title: E2F1 promotes angiogenesis through the VEGF-C/VEGFR-3 axis in a feedback loop for cooperative induction of PDGF-B.
abstract: Angiogenesis is essential for primary tumor growth and metastatic dissemination. E2F1, frequently upregulated in advanced cancers, was recently shown to drive malignant progression. In an attempt to decipher the molecular events underlying this behavior, we demonstrate that the tumor cell-associated vascular endothelial growth factor-C/receptor-3 (VEGF-C/VEGFR-3) axis is controlled by E2F1. Activation or forced expression of E2F1 in cancer cells leads to the upregulation of VEGFR-3 and its ligand VEGF-C, whereas E2F1 depletion prevents their expression. E2F1-dependent receptor induction is crucial for tumor cells to enhance formation of capillary tubes and neovascularization in mice. We further provide evidence for a positive feedback loop between E2F1 and VEGFR-3 signaling to stimulate pro-angiogenic platelet-derived growth factor B (PDGF-B). E2F1 or VEGFR-3 knockdown results in reduced PDGF-B levels, while the coexpression synergistically upregulates promoter activity and endogenous protein expression of PDGF-B. Our findings delineate an as yet unrecognized function of E2F1 as enhancer of angiogenesis via regulation of VEGF-C/VEGFR-3 signaling in tumors to cooperatively activate PDGF-B expression. Targeting this pathway might be reasonable to complement standard anti-angiogenic treatment of cancers with deregulated E2F1.
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Engelmann
authors.forename: Deborah
authors.initials: D
authors.lastname: Mayoli-Nüssle
authors.forename: Christian
authors.initials: C
authors.lastname: Mayrhofer
authors.forename: Katharina
authors.initials: K
authors.lastname: Fürst
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.forename: Anja
authors.initials: A
authors.lastname: Stoll
authors.forename: Alf
authors.initials: A
authors.lastname: Spitschak
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.forename: Sophia
authors.initials: S
authors.lastname: Ran
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; D020574:Proto-Oncogene Proteins c-sis; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: E2F1; PDGF-B; VEGF-C; VEGFR-3; hypoxia; neovascularization; regulatory feedback loop