Format

Send to

Choose Destination
Cell Cycle. 2014;13(9):1501-7. doi: 10.4161/cc.28474. Epub 2014 Mar 11.

Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice.

Author information

1
Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium.
2
Mouse & Animal Pathology Laboratory; Università degli Studi di Milano; Milano, Italy; Center for the Biology of Disease; VIB-KULeuven; Leuven, Belgium; Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven, Belgium.
3
Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium; Australian Centre for Blood Diseases; Monash University; Melbourne, Victoria, Australia.
4
Center for the Biology of Disease; VIB-KULeuven; Leuven, Belgium; Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven, Belgium.
5
Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium; Unit of Molecular and Cellular Oncology; Inflammation Research Center (IRC); VIB-Ghent University; Ghent, Belgium.

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.

KEYWORDS:

VEGF; autocrine; endothelial cell; hemangiosarcoma; mouse model; p53

PMID:
24626176
PMCID:
PMC4050148
DOI:
10.4161/cc.28474
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center