Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis
Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis
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DOI：
10.1038/sj.onc.1210360
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发表时间：
2007-08-01
期刊：
影响因子：
8
通讯作者：
Leenders, W. P. J.
中科院分区：
文献类型：
--
作者：
Kuesters, B.;Kats, G.;Leenders, W. P. J.
肿瘤如何以及为什么转移仍然是一个有争议的问题。假设是突变使肿瘤细胞具有转移表型，使其能够进入淋巴或血管并通过淋巴或血管转运。远缘生长被认为只发生在一个合适的微环境（种子和土壤假说）。然而，癌症患者中大多数转移灶的解剖位置表明肿瘤细胞被截留在遇到的第一个微毛细血管床中。我们在此研究了血管内皮生长因子-A（VEGF-A）在转移过程中的作用。我们在这里描述了VEGF-A通过诱导由血管壁元件包围的异质性肿瘤细胞簇的内渗，经由非侵袭性机制来增强自发转移。这些肿瘤簇在肺动脉中产生转移性组织栓塞。用抗血管生成化合物ZD 6474治疗荷瘤小鼠可防止这种转移表型的发展。这项工作表明，具有高组成性VEGF-A表达的肿瘤通过形成肿瘤栓塞转移，并提供了抗VEGF-A治疗的替代原理，即抑制转移形成。
How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasion-independent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.