Veronica Steri1, Tim S Ellison, Aleksander Maksym Gontarczyk, Katherine Weilbaecher, Jochen G Schneider, Dylan Edwards, Marcus Fruttiger, Kairbaan M Hodivala-Dilke, Stephen Douglas Robinson. 1. From the School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, United Kingdom (V.S., T.S.E., A.M.G., D.E., S.D.R.); Department of Internal Medicine, Division of Molecular Oncology, Washington University in St Louis, MO (K.W.); Luxembourg Center for Systems Biomedicine, University of Luxembourg, Luxembourg and Saarland University Medical Center, Internal Medicine II, Homburg, Germany (J.G.S.); UCL Institute of Ophthalmology, University College London, London, United Kingdom (M.F.); Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London, United Kingdom (K.M.H.-D.).
Abstract
RATIONALE: The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function. OBJECTIVE: Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis. METHODS AND RESULTS: We have crossed β3-integrin-floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression. CONCLUSIONS: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of β3-integrin to inhibit tumor growth and angiogenesis.
RATIONALE: The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin-knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell-specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function. OBJECTIVE: Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis. METHODS AND RESULTS: We have crossed β3-integrin-floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression. CONCLUSIONS: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of β3-integrin to inhibit tumor growth and angiogenesis.
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Authors: Xinming Su; Alison K Esser; Sarah R Amend; Jingyu Xiang; Yalin Xu; Michael H Ross; Gregory C Fox; Takayuki Kobayashi; Veronica Steri; Kirsten Roomp; Francesca Fontana; Michelle A Hurchla; Brett L Knolhoff; Melissa A Meyer; Elizabeth A Morgan; Julia C Tomasson; Joshua S Novack; Wei Zou; Roberta Faccio; Deborah V Novack; Stephen D Robinson; Steven L Teitelbaum; David G DeNardo; Jochen G Schneider; Katherine N Weilbaecher Journal: Cancer Res Date: 2016-05-23 Impact factor: 12.701
Authors: Tim S Ellison; Samuel J Atkinson; Veronica Steri; Benjamin M Kirkup; Michael E J Preedy; Robert T Johnson; Christiana Ruhrberg; Dylan R Edwards; Jochen G Schneider; Katherine Weilbaecher; Stephen D Robinson Journal: Dis Model Mech Date: 2015-07-09 Impact factor: 5.758