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Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

Oncogene volume 26, pages 5808–5815 (2007)Cite this article

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.

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Acknowledgements

We thank Debby Smits, Ilona van den Brink and Geert Poelen for excellent technical assistance with the animal experiments. This study was supported by the Dutch Cancer Society (Grant KUN 2000-2302 (WL) and KUN 2001-2399 (BK).

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Authors and Affiliations

  1. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    B Küsters, G Kats, I Roodink, K Verrijp, P Wesseling, D J Ruiter, R M W de Waal & W P J Leenders

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  1. B Küsters
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  2. G Kats
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  3. I Roodink
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  4. K Verrijp
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Correspondence to W P J Leenders.

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Küsters, B., Kats, G., Roodink, I. et al. Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis. Oncogene 26, 5808–5815 (2007). https://doi.org/10.1038/sj.onc.1210360

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