title: Blockade of her2/neu decreases VEGF expression but does not alter HIF-1 distribution in experimental Wilms tumor.
abstract: Her2/neu regulates angiogenesis in human breast cancer, in part by stabilizing hypoxia-inducible factor 1alpha (HIF-1alpha), causing accumulation of the HIF-1 heterodimer and thus increasing expression of the proangiogenic cytokine VEGF. Her2/neu has recently been shown to be overexpressed in a subset of Wilms tumors. Using her2/neu (+) and her2/neu (-) Wilms tumor cell lines, we tested the effect of blocking anti-her2/neu antibody in vitro and in vivo. Blocking antibody did not alter VEGF expression in vitro, but decreased expression of VEGF in her2/neu (+) Wilms tumor xenografts. Tumor suppression was less marked than in parallel experiments using agents directly blocking VEGF. HIF-1alpha immunostaining was not altered in her2/neu (+) xenografts exposed to blocking antibody. These results suggest that her2/neu contributes to Wilms tumor angiogenesis in vivo by regulating VEGF, but other processes may act to rescue HIF-1alpha and thus to support tumor growth in this system.
authors.affiliation: Division of Pediatric Surgery, Columbia University, New York, NY, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoi
authors.forename: Kimberly W
authors.initials: KW
authors.lastname: McCrudden
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Soffer
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
authors.forename: Anna
authors.initials: A
authors.lastname: Serur
authors.forename: Tamara
authors.initials: T
authors.lastname: New
authors.forename: Jenny
authors.initials: J
authors.lastname: Yuan
authors.forename: Mahesh
authors.initials: M
authors.lastname: Mansukhani
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Toole
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D002455:Cell Division; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000096:biosynthesis*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D009396:Wilms Tumor / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse