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dc.contributor.authorWang, Jiang Huai
dc.contributor.authorWu, Qiong Di
dc.contributor.authorBouchier-Hayes, David
dc.contributor.authorRedmond, H Paul
dc.date.accessioned2012-02-03T15:10:23Z
dc.date.available2012-02-03T15:10:23Z
dc.date.issued2012-02-03T15:10:23Z
dc.identifier.citationCancer. 2002 May 15;94(10):2745-55.en_GB
dc.identifier.issn0008-543X (Print)en_GB
dc.identifier.issn0008-543X (Linking)en_GB
dc.identifier.pmid12173346en_GB
dc.identifier.urihttp://hdl.handle.net/10147/209031
dc.description.abstractBACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.
dc.language.isoengen_GB
dc.subject.meshAngiogenesis Inhibitors/pharmacologyen_GB
dc.subject.meshApoptosisen_GB
dc.subject.meshCell Hypoxia/*physiologyen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshCyclin D1/*analysisen_GB
dc.subject.meshEndothelium/*cytologyen_GB
dc.subject.meshEndothelium, Vascular/cytologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshInterferon-gamma/*pharmacologyen_GB
dc.subject.meshNeovascularization, Pathologic/*physiopathologyen_GB
dc.subject.meshTumor Cells, Cultureden_GB
dc.subject.meshUmbilical Veins/cytologyen_GB
dc.subject.meshUp-Regulation/*physiologyen_GB
dc.titleHypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.en_GB
dc.contributor.departmentDepartment of Surgery, Cork University Hospital, National University of Ireland, , Wilton, Ireland.en_GB
dc.identifier.journalCanceren_GB
dc.description.provinceMunster
html.description.abstractBACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.


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