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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Steri V,Ellison TS,Gontarczyk AM,Weilbaecher K,Schneider JG,Edwards D,Fruttiger M,Hodivala-Dilke KM,Robinson SDdoi
10.1161/CIRCRESAHA.114.301591subject
Has Abstractpub_date
2014-01-03 00:00:00pages
79-91issue
1eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.114.301591journal_volume
114pub_type
杂志文章abstract::It has been shown previously that serotonin stimulates the production of prostacyclin by bovine aortic smooth muscle cells in culture, via 5-HT2 receptors (Coughlin SR, Moskowitz MA, Antoniades HN, Levine L. Proc Natl Acad Sci USA 1981;78:7134-7138). These cells express a synthetic phenotype, whereas the majority of t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.4.806
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abstract::Arterial segments (less than 250 micron o.d.) excised from canine ileum were mounted in a chamber that permitted arterial transmural pressure (TMP) to be altered and measured. Subsequently, the periarterial nerves were field stimulated with single pulses (0.1 msec, 70 V), and the resting membrane potential (Em) as wel...
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pub_type: 杂志文章
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pub_type: 杂志文章,评审
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更新日期:2002-08-23 00:00:00
abstract::The localization patterns of human plasma lipoproteins and their respective apoproteins and of neutral lipid were determined in normal and atherosclerotic arteries. Specific antisera were prepared against plasma low-density lipoproteins(LDL) and their apoproteins (apoB), high-density lipoproteins(HDL) and one of their...
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pub_type: 杂志文章
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journal_title:Circulation research
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journal_title:Circulation research
pub_type: 杂志文章
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.300119
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.1.76
更新日期:1997-07-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2014-06-20 00:00:00
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更新日期:2002-03-08 00:00:00
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更新日期:1991-01-01 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh1701.095642
更新日期:2001-08-31 00:00:00
abstract::Heptanol blocks sodium current (INa) in nerve, but its effects on cardiac INa have not been well characterized. Block of INa by heptanol was studied in 16 internally perfused voltage-clamped cardiac Purkinje cells at reduced Na+ (45 mM outside, 0 mM inside). Heptanol block of peak sodium conductance was well described...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.4.977
更新日期:1991-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:1992-11-01 00:00:00
abstract::Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and...
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pub_type: 杂志文章,评审
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更新日期:2007-10-12 00:00:00
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更新日期:2008-07-18 00:00:00
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更新日期:1987-10-01 00:00:00
abstract::Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated ...
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更新日期:2004-01-09 00:00:00
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更新日期:1984-12-01 00:00:00