Hypoxia upregulates Bcl-2 expression and suppresses interferon-γ induced antiangiogenic activity in human tumor derived endothelial cells†
Version of Record online: 14 MAY 2002
Copyright © 2002 American Cancer Society
Volume 94, Issue 10, pages 2745–2755, 15 May 2002
How to Cite
Wang, J. H., Wu, Q. D., Bouchier-Hayes, D. and Redmond, H. P. (2002), Hypoxia upregulates Bcl-2 expression and suppresses interferon-γ induced antiangiogenic activity in human tumor derived endothelial cells. Cancer, 94: 2745–2755. doi: 10.1002/cncr.10520
The Department of Surgery in Cork University Hospital and the Department of Surgery in Beaumont Hospital contributed equally to this work.
- Issue online: 14 MAY 2002
- Version of Record online: 14 MAY 2002
- Manuscript Accepted: 27 DEC 2001
- Manuscript Revised: 20 DEC 2001
- Manuscript Received: 21 MAR 2001
- tumor-derived endothelial cells;
- Bcl-2 gene protein expression;
- cell proliferation;
- cell apoptosis;
- capillary tube formation
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.
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.
Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-γ-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-γ -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.
These results indicate that hypoxia can protect HTDEC against IFN-γ -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. Cancer 2002;94:2745–55. © 2002 American Cancer Society.