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Results for “Integrin alphaVbeta3”

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At least 919 records · Page 51Linked to original sources
PubMed2003

Specific alpha v integrin receptors modulate K1735 murine melanoma cell behavior.

Expression of beta 3 integrins is increased in invasive melanoma. In this study we show that K1735 cell proliferation is enhanced by the expression of either beta 3 or a constitutively active Src. We investigated possible modulators of FN matrix assembly and found that matrix metalloproteinase 2 (MMP2) was activated by alpha v beta 3. alpha v beta 3 integrin was localized to focal contacts whereas alpha v beta 5 was peripherally distributed. MMP2 was also activated by expression of CASrc. MMP2 activation inversely correlated with FN matrix assembly, in that it dramatically reduced the organization of a FN matrix. K1735 cell migration on VN and invasion through a reconstituted basement membrane were decreased in the presence of anti-MMP2 antibodies. These results demonstrate that the expression of the alpha v beta 3 complex modulates melanoma cell behavior including activation of Src, organization of the cytoskeleton, assembly of the extracellular matrix, cell motility, and activation of MMP2.

Animals↗
PubMed2002

In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation.

In order to determine whether 5-[bis(carboxymethyl) amino]-2-carboxy4-cyano-3-thiopheneacetic acid distrontium salt (S12911-2) inhibits bone resorption by acting on the differentiation and/or function of osteoclasts, its effects were assessed on the 1,25-dihydroxyvitamin D(3)-induced expression of carbonic anhydrase II and vitronectin receptor in chicken bone marrow cells, and on the resorbing activity of authentic rat osteoclasts cultured on bone slices. S12911-2 dose-dependently inhibited, after a 6-day exposure, the expression of carbonic anhydrase II and vitronectin receptor in stimulated osteoclasts (46% and 40%, respectively, at 10(-3) M Sr(2+), P<0.05). A pre-incubation of bone slices with S12911-2 induced a dose-dependent inhibition of bone resorbing activity from 32% at 10(-4) M Sr(2+) to 66% at 10(-3) M Sr(2+) (P<0.05 in each case). A continuous incubation (10(-3) M Sr(2+)) induced a greater inhibition of bone resorbing activity (73%, P<0.05). The inhibition of bone resorption obtained specifically with S12911-2 is related to an inhibition of the differentiation and resorbing activity of the osteoclasts.

Analysis of Variance↗
PubMed2003

High flow drives vascular endothelial cell proliferation during flow-induced arterial remodeling associated with the expression of vascular endothelial growth factor.

Endothelial cell activation and proliferation are the essential steps in flow-induced arterial remodeling. We investigated endothelial cell turnover in the early stages of high-flow in the rabbit common carotid arteries using an arteriovenous fistula (AVF) model by kinetic investigation of cell proliferation and cell molecular analysis. BrdU was administrated to label endothelial cells (ECs) in DNA synthetic phase (S-phase) of the cell mitotic cycle. Pulse labeling revealed that ECs entered S-phase at 1.5 days of AVF (0.93 +/- 0.19%). Endothelial cell labeling index (EC-LI) peaked at 2 days of AVF (8.90 +/- 0.87%) with a high index of endothelial cell mitosis (EC-MI, 1.67 +/- 0.47%). Endothelial cell density increased remarkably at 3 days of AVF with a significant decrease in EC-LI (54%) and EC-MI (60%). Study of kinetics of EC proliferation revealed that endothelial cells took 16-24 h to finish one cycle of cell mitosis. Tracking investigation of pulse BrdU-labeled endothelial cells at 1.5 days showed that more than 66% of endothelial cells were BrdU-labeled 1.5 days after labeling. VEGF, integrin alphanubeta3, PECAM-1, and VE-cadherin were upregulated significantly preceding endothelial cell proliferation and kept at high levels during endothelial cell proliferation. These data suggest that endothelial cell proliferation is the initial step in flow-induced arterial remodeling. Hemodynamic forces may drive endothelial cell downstream migration. Expression of VEGF and cell junction molecules contribute to flow-induced arterial remodeling.

Animals↗
PubMed2003

Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability.

Disintegrins, the snake venom-derived arginine-glycine-aspartic acid-containing peptides, have been demonstrated to inhibit angiogenesis through induction of endothelial cell apoptosis. However, it is not clear how a disintegrin causes endothelial apoptosis. In this study, we elucidated the action mechanism of disintegrin in causing endothelial apoptosis by using rhodostomin as a tool. We showed that cell detachment was observed at the early stage of rhodostomin treatment. It was initiated through the blockade by integrin alphanubeta3 and was accelerated by a mechanical stretch from neighboring cells. Both rhodostomin and poly(HEME) induced a higher percentage of cells at G2-M phase, the cleavage of beta-catenin and poly(ADP-ribose) polymerase during apoptosis, indicating that cell detachment is a prerequisite for rhodostomin-induced apoptosis. Moreover, pp125(FAK) phosphorylation and actin cytoskeleton were affected upon rhodostomin treatment. The activation of caspase-3 but not that of caspase-9 was detected after rhodostomin treatment. In addition, general caspase inhibitors inhibited the cleavage of beta-catenin and poly(ADP-ribose) polymerase, and DNA fragmentation, whereas they did not prevent cell shape change or detachment. According to these results, we concluded that disintegrin-induced endothelial apoptosis is a complex process, not merely caused by a blockade of endothelial integrin alphanubeta3 but also by an accompanied shape change and mechanical stretches among cells.

Actins↗
PubMed2002

Factor XIII mediates adhesion of platelets to endothelial cells through alpha(v)beta(3) and glycoprotein IIb/IIIa integrins.

Coagulation factor XIII (FXIII) is a transglutaminase that catalyzes crosslink formation in fibrin clots. Endothelial cells (EC) were demonstrated to bind FXIII via their alpha(v)beta3 integrin receptor. FXIII was also shown to bind platelet glycoprotein IIb/IIIa receptor. In the present study, we analyzed if FXIII can mediate platelet-EC interaction. Both FXIII and activated FXIII (FXIIIa) bound to EC monolayers; this binding was enhanced by the addition of Mn2+ and was inhibited by the monoclonal antibody L609 against alpha(v)beta3 integrin. Normal washed platelets also bound surface-immobilized or soluble FXIII and FXIIIa, and the binding was GPIIb/IIIa dependent. The effect of FXIII concentrate (Fibrogammin-P) treatment on the interaction of ECs with platelets from six FXIII-deficient patients was studied. Patients' platelets were radiolabeled with 3H-Adenine, washed, resuspended in autologous plasma and allowed to adhere to immortalized EC line EAhy926. Adhesion of platelets from FXIII-deficient patients to ECs increased 1.7+/-0.4-fold (P=.01) following intravenous infusion of FXIII concentrate. Similarly, addition of 1 U/ml of FXIII concentrate to the patients' PRP in vitro increased the adhesion 1.8+/-0.5-fold (P=.008). Preincubation of the EC monolayers with increasing concentrations of either FXIII or FXIIIa augmented the adhesion of normal washed platelets to ECs in a dose-dependent manner. At 10 U/ml of EC-bound FXIII or FXIIIa, platelet adhesion enhanced 1.7+/-0.25-fold (P=.03) and 2.5+/-0.5-fold (P=.02), respectively. The increase in platelet adhesion was completely abolished by pretreatment of ECs with the anti-alpha(v)beta3 antibody L609 or by preincubation of the platelets with the GPIIb/IIIa inhibitor Abciximab. Taken together, our data indicate that FXIII mediates the interaction of platelets with ECs by bridging between endothelial alpha(v)beta3 and platelet GPIIb/IIIa integrins. This interaction may be relevant for tissue remodeling and wound repair after vascular injury in FXIII-deficient patients.

Cell Line↗
PubMed2002

Angiogenesis as a target for cancer therapy.

Antiangiogenic drugs are unique for having highly specific targets while carrying the potential to be effective against a wide variety of tumors. Moreover, some of the major limitations of cytotoxic therapies likely will be avoided by this entirely new class of anticancer weapons. After the realization of the potential advantages of antiangiogenic therapy, the field of angiogenesis research is growing exponentially. Still, there is much to learn about the machinery that tumors use to recruit new blood vessels, and the results of the clinical trials will show the best way to apply that knowledge for cancer therapy.

Angiogenesis Inhibitors↗
PubMed2003

Illuminating adhesion complexes in migrating cells: moving toward a bright future.

Cell migration is a complex, tightly regulated process that involves the continuous formation and disassembly of adhesions. Despite the importance of these processes, very little is known about the factors that regulate adhesion dynamics during migration. Recent advances in imaging technologies are allowing monitoring of these processes during migration and are providing insight into the mechanisms that regulate them.

Animals↗
PubMed2002

Non-peptide alpha(v)beta(3) antagonists. Part 4: potent and orally bioavailable chain-shortened RGD mimetics.

Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors.

Administration, Oral↗
PubMed2003

Thiophene-based vitronectin receptor antagonists.

A series of alpha(v)beta(3) antagonists based on a thiophene scaffold were synthesized via two routes and evaluated for in vitro biological activity. We have identified several structurally similar antagonists with different selectivities towards alpha(IIb)beta(3), alpha(v)beta(5) and alpha(5)beta(1) at the cellular level. In addition, these antagonists exerted an antiangiogenic effect in the chick chorioallantoic membrane (CAM) assay.

Angiogenesis Inhibitors↗
PubMed2003

Biphenyls as potent vitronectin receptor antagonists. Part 2: biphenylalanine ureas.

Vitronectin receptor (alpha(V)beta(3)) antagonism has been implicated in a variety of disease states, like restenosis, osteoporosis and cancer. In this work, we present the development of a novel class of biphenyl vitronectin receptor antagonists. Identified from a focused combinatorial library based on para-bromo phenylalanine, these compounds show nanomolar affinity to the vitronectin receptor and display unprecedented SAR. Their binding mode can be rationalized by computational docking studies using the X-ray structure of alpha(V)beta(3).

Biphenyl Compounds↗
PubMed2002

Incorporation of (2S,3S) and (2S,3R) beta-methyl aspartic acid into RGD-containing peptides.

We report the synthesis and biological activity of a series of side-chain-constrained RGD peptides containing the (2S,3R) or (2S,3S) beta-methyl aspartic acid within the RGD sequence. These compounds have been assayed for binding to the integrin receptors alpha(IIb)beta3 and alpha(v)beta3 and the results demonstrate the importance of the side-chain orientation of this particular residue within the RGD sequence. Based on our findings, the (2S,3S) beta-methylated analogues of our RGD sequences maintain their binding potency to the integrin receptors while the (2S,3R) beta-methylated analogues exhibit a drastically reduced binding affinity. Our studies demonstrate that the three-dimensional orientation of the aspartyl side chain is a very important parameter for integrin binding and that small changes that affect the side-chain orientations give rise to drastic changes in binding affinity. These results provide important information for the design of more potent RGD mimetics.

Aspartic Acid↗
PubMed2003

Direct electrophilic radiofluorination of a cyclic RGD peptide for in vivo alpha(v)beta3 integrin related tumor imaging.

The association of the alpha(v)beta(3) integrin with tumor metastasis and tumor related angiogenesis has been suggested. Therefore, by imaging the alpha(v)beta(3) receptor with PET, information concerning the tumor status could be obtained. Cyclic peptides including the RGD sequence, were radiolabeled by direct electrophilic fluorination with [(18)F]AcOF. In tumor-bearing mice, the labeled peptides accumulated at the tumor with a high tumor to blood ratio. These findings suggest that an assessment of tumor characteristics may be obtained by using these (18)F-labeled peptides.

Acetates↗
PubMed2003

Nanoparticle-mediated gene delivery to tumour neovasculature.

The alpha(v)beta(3) integrin is a potential pharmacological target for anti-angiogenic therapy. A recent report describes the use of alpha(v)beta(3)-targeted nanoparticles to deliver a gene to tumour vasculature selectively. This resulted in substantial tumour regression in several experimental mouse tumour models. Hence, this approach has great potential for the treatment of human cancer.

Angiogenesis Inhibitors↗
PubMed2002

Antiangiogenics meet nanotechnology.

A mutant Raf-1 gene loaded onto nanoparticles, delivered to tumor vasculature with an integrin binding compound, provides effective antiangiogenic gene therapy in mice.

Animals↗
PubMed2004

Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.

Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in metastatic tumors. Periostin expression dramatically enhanced metastatic growth of colon cancer by both preventing stress-induced apoptosis in the cancer cells and augmenting endothelial cell survival to promote angiogenesis. At the molecular level, periostin activated the Akt/PKB signaling pathway through the alpha(v)beta(3) integrins to increase cellular survival. These data demonstrated that the survival-promoting function is crucial for periostin to promote tumor metastasis of colon cancer.

Animals↗