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Angiogenesis

VEGFR3 joins the crew

Nature Reviews Cancer volume 8, pages 660–661 (2008)Cite this article

In adults, VEGFR3 expression is limited to the lymphatic epithelium; however, it is expressed in the tumour vasculature and targeting its activity is known to retard tumour formation by inhibiting angiogenesis. Tammela and colleagues, reporting in Nature, showed that inhibition of VEGFR3 in the mouse retina resulted in a less dense vascular network with a reduced number of endothelial sprouts and branch points. In tumour vessels, immunostaining showed VEGFR3 to be highly expressed in endothelial sprouts, and in lung carcinoma xenografts blocking of VEGFR3 reduced the number of VEGFR3-positive endothelial sprouts, supporting the idea that VEGFR3-related angiogenesis inhibition relies on suppression of endothelial sprouting.

These authors also found that overexpression of VEGFR3 and VEGFR2 ligands had an additive effect in promoting angiogenesis, but the VEGFR3-specific ligand was not itself sufficient to induce angiogenesis, indicating that VEGFR2 signalling is necessary for blood vessels to become sensitive to VEGFR3 ligands. However, the authors found that once VEGFR3 signalling is established, its effect continues when VEGFR2 is blocked. Disruption of Notch signalling is also known to cause increased sprouting and Vegfr3 expression within the vasculature, and Tammela and colleagues showed that blocking VEGFR2 or VEGFR3 in tumours prevented the vascular hyperplasia caused by loss of Notch signalling. Moreover, in mice with decreased Notch signalling they found higher levels of VEGFR3 protein and mRNA, and injection of anti-VEGFR3 antibodies partially attenuated the increased endothelial sprouting observed in these animals.

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ORIGINAL RESEARCH PAPERS

  1. Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008)

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  2. Padera, T. P. et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Therapeut. 6 Aug 2008 (doi: 10.1158/1535-7163.MCT-08-0182)

    Article  CAS  Google Scholar 

  3. Heckman, C. A. et al. The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res. 68, 4754–4762 (2008)

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Authors
  1. Isobel Barry
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Barry, I. VEGFR3 joins the crew. Nat Rev Cancer 8, 660–661 (2008). https://doi.org/10.1038/nrc2446

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