title: Genetic evidence for a tumor suppressor role of HIF-2alpha.
abstract: The hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha are activated in hypoxic tumor regions. However, their role in tumorigenesis remains controversial, as tumor growth promoter and suppressor activities have been ascribed to HIF-1alpha, while the role of HIF-2alpha remains largely unknown. Here, we show that overexpression of HIF-2alpha in rat glioma tumors enhances angiogenesis but reduces growth of these tumors, in part by increasing tumor cell apoptosis. Moreover, siRNA knockdown of HIF-2alpha reduced apoptosis in hypoxic human malignant glioblastoma cells. Furthermore, inhibition of HIF by overexpression of a dominant-negative HIF transgene in glioma cells or HIF-2alpha deficiency in teratomas reduced vascularization but accelerated growth of these tumor types. These findings urge careful consideration of using HIF inhibitors as cancer therapeutic strategies.
authors.affiliation: Edinger Institute, Neuropathology, Johann Wolfgang Goethe University, 60528 Frankfurt, Germany. till.acker@med.uni-frankfurt.de
authors.forename: Till
authors.initials: T
authors.lastname: Acker
authors.forename: Antonio
authors.initials: A
authors.lastname: Diez-Juan
authors.forename: Julian
authors.initials: J
authors.lastname: Aragones
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Koen
authors.initials: K
authors.lastname: Brusselmans
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Maria Paz
authors.initials: MP
authors.lastname: Moreno-Murciano
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Angelika
authors.initials: A
authors.lastname: Burger
authors.forename: Johanna
authors.initials: J
authors.lastname: Riedel
authors.forename: Gerd
authors.initials: G
authors.lastname: Elvert
authors.forename: Ingo
authors.initials: I
authors.lastname: Flamme
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018302:Neoplasms, Neuroepithelial / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1