转移扩散。
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