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Abstract
Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank Dagmar Bonnier and Celine Steyt for help with mice breedings. We also thank Dr Castiglioni Vittoria and Recordati Camilla for aiding some of the necropsies of the mice and Dr Pieter De Bleser for help with statistical analysis. The VIB International PhD program provided M.F.G funding. S.G. is a postdoctoral fellow of the Basic Science Research Foundation-Flanders (FWO). L.H. funding was provided by the agency for Innovation by Science and Technology (IWT). This study was supported by the Belgium Federation against Cancer (Stichting tegen Kanker) and is part of the IUAP-Belspo network DevRepair (P7/07).