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- Title
Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis.
- Authors
Küsters, B.; Kats, G.; Roodink, I.; Verrijp, K.; Wesseling, P.; Ruiter, D. J.; de Waal, R. M. W.; Leenders, W. P. J.
- Abstract
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.Oncogene (2007) 26, 5808–5815; doi:10.1038/sj.onc.1210360; published online 12 March 2007
- Subjects
GENETIC mutation; VASCULAR endothelial growth factors; METASTASIS; BLOOD vessels; CANCER cells; EMBOLISMS
- Publication
Oncogene, 2007, Vol 26, Issue 39, p5808
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210360