Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib
Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib
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DOI：
10.1158/1535-7163.mct-08-0182
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Padera, Timothy P.;Kuo, Angera H.;Jain, Rakesh K.
血管是肿瘤生长所必需的，功能性淋巴管是肿瘤扩散到淋巴结所必需的。为了根除原发性肿瘤及其淋巴转移，我们使用两种不同的酪氨酸激酶抑制剂（TKI）靶向血管和淋巴管：西地尼布和凡德他尼，它们在酶测定中阻断血管内皮生长因子受体（VEGFR）-2和-3。我们发现，尽管西地尼布和凡德他尼都减缓了原发性肿瘤的生长速度并降低了血管密度，但当肿瘤细胞接种到淋巴结后给药时，这两种药物都不能预防淋巴转移。然而，当在肿瘤生长期间给药时，西地尼布降低了引流淋巴管的直径、到达引流淋巴结的肿瘤细胞数量和淋巴转移的发生率。另一方面，凡德他尼对任何这些变量的影响都很小，表明凡德他尼在我们的动物模型中不能有效阻断淋巴管内皮细胞上的VEGFR-3。总的来说，这些数据表明淋巴管对TKI的反应可以决定淋巴转移的发生率，而与TKI对血管的影响无关。
Blood vessels are required for a tumor to grow and functional lymphatic vessels are required for it to disseminate to lymph nodes. In an attempt to eradicate both the primary tumor and its lymphatic metastasis, we targeted both blood and lymphatic vessels using two different tyrosine kinase inhibitors (TKIs): cediranib and vandetanib, which block vascular endothelial growth factor receptor (VEGFR)-2 and -3 in enzymatic assays. We found that although both cediranib and vandetanib slowed the growth rate of primary tumors and reduced blood vessel density, neither agent was able to prevent lymphatic metastasis when given after tumor cells had seeded the lymph node. However, when given during tumor growth, cediranib reduced the diameters of the draining lymphatic vessels, the number of tumor cells arriving in the draining lymph node, and the incidence of lymphatic metastasis. On the other hand, vandetanib had minimal effect on any of these variables, suggesting that vandetanib did not effectively block VEGFR-3 on lymphatic endothelial cells in our animal model. Collectively, these data indicate that the response of lymphatic vessels to a TKI can determine the incidence of lymphatic metastasis, independent of the effect of the TKI on blood vessels.