Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models.
Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models.
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DOI：
10.1186/1471-2407-13-320
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发表时间：
2013-07-01
期刊：
影响因子：
3.8
通讯作者：
Nathan CA
中科院分区：
文献类型：
--
作者：
Ekshyyan O;Moore-Medlin TN;Raley MC;Sonavane K;Rong X;Brodt MA;Abreo F;Alexander JS;Nathan CA
肿瘤通过淋巴结转移至颈部淋巴结是头颈部鳞状细胞癌（HNSCC）转移的第一步，是肿瘤复发的最重要预测因子，使生存率降低50%。mTOR抑制剂的淋巴抑制特性尚未得到很好的理解。使用两种淋巴管内皮细胞（LEC）系在体外评价雷帕霉素的淋巴管抑制作用。使用HNSCC（OSC-19细胞）的原位小鼠模型来评估雷帕霉素的体内抗淋巴管生成作用。评估颈部淋巴结转移的发生率、小鼠舌组织中无肿瘤淋巴管和被肿瘤细胞侵袭的淋巴管的数量以及促淋巴管生成标记物的表达。雷帕霉素显著降低了淋巴管密度（p = 0.027），降低了舌组织中肿瘤细胞侵袭淋巴管的比例（p = 0.013），并降低了转移阳性淋巴结（p = 0.04）。雷帕霉素还显著减弱了淋巴结内转移性肿瘤细胞扩散的程度（p < 0.0001）。我们发现雷帕霉素显著降低LEC增殖，并与LEC和一些HNSCC细胞系中VEGFR-3表达降低相关。本研究的结果证明了mTOR抑制剂在HNSCC中的抗淋巴管生成特性。mTOR抑制剂通过损害VEGF-C/VEGFR-3轴和可溶性VEGFR-2的释放来抑制肿瘤和淋巴管内皮细胞的自分泌和旁分泌生长刺激。在鼠HNSCC原位模型中，雷帕霉素显著抑制淋巴血管侵袭，减少颈部淋巴结转移，并延迟转移性肿瘤细胞在淋巴结内的扩散。
Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood. Lymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. Rapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines. The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR-2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes.
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影响因子：
5.7
作者：
Ekshyyan O;Rong Y;Rong X;Pattani KM;Abreo F;Caldito G;Chang JK;Ampil F;Glass J;Nathan CO
通讯作者：
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作者：
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影响因子：
1.4
作者：
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