title: Effects of HIF-1alpha and HIF2alpha on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts.
abstract: In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1alpha (HIF-1+), HIF-2alpha (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2alpha significantly increased, and HIF-1alpha significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2alpha in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Swethajit
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authors.lastname: Biswas
authors.forename: Helen
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authors.lastname: Troy
authors.forename: Russell
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authors.lastname: Leek
authors.forename: Yuen-Li
authors.initials: YL
authors.lastname: Chung
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Raju R
authors.initials: RR
authors.lastname: Raval
authors.forename: Helen
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authors.lastname: Turley
authors.forename: Kevin
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authors.lastname: Gatter
authors.forename: Francesco
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authors.lastname: Pezzella
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
authors.forename: Marion
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authors.lastname: Stubbs
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris