title: TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
abstract: The p53-family member TAp73 is known to function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis; however, its role in tumor angiogenesis is poorly understood. Here we demonstrate that TAp73 regulates tumor angiogenesis through repression of proangiogenic and proinflammatory cytokines. Importantly, loss of TAp73 results in highly vascularized tumors, as well as an increase in vessel permeability resulting from disruption of vascular endothelial-cadherin junctions between endothelial cells. In contrast, loss of the oncogenic p73 isoform ΔNp73 leads to reduced blood vessel formation in tumors. Furthermore, we show that up-regulated ΔNp73 levels are associated with increased angiogenesis in human breast cancer and that inhibition of TAp73 results in an accumulation of HIF-1α and up-regulation of HIF-1α target genes. Taken together, our data demonstrate that loss of TAp73 or ΔNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Stantic
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Habib A M
authors.initials: HA
authors.lastname: Sakil
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Hanna
authors.initials: H
authors.lastname: Zirath
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Trixy
authors.initials: T
authors.lastname: Fang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Gema
authors.initials: G
authors.lastname: Sanz
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Fernandez-Woodbridge
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Ana
authors.initials: A
authors.lastname: Marin
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Susanto
authors.affiliation: The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada margareta.wilhelm@ki.se tmak@uhnresearch.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and.
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenian Henriksson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; and margareta.wilhelm@ki.se tmak@uhnresearch.ca.
authors.forename: Margareta T
authors.initials: MT
authors.lastname: Wilhelm
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000378:metabolism*; D010539:Permeability; D020033:Protein Isoforms / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D043925:Angiogenesis Inducing Agents; D015820:Cadherins; D016207:Cytokines; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human
keywords: HIF-1 alpha; angiogenesis; p73; tumor microenvironment; vascular permeability