Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice
Identifieur interne : 002927 ( Main/Exploration ); précédent : 002926; suivant : 002928Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice
Auteurs : Morvarid Farhang Ghahremani [Belgique] ; Enrico Radaelli [Italie, Belgique] ; Katharina Haigh [Belgique, Australie] ; Sonia Bartunkova [Belgique] ; Lieven Haenebalcke [Belgique] ; Jean-Christophe Marine [Belgique] ; Steven Goossens [Belgique] ; Jody J. Haigh [Belgique, Australie]Source :
- Cell Cycle [ 1538-4101 ] ; 2014.
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.
Url:
DOI: 10.4161/cc.28474
PubMed: 24626176
PubMed Central: 4050148
Affiliations:
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VIB-KULeuven; Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for the Biology of Disease; VIB-KULeuven; Leuven</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name><affiliation wicri:level="1"><nlm:aff id="A1">Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biomedical Molecular Biology; Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A6">Australian Centre for Blood Diseases; Monash University; Melbourne, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Australian Centre for Blood Diseases; Monash University; Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name><affiliation wicri:level="1"><nlm:aff id="A1">Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biomedical Molecular Biology; Ghent University; Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name><affiliation wicri:level="1"><nlm:aff id="A1">Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biomedical Molecular Biology; Ghent University; Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Marine, Jean Christophe" sort="Marine, Jean Christophe" uniqKey="Marine J" first="Jean-Christophe" last="Marine">Jean-Christophe Marine</name><affiliation wicri:level="1"><nlm:aff id="A4">Center for the Biology of Disease; VIB-KULeuven; Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for the Biology of Disease; VIB-KULeuven; Leuven</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Center for Human Genetics; Faculty of Medicine; Laboratory for Molecular Cancer Biology; KULeuven; Leuven</wicri:regionArea></affiliation></author><author><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name><affiliation wicri:level="1"><nlm:aff id="A1">Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biomedical Molecular Biology; Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A7">Unit of Molecular and Cellular Oncology; Inflammation Research Center (IRC); VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Unit of Molecular and Cellular Oncology; Inflammation Research Center (IRC); VIB-Ghent University; Ghent</wicri:regionArea></affiliation></author><author><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. Haigh</name><affiliation wicri:level="1"><nlm:aff id="A1">Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Vascular Cell Biology Unit; Department for Molecular Biomedical Research; VIB-Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Department of Biomedical Molecular Biology; Ghent University; Ghent, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Biomedical Molecular Biology; Ghent University; Ghent</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A6">Australian Centre for Blood Diseases; Monash University; Melbourne, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Australian Centre for Blood Diseases; Monash University; Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell Cycle</title><idno type="ISSN">1538-4101</idno><idno type="eISSN">1551-4005</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>Italie</li></country></list><tree><country name="Belgique"><noRegion><name sortKey="Farhang Ghahremani, Morvarid" sort="Farhang Ghahremani, Morvarid" uniqKey="Farhang Ghahremani M" first="Morvarid" last="Farhang Ghahremani">Morvarid Farhang Ghahremani</name></noRegion><name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name><name sortKey="Bartunkova, Sonia" sort="Bartunkova, Sonia" uniqKey="Bartunkova S" first="Sonia" last="Bartunkova">Sonia Bartunkova</name><name sortKey="Farhang Ghahremani, Morvarid" sort="Farhang Ghahremani, Morvarid" uniqKey="Farhang Ghahremani M" first="Morvarid" last="Farhang Ghahremani">Morvarid Farhang Ghahremani</name><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name><name sortKey="Goossens, Steven" sort="Goossens, Steven" uniqKey="Goossens S" first="Steven" last="Goossens">Steven Goossens</name><name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name><name sortKey="Haenebalcke, Lieven" sort="Haenebalcke, Lieven" uniqKey="Haenebalcke L" first="Lieven" last="Haenebalcke">Lieven Haenebalcke</name><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. Haigh</name><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. Haigh</name><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name><name sortKey="Marine, Jean Christophe" sort="Marine, Jean Christophe" uniqKey="Marine J" first="Jean-Christophe" last="Marine">Jean-Christophe Marine</name><name sortKey="Marine, Jean Christophe" sort="Marine, Jean Christophe" uniqKey="Marine J" first="Jean-Christophe" last="Marine">Jean-Christophe Marine</name><name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name><name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name></country><country name="Italie"><noRegion><name sortKey="Radaelli, Enrico" sort="Radaelli, Enrico" uniqKey="Radaelli E" first="Enrico" last="Radaelli">Enrico Radaelli</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Haigh, Katharina" sort="Haigh, Katharina" uniqKey="Haigh K" first="Katharina" last="Haigh">Katharina Haigh</name></noRegion><name sortKey="Haigh, Jody J" sort="Haigh, Jody J" uniqKey="Haigh J" first="Jody J" last="Haigh">Jody J. 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