Published online before print July 24, 2008, doi: 10.1161/ATVBAHA.108.172015
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© 2008 American Heart Association, Inc.
Brief Reviews |
Integrins
The Keys to Unlocking Angiogenesis
From the Adhesion and Angiogenesis Group, Centre for Tumour Biology, Cancer Research UK Clinical Centre and the Institute of Cancer, Barts & The London & Queen Mary’s School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London UK.
Correspondence to Louise Reynolds, Cancer Research UK, Charterhouse Square, London EC1M 6BQ, UK. E-mail louise.reynolds{at}cancer.org.uk
Series Editor: Dietmar Vestweber
Vascular Adhesion Molecules
ATVB In Focus
Preview Brief Reviews in this Series:
•van Buul JD, Kanters E, and Hordijk PL. Endothelial signaling by Ig-like cell adhesion molecules. Arterioscler Thromb Vasc Biol. 2007;27:1870–1876.
•Bradfield PF, Nourshargh S, Aurrand-Lions M, Imhof BA. JAM family and related proteins in leukocyte migration. Arterioscler Thromb Vasc Biol. 2007;27:2104–2112.
•Galkina E and Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27: 2292–2301.
•Jalkanen S, Salmi M. VAP-1 and CD73, endothelial cell surface enzymes in leukocyte extravasation. Arterioscler Thromb Vasc Biol. 2008;28:18–26.
•Vestweber, D. VE-cadharin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol. 2008;28:223–232.
•Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol. 2008:28:403–412.
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Abstract |
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 Top Abstract IntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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Angiogenesis, the formation of new blood vessels from preexisting vasculature, contributes to the pathogenesis of many disorders, including ischemic diseases and cancer. Integrins are cell adhesion molecules that are expressed on the surface of endothelial cells and pericytes, making them potential targets for antiangiogenic therapy. Here we review the contribution of endothelial and mural cell integrins to angiogenesis and highlight their potential as antiangiogenesis targets.
Key Words: integrins • endothelial cells • pericytes • angiogenesis • antiangiogenic therapies
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Introduction |
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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Tumor angiogenesis involves increased endothelial cell proliferation and migration, and tube formation into the tumor mass. During angiogenesis endothelial cells become activated, degrade local basement membrane, and the vessel begins to "sprout" with migrating tip cells leading a column of proliferating stalk cells. These blood vessel sprouts eventually form lumens and develop into a network.1 The newly formed vessels are stabilized by the synthesis of a new basement membrane and the recruitment of supporting cells such as pericytes and vascular smooth muscle cells (mural cells). These angiogenic steps involve changes in endothelial or pericyte adhesion. Integrins are a family of noncovalently associated heterodimeric transmembrane glycoprotein adhesion molecules. They comprise an
-subunit, of approximately 1000 amino acids (aa), and a β-subunit, of around 800 aa, which mediate cell-ECM and cell-cell adhesive interactions.2–5 The number of - and β-subunits varies between species and currently, in higher mammals, 18 - and 8 β-subunits combine to form more than 24 different integrin heterodimers. Heterodimer composition confers ligand specificity, with most integrins recognizing several extracellular matrix (ECM) proteins and, in turn, most matrix proteins binding to more than one integrin.
Endothelial cells and pericytes both express a subset of mammalian integrins including: the fibronectin receptors, 4β1, 5β1; the collagen receptors, 1β1, 2β1; the laminin receptors, 3β1, 6β1, and 6β4; and the osteopontin receptor, 9β1.6,7 In addition pericytes also express 7β1 (laminin receptor) and 8β1 (osteopontin receptor) integrins. The vitronectin receptors, vβ3 and vβ5, are expressed by endothelial cells, and vβ3 is also expressed on glial cells. A combination of global genetic ablation and conditional deletion of integrin-subunit genes in endothelial cells or pericytes has allowed a better understanding of the requirements of these molecules in both developmental and pathological angiogenesis.8 Endothelial-specific deletion of integrins involves generating integrin-floxed mice which express Cre-recombinase driven by endothelial promoters such as Tie-1,9 Tie-210 or VE-cadherin,11 whereas pericyte-specific deletion involves generating integrin-floxed mice expressing Cre recombinase driven by pericyte promoters such as PDGF receptor β.12 More recently, inducible endothelial-specific deletion systems have been developed providing the opportunity to delete integrins specifically in endothelial cells in adult mice.11,13 Genetic ablation studies in combination with studies testing the effects of specific integrin inhibitors on angiogenesis have shaped our understanding of the role of integrins in blood vessel formation. Here we evaluate the current literature on all endothelial and pericyte integrins, their role in angiogenesis (Figure, Table 1), and their use as targets in controlling tumor angiogenesis (Table 2).
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Vitronectin Receptors vβ3 and vβ5
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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v Integrin Subunitv-null mice develop normally until embryonic day 9.5. However, only 20% survive until birth and 100% die within the first day of birth.14,15 These mice develop intracerebral hemorrhage attributable to defective interactions between blood vessels and brain parenchymal cells.15 Interestingly, selective genetic ablation of v integrin expression in the vascular endothelium has no detectable effect on cerebral blood vessel development and at birth mutant mice display no phenotypic defects, implying that the loss of v integrin expression in vascular endothelium does not account for the cerebral hemorrhage observed in the complete v integrin knockout mice. In contrast, ablation of v integrin expression specifically from neural cells has a significant impact for cerebral hemorrhage.16 Generation of an endothelial Tie-2 specific v integrin knockout mouse showed no defects in angiogenesis, but these mice had a compromised immune system resulting in severe colitis.17 v integrins are upregulated during angiogenesis18 and blocking their function with antagonists has been shown to inhibit angiogenesis in preclinical models.18–22
vβ3 and vβ5 Integrin
Unlike the v integrin knockout mouse, the β3 and β5 integrin-null mice are viable and fertile and produce a vascular network without any obvious defects.23–25 β3 integrin is undetectable in quiescent blood vessels, but its expression is apparently upregulated during sprouting angiogenesis.26,27 For this reason, antagonists of β3 integrin were developed and some proved to be very successful antiangiogenic agents either in vitro or in preclinical angiogenesis assays in vivo.18–22,28–30 Indeed, some vβ3 antagonists are being used in clinical trials as antiangiogenic therapy, including the humanized monoclonal antibody Vitaxin28 and the RGD-mimetic Cilengitide.31 In addition, the replacement of β3 integrin with a mutated form, which cannot be phosphorylated, in DiYF mice, results in impaired angiogenic responses and reduced tumor growth.32 All considered, these data logically suggest a positive role for this integrin in angiogenesis. Our laboratory has shown, however, that genetic ablation of β3 and β5 integrins can actually enhance tumor growth and pathological angiogenesis25 implying that β3 and β5 integrins are not required for the development of new blood vessels. The enhanced pathological angiogenesis in β3-null mice is attributable to elevated VEGF receptor-2 expression/function33 and to increased sensitivity of endothelial cells to VEGF-A.34 It is therefore especially important to investigate further the role of vβ3/vβ5 integrins in regulating receptor tyrosine kinase expression and function. Previous reports have identified crosstalk between β3 integrin and VEGF receptor-2 (VEGFR-2), necessary for angiogenesis, although two different mechanisms have been proposed. First, β3 integrin binds directly to VEGFR-2, and this interaction is required for VEGFR-2 activation and downstream signaling in the presence of VEGF-A.35 Second, a synergistic relationship exists between β3 integrin and VEGFR-2 in that VEGFR-2 activation induces β3 integrin phosphorylation and, in turn, β3 integrin phosphorylation is required for phosphorylation of VEGFR-2 in the presence of VEGF. Src is critical for this synergy to occur.36 Despite the conflicting roles of vβ3 in angiogenesis, this integrin is currently being targeted in antiangiogenic clinical trials. Unfortunately this approach has been disappointing for the treatment of most cancers.37 The reason for this discrepancy between preclinical and clinical trials is still open to debate. One explanation is that the genetic ablation experiments underestimate the function of vβ3 integrin because of overlapping of functions or compensation by other integrins. Although no evidence for adhesive or migratory compensation has been demonstrated, other forms of untested compensation may prevail. For example, the total loss of vβ3 integrin expression has been shown to cause the upregulation not only of VEGF-receptor 2 in endothelial cells but also transforming growth factor (TGF)β-receptor 1 in fibroblasts, another known proangiogenic factor. Further investigations into the cross-regulation of proangiogenic molecules would help to provide a more complete picture of the regulatory role played by vβ3 integrin in angiogenesis. In addition, integrins are known to have transdominant roles over other integrins thereby regulating overall cell behavior.38,39 It is conceivable that the loss of vβ3 integrin could cause the relief of such transdominant inhibition and enhance the angiogenic functions of proangiogenic integrins, such as 5β1, or even other nonintegrin molecules. In addition, the antiangiogenic function of vβ3 integrin has been implicated by its ability to bind to proteolytic fragments of ECM proteins that have antiangiogenic properties. One example is tumstatin, an endogenous cleaved fragment of the type IV collagen 3-chain, which binds directly with vβ3 and inhibits angiogenesis.40 Thus, it is logical that in the absence of vβ3, tumstatin does not negatively regulate angiogenesis, and indeed this has been demonstrated in vivo.40 Another explanation for the differences in the genetic ablation, mutational, and inhibitor studies is that some studies have indicated that integrins can control apoptosis depending on their ligation state. For example, Stupack et al41 have shown that unligated vβ3 can act as a negative regulator of cell survival, initiating a process referred to as "integrin mediated death," ie, unligated integrins are thought to promote apoptosis by the recruitment of caspase-8 to the plasma membrane, whereas ligated integrins do not. Furthermore, the decreasing expression of vβ3 integrin promotes survival of endothelial cells. Thus it is plausible that genetic ablation of β3 integrin could enhance endothelial cell survival and thus increase angiogenesis, whereas the DiFY functional mutation in β3 integrin would have the opposite effect. It should be noted that this phenomenon would not explain the reason for the apparently normal angiogenesis observed in unchallenged β3-null, or DiYF mice, nor would it be likely to be essential because blockade of VEGFR-2 function is sufficient to block angiogenesis in the β3-knockout mice.33 However, examination of the apoptotic index in the presence or absence of vβ3 integrin would be valuable in clarifying this. Another reason for the discrepancies between the inhibition and genetic ablation data may involve the regulation of VEGFR-2 at the protein level. Both vβ3 integrin and VEGFR-2 are internalized from the cell surface into the endocytic pathway, from where they may be either degraded or recycled back to the cell membrane.42–45 Given that vβ3 integrin and VEGFR-2 have been shown to interact with each other it would be of interest to examine the possibility that vβ3 inhibitors, mutants, or full-length vβ3 may affect the internalization and recycling of VEGFR-2 differently and thus regulate angiogenesis. Lastly, one reason for the lack of general success of the vβ3 integrin drugs in clinical trials may be a reflection of the dose administered and the pharmacokinetics of the drugs. In general, such clinical trials involve periodic bolus of injections of drugs between which the plasma concentration of the inhibitors drop significantly. For example, the half-life of Cilengitide is approximately 3 to 4 hours in humans.46 Several studies have shown that low doses of drugs can have agonistic effects. Indeed, Legler et al47 showed that low doses of an RGD-peptide can actually enhance the adhesive function of vβ3 to vitronectin. It would be of value to investigate the possibility that such phenomenon exist in vivo. We have new data suggesting that vβ3/vβ5 integrin inhibitors are less effective in repressing tumor growth and angiogenesis than originally predicted because when the plasma concentrations of such inhibitors are allowed to drop to very low levels they act to enhance VEGFR-2 levels and enhance tumor growth and angiogenesis (A.R. Reynolds and K.M. Hodivala-Dilke, personal communication, 2008). This could obviously have counteractive effects on the treatment of cancer under such therapeutic regimens. It is therefore crucial to clarify the mechanism by which such drugs affect integrin function to develop safe and more effective therapeutic strategies. Regardless of the apparently conflicting data, vβ3, although not required, is involved in angiogenesis and likely plays both pro- and antiangiogenic roles.
vβ8 Integrin
Although vβ8 is not expressed by endothelial cells or pericytes, genetic ablation of β8 integrin results in embryonic or perinatal lethality with profound defects in vascular development. vβ8 binds to the latency-associated peptide of TGFβ1, LAP, and vitronectin,48–51 and it may also bind collagen IV and laminin.52 β8-null mice have a strikingly similar phenotype to the v-null mice, suggesting that many of the defects in the v-null mice are primarily attributable to the loss of vβ8.53 Ultrastructural and immunocytochemical examination of the β8-null mice reveal a primary defect of end-feet association of a major subset of perivascular cells with endothelial cells. The majority of the β8-deficient embryos die at midgestation because of insufficient vascularization of the placenta and yolk sac, those that do survive die shortly after birth with extensive intracerebral hemorrhage.53 In vitro studies on the close relationship between endothelial cells and astrocytes in the developing brain have revealed that astrocytic vβ8 is an important regulator of brain vessel homeostasis, through regulation of TGFβ activation, present in the basement membrane of brain blood vessels. Specifically, on binding of vβ8 to LAP, TGFβ is activated and diffuses to the endothelial cells where it binds to TGFβ receptors inducing downstream activation of antiangiogenic factors such as plasminogen activator inhibitor (PAI)-1 and TSP-1. Therefore, it is likely that the interaction between vβ8 and TGFβ is important for the stabilization of the cerebral vasculature by astrocytes.
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Fibronectin Receptors 4β1 and 5β1
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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β1 Integrin Subunit
β1 integrins are essential for angiogenesis, yet the roles of specific β1 integrin heterodimers in this process remain unclear. β1 integrins are expressed on endothelial cells, endothelial supporting cells, and pericytes of both quiescent and angiogenic vessels.54,55 β1 integrin-null embryos die early in gestation and do not develop far enough to begin to produce vasculature.56,57 For this reason, analysis of β1-null teratomas and β1-null embryoid bodies has been used to define the role of β1 integrin in angiogenesis: β1-null teratomas have fewer vessels to support tumor growth, and these are host derived. β1-null ES cells can differentiate into ECs but the formation of a complex vascular network is delayed significantly and of poor quality. Furthermore, β1-null embryoid bodies are resistant to VEGF-induced proliferation and branching.58 Recently, deletion of β1 integrin in the endothelium has shown a requirement for this integrin in vascular development and patterning.59 In a similar study, a Cre-lox system was used to delete β1 integrin specifically on Tie-2-positive endothelial cells. Unlike the global knockout mouse, which dies at E5.5, these embryos survived to E9.5-E10.5, allowing the formation of a simple vasculature. Analysis of the vasculature revealed defects in angiogenic sprouting and vascular branching morphogenesis, implying that β1 integrin is essential for angiogenesis but not vasculogenesis.60
β1 integrin expression on pericytes is thought to help stabilize the blood vessels.55 In ex vivo aortic ring assays, inhibition of this integrin induced a rounded morphology of the pericytes, suggesting pericyte adhesive properties were affected or that these cells were undergoing apoptosis. In vivo, β1 integrin deficiency results in pericytes being unable to spread properly.54 Based on these data one would predict that targeting β1 integrin expression would destabilize pericytes, exposing the underlying endothelial cells and making them more accessible to other antiangiogenic drugs. However, because β1 integrin subunits are expressed on almost all cell types it is unlikely that targeting this subunit would ever be a viable antiangiogenic approach.
5β1 Integrin
The role for 5β1 in developmental angiogenesis is exemplified in the phenotype of the 5-null mice. Genetic ablation of 5 integrin results in a lethal phenotype where embryos die at day 10 to 11 of gestation where the yolk sac and embryonic vascular network fail to form properly.61–63 Similar defects in vessel development are recapitulated in 5-null embryoid bodies, 5-null teratomas,63,64 and, to a greater extent, in the Fn-null embryos, highlighting the importance of 5-Fn interactions during vessel development. 5β1 integrin is poorly expressed on normal quiescent endothelial cells, but its expression is markedly upregulated during angiogenesis65,66 and it is highly expressed in the vasculature of both mouse and human tumors.67 Antagonists for 5β1, such as SJ749 and ATN-161, are able to reduce tumor growth by inhibiting angiogenesis in vivo,66–68 and the ATN-161 peptide is currently being tested in Phase I clinical trials.69 Furthermore, volociximab, a monoclonal antibody that inhibits the functional activity of 5β1, is currently being tested in patients with advanced solid tumors.70 5 integrin has been reported to enhance migration by binding directly to angiopoietin-171 or to VEGFR-1,72 and more recently it was shown to cross-talk with the endothelial receptor Tie-2, both in vitro and in vivo.73 The examination of 5β1 function in vascular smooth muscle cells (VSMCs) has been restricted to analysis of these cells in culture. Microarray analysis of the genes expressed when mesenchymal cells differentiate to pericytes revealed an upregulation of several genes implicated in angiogenesis, including 5 integrin.74,75 In addition to positive roles in angiogenesis, 5β1 interacts with the potent antiangiogenic molecule endostatin,76,77 suggesting a complex role in neovascularization and the need for further investigations.
4β1 and 4β7 Integrin
a4β1 and 4β7 are both fibronectin receptors.78–81 Although both integrins have been reported to be expressed on endothelial cells,82–84 4β1 is generally considered to be a leukocyte-specific integrin.85 In addition, 4β1 is also expressed on pericytes and smooth muscle cells.83,86 Global deletion of the 4 integrin subunit results in an embryonic lethal phenotype caused by failure of the allantois to fuse with the chorion during placentation and defects in the developing epicardium and coronary vessels.87 Using an elegant system in which the 4-subunit gene was replaced with LacZ driven by the 4-subunit promoter, the pattern of 4 expression was examined and localized predominantly on pericytes associated with angiogenic vessels. Closer examination of the 4-null embryos revealed that pericytes and VSMCs fail to migrate and tend to cluster at angiogenic branch points.86 4β1 integrin and one of its ligands, vascular cell adhesion molecule (VCAM) 1, are critical for the correct interaction between endothelial cells and mural cells during blood vessel formation, in part, by promoting cell survival in both cell types.88 Mice deficient in VCAM-1 display a similar phenotype to that observed in the 4 integrin-null mice.89 In contrast to the embryo studies, 4β1 integrin was more highly expressed on proliferating endothelial cells of tumor vessels implicating endothelial 4β1 in tumor angiogenesis.84,88 In line with these findings, although deletion of 4 integrin specifically in endothelial and hematopoetic cells results in viable mice with no apparent defects in vessel development, they do present a significant increase in numbers of circulating progenitors, suggesting that 4 integrin expression is necessary for progenitor retention in the bone marrow.90 In contrast, it has been shown that 4β1 enhances the homing of bone marrow-derived endothelial progenitor cells (EPCs) and monocytes to sites of neovascularization. Moreover, the use of 4β1 antagonists leads to a significant reduction in the number of EPCs and monocytes found in tumors with a corresponding reduction in the numbers of blood vessels.84,91 With this in mind, 4β1 integrin inhibitors such as natalizumab, currently being used to treat antiinflammatory diseases, such as multiple sclerosis92 and Crohn disease,93 might affect neovascularization and prove useful as an antiangiogenic therapy. Currently, 4β7 integrin has not been implicated in angiogenesis.
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Collagen Receptors 1β1 and 2β1
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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1β1 and 2β1 IntegrinsAntagonists to
1 and 2 integrins have been shown to selectively inhibit VEGF-driven angiogenesis in vivo, without affecting the preexisting vasculature.94,95 In addition, Obtustatin, a potent and selective inhibitor of 1β1 integrin, is able to inhibit angiogenesis in vivo,96 suggesting a positive role for 1β1 integrin in pathological angiogenesis. Although 1-null mice are viable and fertile, they display defects in collagen synthesis97 and reduced tumor angiogenesis, probably attributable to elevated matrix metalloproteinase (MMP) production.98 Recently, enhanced tumor growth and angiogenesis was observed in B16 melanomas, but not Lewis Lung Cell carcinomas (LLC), grown in 2-null mice. 2-null endothelial cells express higher levels of VEGFR-1—a proangiogenic receptor for placental growth factor (PlGF). Because B16 melanomas secrete higher levels of PlGF when compared with LLC, angiogenesis was enhanced in 2-null mice with B16, but not LLC tumors. Thus, 2β1 controls angiogenesis via the regulation of VEGFR-1 in a PlGF-rich environment.99 Despite both 1β1 and 2β1 integrins binding to the same ECMs, their genetic ablation leads to opposing pathological angiogenic phenotypes in vivo. These data suggest that 1β1 and 2β1 can regulate/activate different signaling pathways that, in turn, have differing effects on angiogenesis. |
Laminin Receptors, 3β1, 6β1, and 6β4
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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3β1 Integrin3β1 integrin was identified as a receptor for several ligands, which in blood vessels include laminins 8 and 10 and thrombospondin.100,101 It interacts with other molecules such as the tetraspanin, CD151,102 the metalloproteinase inhibitor, TIMP2,103 and the 3-noncollagenous (3NC1) domain of collagen IV,104,105 all of which have been implicated in either promoting or inhibiting angiogenesis. Ablation of 3 integrin is lethal within hours after birth,106 and mice display a combination of defects including abnormal branching in the bronchi of the lungs, kidney glomeruli, and neurons106 and microblister formation in the skin,107 but no reported effect on angiogenesis per se. Other studies suggest either a positive or a negative role for this integrin in angiogenesis,102–105 and despite the dispute in its actual function during angiogenesis 3β1-directed inhibitors are being designed as antiangiogenic therapeutics.108,109 We have data demonstrating that genetic ablation of 3 integrin in Tie-1-positive endothelial cells does not affect viability or fertility but does enhance tumor growth and tumor angiogenesis, stressing that the use of anti-3 integrin agents in the clinic should be approached with caution (R. Silva and K.M Hodivala-Dilke, personal communication, 2008). Evidence for a role for pericyte 3β1 in angiogenesis is yet to be determined.
6β1 and 6β4 Integrin
Genetic ablation of this integrin results in a lethal phenotype110 where mice present severe epidermal and blistering defects,110–112 but no vascular defects have been reported to date. 6 integrin can heterodimerize with either β1 or β4 integrin subunit, and 6β4 integrin expression has been detected on human and murine tumor endothelium.113 Mice carrying a targeted deletion of the signaling portion of the β4 subunit display significantly reduced angiogenesis,113 suggesting that the β4 subunit might enhance adult pathological angiogenesis. Other studies suggest that endothelial expression of 6β4 may be a negative component of angiogenesis and that its expression is downregulated at the onset of neovascularization.114 However, these opposing findings may reflect the differences between using in vitro and in vivo experimental systems. Moreover, because β4 integrin is not detectable in cultured endothelial cells,113 the interpretation of such experiments is complicated further. In contrast, we have preliminary data to suggest that genetic ablation of 6 integrins can actually enhance angiogenesis in ex vivo aortic ring assays (M. Germain and K.M. Hodivala-Dilke, personal communication, 2008). The 6β1 integrin heterodimer is also important for angiogenesis; it can bind to the proangiogenic member of the CCN family, CYR61, and is also thought to promote tube formation in ex vivo models of angiogenesis.115,116 Furthermore, blocking 6 integrin with a specific antibody, GoH3, inhibits VEGF-induced adhesion and migration of brain microvascular endothelial cells as well as in vivo angiogenesis.117 Taken together, evidence for a role for 6 integrins in angiogenesis is conflicting and requires further investigation before it can be used as a target for cancer therapies.81 As for 3β1, no studies on the function of 6 integrin in pericytes have been reported.
9β1 Integrin
The integrin 9-subunit forms a single heterodimer, 9β1 integrin and is a receptor for the extracellular matrix proteins osteopontin,7 tenascin-C,118 and VCAM-1.119 Mice deficient in 9 integrin appear normal at birth but develop respiratory failure and die between 6 and 12 days of age from bilateral chylothorax.120 This integrin has been shown to be important for proper lymphatic development,121 although its role in angiogenesis has received very little attention. Recently it has been shown that VEGF-A-induced adhesion and migration of human endothelial cells are dependent on 9β1 and that VEGF-A is a direct ligand for this integrin.122 Additionally, 9β1 integrin is able to mediate adhesion to activated endothelial cells119 and can interact with thrombospondin-1 to promote angiogenesis in microvascular endothelial cells. This in turn can be inhibited by the use of specific 9β1-blocking antibodies.123
7β1 Integrin
Although 7β1 integrin is expressed on VSMCs it has not been found on endothelial cells. 7β1 integrin deficiency results in partial embryonic lethality which is a consequence of reduced numbers, assembly and differentiation of VSMCs leading to incomplete cerebral vascularization, and cerebral hemorrhage.124 Surprisingly, unlike the embryonic phenotype, the surviving mice showed VSMC hyperplasia. In a more recent in vitro study 7β1 integrin expression levels and adhesion to laminin were shown to be elevated in the presence of a proangiogenic growth factor PDGF, suggesting a potential crosstalk between PDGF-receptors and 7β1 on VSMCs.125 To date, there has been no work on 7 integrin expression and pathological angiogenesis.
In general, the roles of integrins in angiogenesis are somewhat opposing but some are also overlapping, suggesting redundancy of integrin function in this process. However, it could well be the case that the angiogenic function of an integrin in one cell type is different to its function on another. Indeed, the different subtypes of endothelial cells, such as tip cells and stalk cells, have been shown to have different functions but their integrin and growth factor receptor profiles are still being elucidated. Thus, without a complete understanding of all the integrin functions, in individual cell subtypes it is presently impossible to claim that redundancy of integrin function exists.
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Endothelial Cells, Pericytes, and Antiangiogenic Therapy |
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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This review has highlighted the importance of endothelial and mural cell integrins in developmental angiogenesis and with respect to endothelial cell integrins, as regulators of tumor angiogenesis. Given the central role of integrins in angiogenesis and that the growth of solid tumors is dependent on neovascularization, these molecules provide a temptingly attractive target for antiangiogenic therapy. Of the 30 or more angiogenesis inhibitors in clinical trials for the treatment of cancer,126 the majority target endothelial cells, with a major subset targeting
vβ3 and vβ5 integrins, both of which are highly expressed on activated endothelial cells (Table 2). Currently, there are three classes of integrin inhibitors in preclinical and clinical trials: synthetic peptides including Cilengitide (vβ3/vβ5-antagonist; Merck KGaA); monoclonal antibodies such as Abergin (vβ3 antagonist [aka Vitaxin]; MedImmune), and peptidomimetics such as S247 (vβ3/vβ5-antagonist; Pfizer). Of all the drugs currently being tested, Vitaxin has been most widely used. Initial phase I clinical trials demonstrated that Vitaxin I was unsuccessful at inhibiting tumor growth,28 although the drug did show significant lack of toxicity in patients. The second generation of Vitaxin II was modified to give greater binding affinity to vβ3 but still produced no significant antitumor effect.127–129 In addition, Cilengitide is presently in phase I and II clinical trials for cancer therapy. Recent studies have shown that although Cilengitide has some efficacy in treatment of glioma its action appears to be more antitumor cell specific (because glioma cells express vβ3) rather than antiangiogenic. In addition, clinical trials in patients with other forms of cancer have been less promising.31,130 The lower than expected efficacy of vβ3/vβ5-antagonist in clinical trials raises important issues regarding a lack of understanding of the mechanisms of action of integrins in angiogenesis, diminishing their targeting potential in the treatment of various cancers. It is open to question whether these integrin antagonists target endothelial cells, tumor cells, or both.
First, are vβ3 and vβ5 integrin the best integrins to target? Their apparent elevated expression during neovascularization and the success of vβ3/vβ5-inhibitors in reducing angiogenesis in preclinical trials make them an attractive target, but, as this review has shown, other vascular integrins have the potential to be used as antiangiogenic targets with some currently being tested in clinical trials. For example, the 2β1 integrin-inhibitor, E7820 (Eisia Medical Research Inc), is presently in Phase I trials for lymphoma and Phase II trials for colorectal cancer and has shown to be effective at inhibiting tumor angiogenesis in a mouse model of cancer by specifically blocking 2 integrin expression on platelets.131,132 Other promising inhibitors currently in preclinical development include a blocking peptide for the 5β1 integrin.68 A humanized anti-5β1 antibody is also currently in Phase I trials for cancer.133 Furthermore, genetic ablation studies have revealed that vβ3 and vβ5 integrins are not required for pathological angiogenesis25 and in their absence endothelial cells express more Flk-1/VEGFR-2,33 suggesting a possible role for vβ3 as a regulator of VEGFR-2 expression. In addition, other studies have shown that other molecules including Del1 and tumstatin can also bind to vβ3 and either enhance134–136 or inhibit angiogenesis respectively.76,137–145 These results highlight the need to fully investigate the mechanisms of action of integrins in the regulation of angiogenesis and may go some way to explain why some antiangiogenic drugs have not been as successful as expected in clinical trials. It is also crucial to understand how dose efficacy affects angiogenesis because recent studies have shown that some inhibitors are agonists at low doses.47,146 Treatment of glioblastoma with Cilengitide has shown a response at both low and high doses, preventing any conclusive evidence as to the appropriate dose to use for future trials.31 Furthermore, because of the short plasma half-life of this drug (2.5 to 3 hours), it may be more important to determine the most suitable method and frequency for administering the drug, rather than the dose. Together, these data highlight the complex role integrins play in angiogenesis and how precise regulation of these, combined with pharmacokinetic data on antagonists, is essential.
The second issue involves monotherapy versus combined therapy. Integrin inhibition as a monotherapy has been shown to be relatively unsuccessful. Preclinical data have suggested that combination therapy, ie, combining antiangiogenic therapies with existing chemotherapy drugs, is more effective at reducing tumor growth. For example, Cilengitide in combination with gemcitabine, a wide spectrum anticancer drug, was used successfully in reducing tumor growth in a head and neck cancer patient.147 More recently, albeit at the preclinical stage, scientists have begun to experiment with combining three types of antiangiogenic treatment—chemotherapy, radiotherapy, and antiangiogenesis treatment—with greater success than mono- or combined therapy.148 Given the success of combination therapy to date, it is expected that many more tricombination trials will be initiated in the future and may provide the key to the successful treatment of different cancers.
Although the targeting of integrins on endothelial cells has proved to be relatively beneficial in preventing neovascularization of tumors, successful treatment of established tumors might require not only prevention of neovascularization but also destruction of existing tumor blood vessels to reduce an already existing tumor mass. This is important because cancer and other angiogenesis-dependent diseases are often diagnosed after blood vessels are established. For this reason, mural cells/pericytes are also being targeted for antiangiogenic therapy—targeting both their recruitment and interaction with endothelial cells. Several studies have shown that targeting endothelial cells by VEGFR-2 inhibition is not beneficial in regressing established tumor blood vessels, because of resistance of treatment conferred by the overlying pericytes,149 but combining VEGFR-2 inhibitors with PDGFR-β inhibitors (expressed by pericytes) resulted in regression of late-stage tumors,150 specific endothelial cell apoptosis, blood vessel destabilization and regression, and finally tissue hypoxia. Additionally, by targeting both cell types the hydrostatic pressure of the tumor vessels was reduced, allowing drug delivery to be increased151 and enhancing the effect of chemotherapy. Targeting of other specific markers expressed by pericytes, and which have shown to reduce angiogenesis, include the proteoglycan NG2152 and MMPs that are secreted by pericytes.153 In conclusion, recent findings have revealed the importance of pericytes in angiogenesis, which in turn has led to a new concept of antiangiogenic therapy: combined targeting of endothelial cells and pericytes to more efficiently decrease both blood vessel number and tumor growth and hopefully will provide a more effective mode of treatment for established tumors.
Overall, this review has described the important role performed by integrins in regulating endothelial cell behavior during angiogenesis. It also highlights the requirement to discover more about the roles of pericyte integrins and combine the knowledge from both systems when developing new antiangiogenic strategies.
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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Original received January 30, 2008; final version accepted July 14, 2008.
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References |
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TopAbstractIntroductionVitronectin Receptors...Fibronectin Receptors...Collagen Receptors...Laminin Receptors,...Endothelial Cells, Pericytes,...References |
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1. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007; 445: 776–780.[CrossRef][Medline] [Order article via Infotrieve]
2. Hynes RO, Lively JC, McCarty JH, Taverna D, Francis SE, Hodivala-Dilke K, Xiao Q. The diverse roles of integrins and their ligands in angiogenesis. Cold Spring Harb Symp Quant Biol. 2002; 67: 143–153.[CrossRef][Medline] [Order article via Infotrieve]
3. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992; 69: 11–25.[CrossRef][Medline] [Order article via Infotrieve]
4. van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res. 2001; 305: 285–298.[CrossRef][Medline] [Order article via Infotrieve]
5. Springer TA. Leucocyte adhesion to cells. Scand J Immunol. 1990; 32: 211–216.[CrossRef][Medline] [Order article via Infotrieve]
6. Albelda SM, Daise M, Levine EM, Buck CA. Identification and characterization of cell-substratum adhesion receptors on cultured human endothelial cells. J Clin Invest. 1989; 83: 1992–2002.[Medline] [Order article via Infotrieve]
7. Smith LL, Cheung HK, Ling LE, Chen J, Sheppard D, Pytela R, Giachelli CM. Osteopontin N-terminal domain contains a cryptic adhesive sequence recognized by alpha9beta1 integrin. J Biol Chem. 1996; 271: 28485–28491.
8. Gustafsson E, Fassler R. Insights into extracellular matrix functions from mutant mouse models. Exp Cell Res. 2000; 261: 52–68.[CrossRef][Medline] [Order article via Infotrieve]
9. Gustafsson E, Brakebusch C, Hietanen K, Fassler R. Tie-1-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. J Cell Sci. 2001; 114: 671–676.[Abstract]
10. Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol. 2001; 230: 230–242.[CrossRef][Medline] [Order article via Infotrieve]
11. Alva JA, Zovein AC, Monvoisin A, Murphy T, Salazar A, Harvey NL, Carmeliet P, Iruela-Arispe ML. VE-Cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells. Dev Dyn. 2006; 235: 759–767.[CrossRef][Medline] [Order article via Infotrieve]
12. Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fassler R, Betsholtz C. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development. 2004; 131: 1847–1857.
13. Monvoisin A, Alva JA, Hofmann JJ, Zovein AC, Lane TF, Iruela-Arispe ML. VE-cadherin-CreERT2 transgenic mouse: a model for inducible recombination in the endothelium. Dev Dyn. 2006; 235: 3413–3422.[CrossRef][Medline] [Order article via Infotrieve]
14. Bader BL, Rayburn H, Crowley D, Hynes RO. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell. 1998; 95: 507–519.[CrossRef][Medline] [Order article via Infotrieve]
15. McCarty JH, Monahan-Earley RA, Brown LF, Keller M, Gerhardt H, Rubin K, Shani M, Dvorak HF, Wolburg H, Bader BL, Dvorak AM, Hynes RO. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol. 2002; 22: 7667–7677.
16. McCarty JH, Lacy-Hulbert A, Charest A, Bronson RT, Crowley D, Housman D, Savill J, Roes J, Hynes RO. Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development. 2005; 132: 165–176.
17. Lacy-Hulbert A, Smith AM, Tissire H, Barry M, Crowley D, Bronson RT, Roes JT, Savill JS, Hynes RO. Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. Proc Natl Acad Sci USA. 2007; 104: 15823–15828.
18. Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994; 79: 1157–1164.[CrossRef][Medline] [Order article via Infotrieve]
19. Hammes HP, Brownlee M, Jonczyk A, Sutter A, Preissner KT. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat Med. 1996; 2: 529–533.[CrossRef][Medline] [Order article via Infotrieve]
20. Kumar CC, Malkowski M, Yin Z, Tanghetti E, Yaremko B, Nechuta T, Varner J, Liu M, Smith EM, Neustadt B, Presta M, Armstrong L. Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist. Cancer Res. 2001; 61: 2232–2238.
21. Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest. 1995; 96: 1815–1822.[Medline] [Order article via Infotrieve]
22. Eliceiri BP, Cheresh DA. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest. 1999; 103: 1227–1230.[Medline] [Order article via Infotrieve]
23. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Cullere M, Ross FP, Coller BS, Teitelbaum S, Hynes RO. Beta3 integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest. 1999; 103: 229–238.[Medline] [Order article via Infotrieve]
24. Huang X, Griffiths M, Wu J, Farese RV Jr, Sheppard D. Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol. 2000; 20: 755–759.
25. Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med. 2002; 8: 27–34.[CrossRef][Medline] [Order article via Infotrieve]
26. Max R, Gerritsen RR, Nooijen PT, Goodman SL, Sutter A, Keilholz U, Ruiter DJ, De Waal RM. Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer. 1997; 71: 320–324.[CrossRef][Medline] [Order article via Infotrieve]
27. Sepp NT, Li LJ, Lee KH, Brown EJ, Caughman SW, Lawley TJ, Swerlick RA. Basic fibroblast growth factor increases expression of the alpha v beta 3 integrin complex on human microvascular endothelial cells. J Invest Dermatol. 1994; 103: 295–299.[CrossRef][Medline] [Order article via Infotrieve]
28. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res. 2000; 6: 3056–3061.
29. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994; 264: 569–571.
30. Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995; 270: 1500–1502.
31. Nabors LB, Mikkelsen T, Rosenfeld SS, Hochberg F, Akella NS, Fisher JD, Cloud GA, Zhang Y, Carson K, Wittemer SM, Colevas AD, Grossman SA. Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol. 2007; 25: 1651–1657.
32. Mahabeleshwar GH, Feng W, Phillips DR, Byzova TV. Integrin signaling is critical for pathological angiogenesis. J Exp Med. 2006; 203: 2495–2507.
33. Reynolds AR, Reynolds LE, Nagel TE, Lively JC, Robinson SD, Hicklin DJ, Bodary SC, Hodivala-Dilke KM. Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3 integrin-deficient mice. Cancer Res. 2004; 64: 8643–8650.
34. Robinson SD, Reynolds LE, Wyder L, Hicklin DJ, Hodivala-Dilke KM. Beta3 integrin regulates vascular endothelial growth factor-A-dependent permeability. Arterioscler Thromb Vasc Biol. 2004; 24: 2108–2114.
35. Soldi R, Mitola S, Strasly M, Defilippi P, Tarone G, Bussolino F. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. Embo J. 1999; 18: 882–892.[CrossRef][Medline] [Order article via Infotrieve]
36. Mahabeleshwar GH, Feng W, Reddy K, Plow EF, Byzova TV. Mechanisms of integrin-vascular endothelial growth factor receptor cross-activation in angiogenesis. Circ Res. 2007; 101: 570–580.
37. Stupp R, Ruegg C. Integrin inhibitors reaching the clinic. J Clin Oncol. 2007; 25: 1637–1638.
38. Diaz-Gonzalez F, Forsyth J, Steiner B, Ginsberg MH. Trans-dominant inhibition of integrin function. Mol Biol Cell. 1996; 7: 1939–1951.[Abstract]
39. Hodivala-Dilke KM, DiPersio CM, Kreidberg JA, Hynes RO. Novel roles for alpha3beta1 integrin as a regulator of cytoskeletal assembly and as a trans-dominant inhibitor of integrin receptor function in mouse keratinocytes. J Cell Biol. 1998; 142: 1357–1369.
40. Hamano Y, Zeisberg M, Sugimoto H, Lively JC, Maeshima Y, Yang C, Hynes RO, Werb Z, Sudhakar A, Kalluri R. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell. 2003; 3: 589–601.[CrossRef][Medline] [Order article via Infotrieve]
41. Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol. 2001; 155: 459–470.
42. Lampugnani MG, Orsenigo F, Gagliani MC, Tacchetti C, Dejana E. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J Cell Biol. 2006; 174: 593–604.
43. Gampel A, Moss L, Jones MC, Brunton V, Norman JC, Mellor H. VEGF regulates the mobilization of VEGFR2/KDR from an intracellular endothelial storage compartment. Blood. 2006; 108: 2624–2631.
44. Roberts M, Barry S, Woods A, van der Sluijs P, Norman J. PDGF-regulated rab4-dependent recycling of alphavbeta3 integrin from early endosomes is necessary for cell adhesion and spreading. Curr Biol. 2001; 11: 1392–1402.[CrossRef][Medline] [Order article via Infotrieve]
45. White DP, Caswell PT, Norman JC. alpha v beta3 and alpha5beta1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration. J Cell Biol. 2007; 177: 515–525.
46. Friess H, Langrehr JM, Oettle H, Raedle J, Niedergethmann M, Dittrich C, Hossfeld DK, Stoger H, Neyns B, Herzog P, Piedbois P, Dobrowolski F, Scheithauer W, Hawkins R, Katz F, Balcke P, Vermorken J, van Belle S, Davidson N, Esteve AA, Castellano D, Kleeff J, Tempia-Caliera AA, Kovar A, Nippgen J. A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer. BMC Cancer. 2006; 6: 285.[CrossRef][Medline] [Order article via Infotrieve]
47. Legler DF, Wiedle G, Ross FP, Imhof BA. Superactivation of integrin alphavbeta3 by low antagonist concentrations. J Cell Sci. 2001; 114: 1545–1553.[Abstract]
48. Moyle M, Napier MA, McLean JW. Cloning and expression of a divergent integrin subunit beta 8. J Biol Chem. 1991; 266: 19650–19658.
49. Nishimura SL, Sheppard D, Pytela R. Integrin alpha v beta 8. Interaction with vitronectin and functional divergence of the beta 8 cytoplasmic domain. J Biol Chem. 1994; 269: 28708–28715.
50. Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, Sheppard D, Broaddus VC, Nishimura SL. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J Cell Biol. 2002; 157: 493–507.
51. Milner R, Relvas JB, Fawcett J, ffrench-Constant C. Developmental regulation of alphav integrins produces functional changes in astrocyte behavior. Mol Cell Neurosci. 2001; 18: 108–118.[CrossRef][Medline] [Order article via Infotrieve]
52. Venstrom K, Reichardt L. Beta 8 integrins mediate interactions of chick sensory neurons with laminin-1, collagen IV, and fibronectin. Mol Biol Cell. 1995; 6: 419–431.[Abstract]
53. Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. beta8 integrins are required for vascular morphogenesis in mouse embryos. Development. 2002; 129: 2891–2903.[Medline] [Order article via Infotrieve]
54. Abraham S, Kogata N, Fassler R, Adams RH. Integrin {beta}1 subunit controls mural cell adhesion, spreading, and blood vessel wall stability. Circ Res. 2008; 102: 562–570.
55. Carnevale E, Fogel E, Aplin AC, Gelati M, Howson KM, Zhu WH, Nicosia RF. Regulation of postangiogenic neovessel survival by beta1 and beta3 integrins in collagen and fibrin matrices. J Vasc Res. 2007; 44: 40–50.[CrossRef][Medline] [Order article via Infotrieve]
56. Fassler R, Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 1995; 9: 1896–1908.
57. Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA, Damsky CH. Deletion of beta 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev. 1995; 9: 1883–1895.
58. Bloch W, Forsberg E, Lentini S, Brakebusch C, Martin K, Krell HW, Weidle UH, Addicks K, Fassler R. Beta 1 integrin is essential for teratoma growth and angiogenesis. J Cell Biol. 1997; 139: 265–278.
59. Lei L, Liu D, Huang Y, Jovin I, Shai SY, Kyriakides T, Ross RS, Giordano FJ. Endothelial expression of beta1 integrin is required for embryonic vascular patterning and postnatal vascular remodeling. Mol Cell Biol. 2008; 28: 794–802.
60. Tanjore H, Zeisberg EM, Gerami-Naini B, Kalluri R. beta1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis. Dev Dyn. 2008; 237: 75–82.[CrossRef][Medline] [Order article via Infotrieve]
61. Yang JT, Rayburn H, Hynes RO. Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development. 1993; 119: 1093–1105.[Abstract]
62. Goh KL, Yang JT, Hynes RO. Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development. 1997; 124: 4309–4319.[Abstract]
63. Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, Hynes RO. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol. 2002; 22: 927–933.
64. Taverna D, Hynes RO. Reduced blood vessel formation and tumor growth in alpha5 integrin-negative teratocarcinomas and embryoid bodies. Cancer Res. 2001; 61: 5255–5261.
65. Parsons-Wingerter P, Kasman IM, Norberg S, Magnussen A, Zanivan S, Rissone A, Baluk P, Favre CJ, Jeffry U, Murray R, McDonald DM. Uniform overexpression and rapid accessibility of alpha5beta1 integrin on blood vessels in tumors. Am J Pathol. 2005; 167: 193–211.
66. Kim S, Bakre M, Yin H, Varner JA. Inhibition of endothelial cell survival and angiogenesis by protein kinase A. J Clin Invest. 2002; 110: 933–941.[CrossRef][Medline] [Order article via Infotrieve]
67. Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol. 2000; 156: 1345–1362.
68. Stoeltzing O, Liu W, Reinmuth N, Fan F, Parry GC, Parikh AA, McCarty MF, Bucana CD, Mazar AP, Ellis LM. Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer. 2003; 104: 496–503.[CrossRef][Medline] [Order article via Infotrieve]
69. Cianfrocca ME, Kimmel KA, Gallo J, Cardoso T, Brown MM, Hudes G, Lewis N, Weiner L, Lam GN, Brown SC, Shaw DE, Mazar AP, Cohen RB. Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH(2)), a beta integrin antagonist, in patients with solid tumours. Br J Cancer. 2006; 94: 1621–1626.[Medline] [Order article via Infotrieve]
70. Kuwada SK. Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. Curr Opin Mol Ther. 2007; 9: 92–98.[Medline] [Order article via Infotrieve]
71. Carlson TR, Feng Y, Maisonpierre PC, Mrksich M, Morla AO. Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem. 2001; 276: 26516–26525.
72. Orecchia A, Lacal PM, Schietroma C, Morea V, Zambruno G, Failla CM. Vascular endothelial growth factor receptor-1 is deposited in the extracellular matrix by endothelial cells and is a ligand for the alpha 5 beta 1 integrin. J Cell Sci. 2003; 116: 3479–3489.
73. Cascone I, Napione L, Maniero F, Serini G, Bussolino F. Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J Cell Biol. 2005; 170: 993–1004.
74. Hirschi KK, Rohovsky SA, D'Amore PA. PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol. 1998; 141: 805–814.
75. Kale S, Hanai J, Chan B, Karihaloo A, Grotendorst G, Cantley L, Sukhatme VP. Microarray analysis of in vitro pericyte differentiation reveals an angiogenic program of gene expression. Faseb J. 2005; 19: 270–271.
76. Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci USA. 2003; 100: 4766–4771.
77. Wickstrom SA, Alitalo K, Keski-Oja J. Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res. 2002; 62: 5580–5589.
78. Wayner EA, Garcia-Pardo A, Humphries MJ, McDonald JA, Carter WG. Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol. 1989; 109: 1321–1330.
79. Guan JL, Hynes RO. Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 1990; 60: 53–61.[CrossRef][Medline] [Order article via Infotrieve]
80. Mould AP, Wheldon LA, Komoriya A, Wayner EA, Yamada KM, Humphries MJ. Affinity chromatographic isolation of the melanoma adhesion receptor for the IIICS region of fibronectin and its identification as the integrin alpha 4 beta 1. J Biol Chem. 1990; 265: 4020–4024.
81. Ruegg C, Postigo AA, Sikorski EE, Butcher EC, Pytela R, Erle DJ. Role of integrin alpha 4 beta 7/alpha 4 beta P in lymphocyte adherence to fibronectin and VCAM-1 and in homotypic cell clustering. J Cell Biol. 1992; 117: 179–189.
82. Brezinschek RI, Brezinschek HP, Lazarovits AI, Lipsky PE, Oppenheimer-Marks N. Expression of the beta 7 integrin by human endothelial cells. Am J Pathol. 1996; 149: 1651–1660.[Abstract]
83. Sheppard AM, Onken MD, Rosen GD, Noakes PG, Dean DC. Expanding roles for alpha 4 integrin and its ligands in development. Cell Adhes Commun. 1994; 2: 27–43.[Medline] [Order article via Infotrieve]
84. Jin H, Su J, Garmy-Susini B, Kleeman J, Varner J. Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Res. 2006; 66: 2146–2152.
85. Hynes RO. Cell-matrix adhesion in vascular development. J Thromb Haemost. 2007; 5 Suppl 1: 32–40.[CrossRef][Medline] [Order article via Infotrieve]
86. Grazioli A, Alves CS, Konstantopoulos K, Yang JT. Defective blood vessel development and pericyte/pvSMC distribution in alpha 4 integrin-deficient mouse embryos. Dev Biol. 2006; 293: 165–177.[CrossRef][Medline] [Order article via Infotrieve]
87. Yang JT, Rayburn H, Hynes RO. Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development. 1995; 121: 549–560.[Abstract]
88. Garmy-Susini B, Jin H, Zhu Y, Sung RJ, Hwang R, Varner J. Integrin alpha4beta1-VCAM-1-mediated adhesion between endothelial and mural cells is required for blood vessel maturation. J Clin Invest. 2005; 115: 1542–1551.[CrossRef][Medline] [Order article via Infotrieve]
89. Gurtner GC, Davis V, Li H, McCoy MJ, Sharpe A, Cybulsky MI. Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev. 1995; 9: 1–14.
90. Priestley GV, Ulyanova T, Papayannopoulou T. Sustained alterations in biodistribution of stem/progenitor cells in Tie2Cre+ alpha4(f/f) mice are hematopoietic cell autonomous. Blood. 2007; 109: 109–111.
91. Jin H, Aiyer A, Su J, Borgstrom P, Stupack D, Friedlander M, Varner J. A homing mechanism for bone marrow-derived progenitor cell recruitment to the neovasculature. J Clin Invest. 2006; 116: 652–662.[CrossRef][Medline] [Order article via Infotrieve]
92. O'Connor P. Natalizumab and the role of alpha 4 integrin antagonism in the treatment of multiple sclerosis. Expert Opin Biol Ther. 2007; 7: 123–136.[CrossRef][Medline] [Order article via Infotrieve]
93. MacDonald JK, McDonald JW. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2007: CD006097.
94. Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci USA. 1997; 94: 13612–13617.
95. Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol. 2002; 160: 195–204.
96. Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP, Lobb RR. Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res. 2003; 63: 2020–2023.
97. Gardner H, Kreidberg J, Koteliansky V, Jaenisch R. Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol. 1996; 175: 301–313.[CrossRef][Medline] [Order article via Infotrieve]
98. Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci USA. 2000; 97: 2202–2207.
99. Zhang Z, Ramirez NE, Yankeelov TE, Li Z, Ford LE, Qi Y, Pozzi A, Zutter MM. alpha2beta1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner. Blood. 2008; 111: 1980–1988.
100. Zhou Z, Doi M, Wang J, Cao R, Liu B, Chan KM, Kortesmaa J, Sorokin L, Cao Y, Tryggvason K. Deletion of laminin-8 results in increased tumor neovascularization and metastasis in mice. Cancer Res. 2004; 64: 4059–4063.
101. Chandrasekaran L, He CZ, Al-Barazi H, Krutzsch HC, Iruela-Arispe ML, Roberts DD. Cell contact-dependent activation of alpha3beta1 integrin modulates endothelial cell responses to thrombospondin-1. Mol Biol Cell. 2000; 11: 2885–2900.
102. Yanez-Mo M, Alfranca A, Cabanas C, Marazuela M, Tejedor R, Ursa MA, Ashman LK, de Landazuri MO, Sanchez-Madrid F. Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol. 1998; 141: 791–804.
103. Seo DW, Li H, Guedez L, Wingfield PT, Diaz T, Salloum R, Wei BY, Stetler-Stevenson WG. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell. 2003; 114: 171–180.[CrossRef][Medline] [Order article via Infotrieve]
104. Borza CM, Pozzi A, Borza DB, Pedchenko V, Hellmark T, Hudson BG, Zent R. Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3. J Biol Chem. 2006; 281: 20932–20939.
105. Boosani CS, Mannam AP, Cosgrove D, Silva R, Hodivala-Dilke KM, Keshamouni VG, Sudhakar A. Regulation of COX-2 mediated signaling by alpha3 type IV noncollagenous domain in tumor angiogenesis. Blood. 2007; 110: 1168–1177.
106. Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC, Jaenisch R. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development. 1996; 122: 3537–3547.[Abstract]
107. DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO. alpha3beta1 Integrin is required for normal development of the epidermal basement membrane. J Cell Biol. 1997; 137: 729–742.
108. Lillo AM, Sun C, Gao C, Ditzel H, Parrish J, Gauss CM, Moss J, Felding-Habermann B, Wirsching P, Boger DL, Janda KD. A human single-chain antibody specific for integrin alpha3beta1 capable of cell internalization and delivery of antitumor agents. Chem Biol. 2004; 11: 897–906.[CrossRef][Medline] [Order article via Infotrieve]
109. Furrer J, Luy B, Basrur V, Roberts DD, Barchi JJ Jr. Conformational analysis of an alpha3beta1 integrin-binding peptide from thrombospondin-1: implications for antiangiogenic drug design. J Med Chem. 2006; 49: 6324–6333.[CrossRef][Medline] [Order article via Infotrieve]
110. Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet. 1996; 13: 370–373.[CrossRef][Medline] [Order article via Infotrieve]
111. Dowling J, Yu QC, Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol. 1996; 134: 559–572.
112. van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet. 1996; 13: 366–369.[CrossRef][Medline] [Order article via Infotrieve]
113. Nikolopoulos SN, Blaikie P, Yoshioka T, Guo W, Giancotti FG. Integrin beta4 signaling promotes tumor angiogenesis. Cancer Cell. 2004; 6: 471–483.[CrossRef][Medline] [Order article via Infotrieve]
114. Hiran TS, Mazurkiewicz JE, Kreienberg P, Rice FL, LaFlamme SE. Endothelial expression of the alpha6beta4 integrin is negatively regulated during angiogenesis. J Cell Sci. 2003; 116: 3771–3781.
115. Leu SJ, Lam SC, Lau LF. Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cells. J Biol Chem. 2002; 277: 46248–46255.
116. Leu SJ, Liu Y, Chen N, Chen CC, Lam SC, Lau LF. Identification of a novel integrin alpha 6 beta 1 binding site in the angiogenic inducer CCN1 (CYR61). J Biol Chem. 2003; 278: 33801–33808.
117. Lee TH, Seng S, Li H, Kennel SJ, Avraham HK, Avraham S. Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis. J Biol Chem. 2006; 281: 40450–40460.
118. Yokosaki Y, Monis H, Chen J, Sheppard D. Differential effects of the integrins alpha9beta1, alphavbeta3, and alphavbeta6 on cell proliferative responses to tenascin. Roles of the beta subunit extracellular and cytoplasmic domains. J Biol Chem. 1996; 271: 24144–24150.
119. Taooka Y, Chen J, Yednock T, Sheppard D. The integrin alpha9beta1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1. J Cell Biol. 1999; 145: 413–420.
120. Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV Jr, Sheppard D. Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol. 2000; 20: 5208–5215.
121. Vlahakis NE, Young BA, Atakilit A, Sheppard D. The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J Biol Chem. 2005; 280: 4544–4552.
122. Vlahakis NE, Young BA, Atakilit A, Hawkridge AE, Issaka RB, Boudreau N, Sheppard D. Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis. J Biol Chem. 2007; 282: 15187–15196.
123. Staniszewska I, Zaveri S, Del Valle L, Oliva I, Rothman VL, Croul SE, Roberts DD, Mosher DF, Tuszynski GP, Marcinkiewicz C. Interaction of alpha9beta1 integrin with thrombospondin-1 promotes angiogenesis. Circ Res. 2007; 100: 1308–1316.
124. Flintoff-Dye NL, Welser J, Rooney J, Scowen P, Tamowski S, Hatton W, Burkin DJ. Role for the alpha7beta1 integrin in vascular development and integrity. Dev Dyn. 2005; 234: 11–21.[CrossRef][Medline] [Order article via Infotrieve]
125. Chao JT, Martinez-Lemus LA, Kaufman SJ, Meininger GA, Ramos KS, Wilson E. Modulation of alpha7 integrin-mediated adhesion and expression by platelet-derived growth factor in vascular smooth muscle cells. Am J Physiol Cell Physiol. 2006; 290: C972–C980.
126. Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007; 6: 273–286.[CrossRef][Medline] [Order article via Infotrieve]
127. Patel SR, Jenkins J, Papadopolous N, Burgess MA, Plager C, Gutterman J, Benjamin RS. Pilot study of vitaxin-an angiogenesis inhibitor-in patients with advanced leiomyosarcomas. Cancer. 2001; 92: 1347–1348.[CrossRef][Medline] [Order article via Infotrieve]
128. Posey JA, Khazaeli MB, DelGrosso A, Saleh MN, Lin CY, Huse W, LoBuglio AF. A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. Cancer Biother Radiopharm. 2001; 16: 125–132.[CrossRef][Medline] [Order article via Infotrieve]
129. Mulgrew K, Kinneer K, Yao XT, Ward BK, Damschroder MM, Walsh B, Mao SY, Gao C, Kiener PA, Coats S, Kinch MS, Tice DA. Direct targeting of alphavbeta3 integrin on tumor cells with a monoclonal antibody, Abegrin. Mol Cancer Ther. 2006; 5: 3122–3129.
130. Eskens FA, Dumez H, Hoekstra R, Perschl A, Brindley C, Bottcher S, Wynendaele W, Drevs J, Verweij J, van Oosterom AT. Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer. 2003; 39: 917–926.[CrossRef][Medline] [Order article via Infotrieve]
131. Funahashi Y, Sugi NH, Semba T, Yamamoto Y, Hamaoka S, Tsukahara-Tamai N, Ozawa Y, Tsuruoka A, Nara K, Takahashi K, Okabe T, Kamata J, Owa T, Ueda N, Haneda T, Yonaga M, Yoshimatsu K, Wakabayashi T. Sulfonamide derivative, E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin alpha2 subunit on endothelium. Cancer Res. 2002; 62: 6116–6123.
132. Semba T, Funahashi Y, Ono N, Yamamoto Y, Sugi NH, Asada M, Yoshimatsu K, Wakabayashi T. An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker. Clin Cancer Res. 2004; 10: 1430–1438.
133. Jin H, Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004; 90: 561–565.[CrossRef][Medline] [Order article via Infotrieve]
134. Byzova TV, Plow EF. Activation of alphaVbeta3 on vascular cells controls recognition of prothrombin. J Cell Biol. 1998; 143: 2081–2092.
135. Aoka Y, Johnson FL, Penta K, Hirata Ki K, Hidai C, Schatzman R, Varner JA, Quertermous T. The embryonic angiogenic factor Del1 accelerates tumor growth by enhancing vascular formation. Microvasc Res. 2002; 64: 148–161.[CrossRef][Medline] [Order article via Infotrieve]
136. Xu J, Rodriguez D, Petitclerc E, Kim JJ, Hangai M, Moon YS, Davis GE, Brooks PC. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol. 2001; 154: 1069–1079.
137. Lawler J. The functions of thrombospondin-1 and -2. Curr Opin Cell Biol. 2000; 12: 634–640.[CrossRef][Medline] [Order article via Infotrieve]
138. Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest. 1998; 101: 982–992.[Medline] [Order article via Infotrieve]
139. Adams JC. Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol. 2001; 17: 25–51.[CrossRef][Medline] [Order article via Infotrieve]
140. Kyriakides TR, Zhu YH, Smith LT, Bain SD, Yang Z, Lin MT, Danielson KG, Iozzo RV, LaMarca M, McKinney CE, Ginns EI, Bornstein P. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis. J Cell Biol. 1998; 140: 419–430.
141. Rehn M, Veikkola T, Kukk-Valdre E, Nakamura H, Ilmonen M, Lombardo C, Pihlajaniemi T, Alitalo K, Vuori K. Interaction of endostatin with integrins implicated in angiogenesis. Proc Natl Acad Sci USA. 2001; 98: 1024–1029.
142. Tarui T, Miles LA, Takada Y. Specific interaction of angiostatin with integrin alpha(v)beta(3) in endothelial cells. J Biol Chem. 2001; 276: 39562–39568.
143. Maeshima Y, Colorado PC, Kalluri R. Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties. J Biol Chem. 2000; 275: 23745–23750.
144. Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science. 2002; 295: 140–143.
145. Maeshima Y, Yerramalla UL, Dhanabal M, Holthaus KA, Barbashov S, Kharbanda S, Reimer C, Manfredi M, Dickerson WM, Kalluri R. Extracellular matrix-derived peptide binds to alpha(v) beta(3) integrin and inhibits angiogenesis. J Biol Chem. 2001; 276: 31959–31968.
146. Du XP, Plow EF, Frelinger AL III, O'Toole TE, Loftus JC, Ginsberg MH. Ligands "activate" integrin alpha IIb beta 3 (platelet GPIIb-IIIa). Cell. 1991; 65: 409–416.[CrossRef][Medline] [Order article via Infotrieve]
147. Raguse JD, Gath HJ, Bier J, Riess H, Oettle H. Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. Oral Oncol. 2004; 40: 228–230.[CrossRef][Medline] [Order article via Infotrieve]
148. Huber PE, Bischof M, Jenne J, Heiland S, Peschke P, Saffrich R, Grone HJ, Debus J, Lipson KE, Abdollahi A. Trimodal cancer treatment: beneficial effects of combined antiangiogenesis, radiation, and chemotherapy. Cancer Res. 2005; 65: 3643–3655.
149. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. Faseb J. 2004; 18: 338–340.
150. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003; 111: 1287–1295.[CrossRef][Medline] [Order article via Infotrieve]
151. Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004; 64: 3731–3736.
152. Ozerdem U, Stallcup WB. Pathological angiogenesis is reduced by targeting pericytes via the NG2 proteoglycan. Angiogenesis. 2004; 7: 269–276.[CrossRef][Medline] [Order article via Infotrieve]
153. Chantrain CF, Henriet P, Jodele S, Emonard H, Feron O, Courtoy PJ, DeClerck YA, Marbaix E. Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer. 2006; 42: 310–318.[CrossRef][Medline] [Order article via Infotrieve]
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