PUBLICATION

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Authors
Stratman, A.N., Farrelly, O.M., Mikelis, C.M., Miller, M.F., Wang, Z., Pham, V.N., Davis, A.E., Burns, M.C., Pezoa, S.A., Castranova, D., Yano, J.J., Kilts, T.M., Davis, G.E., Gutkind, J.S., Weinstein, B.M.
ID
ZDB-PUB-200307-18
Date
2020
Source
Nature communications   11: 1204 (Journal)
Registered Authors
Castranova, Dan, Davis, Andrew, Miller, Mayumi, Pham, Van, Stratman, Amber, Weinstein, Brant M.
Keywords
none
MeSH Terms
  • Cell Proliferation/drug effects
  • Neovascularization, Physiologic/drug effects
  • Zebrafish
  • Cell Line, Tumor
  • Phosphatidylinositols/metabolism*
  • Allografts/drug effects
  • Diacylglycerol Cholinephosphotransferase/deficiency
  • Diacylglycerol Cholinephosphotransferase/metabolism
  • Signal Transduction
  • Organ Specificity
  • Humans
  • Human Umbilical Vein Endothelial Cells/drug effects
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Mice, Knockout
  • Angiogenesis Inhibitors/pharmacology*
  • Models, Biological
  • Cattle
  • Endothelium, Vascular/drug effects
  • Endothelium, Vascular/metabolism*
  • Animals
  • Gene Deletion
  • Vascular Endothelial Growth Factors/metabolism*
(all 22)
PubMed
32139674 Full text @ Nat. Commun.
Abstract
Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumor's own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-15
cds2y54/y54; y1TgcontrolPrim-25
cds2y54/y54; y1TgcontrolPrim-25
cds2y54/y54; y1TgcontrolPrim-25
cds2y54/y54; y1TgcontrolProtruding-mouth
1 - 10 of 18
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    y10
      		Point Mutation
      y11
        		Insertion
        y17
          		Point Mutation
          y25
            		Point Mutation
            y54
              		Point Mutation
              y602
                		Small Deletion
                1 - 7 of 7
                Show
                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                cds2MO2-cds2MRPHLNO
                impa2CRISPR1-impa2CRISPR
                vegfaaMO3-vegfaaMRPHLNO
                1 - 3 of 3
                Show
                Fish
                Fish
                cds2y54/y54; y1Tg
                etsrpy11/y11; y1Tg
                impa2y602; y1Tg
                kdrly17/y17; y1Tg
                plcg1y10/y10; y1Tg
                y1Tg + MO2-cds2
                1 - 6 of 6
                Show
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab1-cds2polyclonal
                  		IgGRabbit
                  Ab3-tubamonoclonal
                    		IgG1Mouse
                    Ab5-aktmonoclonal
                      		Rabbit
                      Ab9-mapkmonoclonal
                        		IgGRabbit
                        Ab11-mapkmonoclonal
                          		IgGRabbit
                          Ab15-aktmonoclonal
                            		IgG1Mouse
                            1 - 6 of 6
                            Show
                            Orthology
                            No data available
                            Engineered Foreign Genes
                            Marker Marker Type Name
                            EGFPEFGEGFP
                            1 - 1 of 1
                            Show
                            Mapping
                            No data available
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                            Citation
                            Stratman, A.N., Farrelly, O.M., Mikelis, C.M., Miller, M.F., Wang, Z., Pham, V.N., Davis, A.E., Burns, M.C., Pezoa, S.A., Castranova, D., Yano, J.J., Kilts, T.M., Davis, G.E., Gutkind, J.S., Weinstein, B.M. (2020) Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling. Nature communications. 11:1204.