title: Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice.
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.
authors.affiliation: Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Farhang Ghahremani
authors.affiliation: 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.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: 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.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haigh
authors.affiliation: Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bartunkova
authors.affiliation: Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium; Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Haenebalcke
authors.affiliation: 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.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: 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.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
mesh_terms: D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006394:Hemangiosarcoma / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A
keywords: VEGF; autocrine; endothelial cell; hemangiosarcoma; mouse model; p53