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PubMed2005

Interaction between integrin alpha(5) and fibronectin is required for metastasis of B16F10 melanoma cells.

In this study, we report the role of integrin alpha(5) in promoting melanoma metastasis. The alpha(5) expression was remarkably elevated in highly metastatic B16F10 melanoma cells compared to lowly metastatic B16F1 cells, whereas no significant changes were detected in those of integrin alpha(4), alpha(v), and beta(1) subunits. Neutralization of alpha(5) with anti-alpha(5) antibody significantly suppressed the potential of B16F10 cells for pulmonary metastasis in mice and inhibited cell adhesion or spreading to fibronectin in vitro. Furthermore, loss of the interaction between alpha(5) and fibronectin diminished cell survival and induced apoptosis in B16F10 cells. Above results provide clear evidence that integrin alpha(5) is positively correlated with melanoma metastasis and might be an anti-melanoma target.

Animals↗
PubMed2005

Integrinalpha5 and delta/notch signaling have complementary spatiotemporal requirements during zebrafish somitogenesis.

Somitogenesis is the process by which the segmented precursors of the skeletal muscle and vertebral column are generated during vertebrate embryogenesis. While somitogenesis appears to be a serially homologous, reiterative process, we find that there are differences between the genetic control of early/anterior and late/posterior somitogenesis. We demonstrate that point mutations can cause segmentation defects in either the anterior, middle, or posterior somites in the zebrafish. We find that mutations in zebrafish integrinalpha5 disrupt anterior somite formation, giving a phenotype complementary to the posterior defects seen in the notch pathway mutants after eight/deltaD and deadly seven/notch1a. Double mutants between the notch pathway and integrinalpha5 display somite defects along the entire body axis, with a complete loss of the mesenchymal-to-epithelial transition and Fibronectin matrix assembly in the posterior. Our data suggest that notch- and integrinalpha5-dependent cell polarization and Fibronectin matrix assembly occur concomitantly and interdependently during border morphogenesis.

Amino Acid Sequence↗
PubMed2005

Integrinalpha5-dependent fibronectin accumulation for maintenance of somite boundaries in zebrafish embryos.

Boundary formation and epithelialization are crucial processes in the morphological segmentation of vertebrate somites. By a genetic screening procedure with zebrafish, we identified two genes, integrinalpha5 (itga5) and fibronectin (fn), required for these processes. Fibronectin proteins accumulate at somite boundaries in accordance with epithelialization of the somites. Both Fibronectin accumulation and the epithelialization are dependent on itga5, which is expressed in the most medial part of somites. Although somite boundaries are initially formed, but not maintained, in the anterior trunk of the mutant embryos deficient in either gene, their maintenance is defective at all axial levels of embryos deficient for both of these genes. Therefore, Integrinalpha5-directed assembly of Fibronectin appears critical for epithelialization and boundary maintenance of somites. Furthermore, with an additional deficiency in ephrin-B2a, the segmental defect in itga5 or fn mutant embryos is expanded posteriorly, indicating that both Integrin-Fibronectin and Eph-Ephrin systems function cooperatively in maintaining somite boundaries.

Animals↗
PubMed2005

alpha(v)beta(3) Integrin in central nervous system tumors.

alpha(v)beta(3) Is an integrin specifically expressed in endothelial cells of newly forming blood vessels. Integrin-mediated angiogenesis is hypothesized to play a central role in the development and the progression of central nervous system neoplasms. Accordingly, it is considered a potential target for antiangiogenic therapy. In the current study, we compare the expression of alpha(v)beta(3) in ependymomas, oligodendrogliomas, pilocytic astrocytomas, medulloblastomas, and vestibular schwannomas (acoustic neuromas). Samples of 5 tumors of each of the 5 tumor types were harvested surgically and frozen. After the pathological diagnosis was confirmed, immunohistochemistry was performed using an anti- alpha(v)beta(3) monoclonal antibody (LM609). The expression of alpha(v)beta(3) was assessed using a 4-tiered (0-3) grading scheme reflecting the percentage of positively staining vessels. All vestibular schwannomas demonstrated strong (grade 3) alpha(v)beta(3) expression. The expression was uniformly prominent in Antoni B regions of the tumors. Of 5 ependymomas, 4 demonstrated uniformly strong alpha(v)beta(3). Oligodendrogliomas, medulloblastomas, and pilocytic astrocytomas demonstrated more variable alpha(v)beta(3). alpha(v)beta(3) may contribute significantly to angiogenesis in vestibular schwannomas and ependymomas. Despite the high vascular density of oligodendrogliomas, pilocytic astrocytomas, and medulloblastomas, these tumors had variable moderate alpha(v)beta(3) expression. This discrepancy suggests temporal and/or regional variability in the angiogenesis in these types of tumor. This study provides the first demonstration of alpha(v)beta(3) expression in vestibular schwannomas, medulloblastomas, and pilocytic astrocytomas.

Astrocytoma↗
PubMed2003

Blocking of alpha 5 integrin stimulates production of TGF-beta and PAI-1 by human mesangial cells.

Expression of integrin, which mediates cell-matrix interaction, is affected by several cytokines, in particular by transforming growth factor-beta (TGF-beta). However, it is unknown whether, in an opposite way, a specific integrin is involved in cytokine synthesis. We tested this hypothesis. Function-blocking anti-alpha 5 integrin (fibronectin receptor) antibody increased TGF-beta secretion in growth-arrested human mesangial cells (2.3-fold) compared with control IgG or anti-alpha v beta 3 integrin (receptor for several matrix proteins) antibody. It also increased the secretion of plasminogen activator inhibitor-1 (PAI-1), a protein associated with matrix increase, by 3.2-fold. The increase in PAI-1 secretion induced by anti-alpha 5 integrin antibody was not abrogated by anti-TGF-beta neutralizing antibody. These results indicate that function-blocking of anti-alpha 5 integrin stimulates TGF-beta as well as PAI-1 production, suggesting that alpha 5 integrin is involved in fibrotic process. Function-modulation of a specific integrin thus appears to play a role in glomerular remodeling.

Antibodies↗
PubMed1998

Prevention of arterial structural alterations with verapamil and trandolapril and consequences for mechanical properties in spontaneously hypertensive rats.

We compared the chronic effects in spontaneously hypertensive rats (SHR) of low doses of an angiotensin converting enzyme inhibitor, trandolapril, a Ca2+ channel antagonist, verapamil, and their combination (trandolapril-verapamil), on arterial mechanical properties, arterial wall hypertrophy and extracellular matrix proteins. Four-week-old SHR were randomly allocated to oral treatment with verapamil (50 mg kg(-1) day(-1)), trandolapril (0.3 mg kg(-1) day(-1)), the combination of verapamil (50 mg kg(-1) day(-1)) plus trandolapril (0.3 mg kg(-1) day(-1)), or placebo for 4 months. A group of Wistar Kyoto (WKY) control rats received placebo for the same period of time. At the end of the treatment, mean blood pressure was lower in verapamil-trandolapril than in trandolapril SHR, but remained higher than in WKY. Verapamil had no effects on blood pressure. Equivalent reduction in aortic wall hypertrophy was obtained in all treated SHR. Trandolapril and verapamil-trandolapril combination produced a significant reduction of aortic collagen density compared with placebo SHR. Carotid total fibronectin, EIIIA fibronectin isoform and alpha5beta1 integrin, were higher in the media of placebo SHR than in WKY. EIIIA fibronectin isoform and alpha5beta1 integrin were reduced in verapamil-SHR compared with placebo-SHR and normalized in trandolapril and verapamil-trandolapril-SHR compared with WKY. SHR-placebo and SHR treated with either verapamil or trandolapril as single-drug treatment showed a 4-fold increase in total fibronectin compared to the WKY. Only SHR treated with verapamil-trandolapril combination had total fibronectin not significantly different from that of WKY. Carotid arterial distensibility increased only in verapamil-trandolapril treated rats. Multivariate analysis showed arterial distensibility to be negatively correlated to mean blood pressure (P < 0.0001) and total fibronectin (P < 0.01). In conclusion, chronic treatment with the verapamil-trandolapril combination significantly improved in vivo arterial distensibility in SHR. The most important effects of the combination on arterial mechanics compared to those of verapamil or trandolapril alone may have been the consequence of its stronger action on arterial pressure, arterial wall hypertrophy and total fibronectin density. However we suggest that, in addition to the structural effects, complete normalization of blood pressure is necessary to obtain normal arterial distensibility.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Congenital epulis and granular cell tumor: a histologic and immunohistochemical study.

OBJECTIVES: Although it is now reasonably certain that granular cell tumors derive from Schwann cells, the histogenesis of congenital epulis, which is largely isomorphic with granular cell tumor, remains unclear. A study was undertaken to compare the immunophenotype of these tumors with particular emphasis on the expression of matrix proteins and macrophage markers because such information is not available in the literature. STUDY DESIGN: Four granular cell tumors and two congenital epulis were immunostained with a panel of 29 antibodies. Two congenital epulis and one granular cell tumor were investigated by electron microscopy, the latter also by immunoelectron microscopy. RESULTS: Many similarities in immunostaining were found, for example, both tumor types were CD68+, Ki-M1P+, lysozyme-, vimentin+, fibronectin+, laminin+, lectin PHAE+, and lectin WGA+. However, differences were also noted, for example, granular cell tumor was always S100 protein+, but only one congenital epulis case was reactive (weak reactivity after microwave treatment), and staining with the proliferation markers anti-proliferating cell nuclear antigen and MIB 1 was found only in congenital epulis. Both tumor types exhibited pericellular and diffuse cytoplasmic staining for fibronectin and laminin. CONCLUSIONS: The hypothesis that congenital epulis and granular cell tumor would exhibit similar reactivity for macrophage markers was confirmed: both were reactive with anti-CD68 and Ki-M1P and nonreactive with MAC387, anti-lysozyme, and 3A5. Intracytoplasmic staining for fibronectin and laminin, which has not been described previously in these tumors, appears to be a characteristic feature common to both tumors. This finding suggests that there could be a disturbance of synthesis and secretion of extracellular matrix proteins or a derangement of their receptor systems. This theory could be supported by the finding of intracytoplasmic CD49e-positive material in two cases.

Antibodies, Monoclonal↗
PubMed1999

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts.

Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix-loop-helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1-Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/- Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.

Animals↗
PubMed1996

Correlation between integrin alpha 5 expression and the malignant phenotype of transitional cell carcinoma.

We examined the expression of alpha 1, alpha 2, alpha 3, alpha 4, alpha 5 and beta 1 integrin on 36 transitional cell cancers (TCCs) in the bladder by immunohistochemistry. Only alpha 2, alpha 3 and beta 1 were detected on normal transitional cell epithelium, but four TCCs (12.5%) revealed positive staining for alpha 1, seven (19.4%) for alpha 4 and seven (20%) for alpha 5. These altered expressions of integrin alpha chain were more frequent in histologically higher stage or grade of TCC, and a correlation was found between increased alpha 5 expression and histological stage. alpha 5 was positive in 6 (35.3%) of 17 invasive TCCs whereas only 1 (5.9%) of 17 superficial TCCs. Flow cytometric analysis on bladder cancer cell lines showed that T24 and HT1376, which are undifferentiated TCC cell lines, highly expressed alpha 5 and beta 1. Also, SCaBER, which is derived from urinary bladder squamous cell cancer and which is recognised as the most malignant phenotype after metaplasia of transitional epithelium, had alpha 5 and beta 1. However, RT4, which is derived from transitional cell papilloma, showed no expression of alpha 5. Furthermore, reverse transcriptase-polymerase chain reaction (RT-PCR) showed the presence of mRNA of alpha 5 on T24, SCaBER and HT1376, but not on RT4. Taken together, it seems that the presence of alpha 5 integrin might be a more malignant phenotype in transitional cell carcinoma.

Adult↗
PubMed2003

Expression level of integrin alpha 5 on tumour cells affects the rate of metastasis to the kidney.

Tumour metastasis is known clinically to have organ specificity. We hypothesised that integrins might be involved in determining the organ specificity of tumour metastasis. Here, we report the results of spontaneous metastasis tested in nude mice that were inoculated with Chinese hamster ovary (CHO) cells expressing integrin alpha 5 beta 1 at various levels. The growth of the primary tumour inversely correlated with the alpha 5 expression level on CHO cells, which is consistent with a previous report (Schreiner et al, 1991). The rates of pulmonary, lymph node, and adrenal metastases that developed in nude mice were not related to changes of the alpha 5 expression level on CHO cells. Kidney metastasis developed in 40% of nude mice inoculated with alpha 5B2 cells (CHO cells overexpressing alpha 5) and in 20% of mice with CHO-K1 cells (CHO cells expressing native alpha 5), whereas inoculation with CHO-B2 cells (alpha 5-defective mutants) and alpha 5CHO cells with the highest expression of alpha 5 did not lead to development of kidney metastasis. Furthermore, alpha 5CHO, which shows the slowest growth of these cell types, did not lead to primary tumours in nude mice. These findings suggest that there is an appropriate level of alpha 5 expression on tumour cells that leads to metastasis. Microscopic observations revealed that micrometastasis in the kidney was formed in glomeruli. An adhesion assay using frozen sections of the kidney demonstrated that alpha 5B2 cells, but not CHO-B2 cells, effectively adhered to glomeruli. Kidney metastasis in vivo and the adhesion of alpha 5B2 to glomeruli shown ex vivo were significantly suppressed by the administration of GRGDS peptide. Finally, we conclude that the interaction of alpha 5 beta 1 on tumour cells with fibronectin in kidney glomeruli is involved in kidney metastasis and that the tumour has appropriate levels of integrins crucial for metastasis.

Adrenal Gland Neoplasms↗
PubMed2003

Expression of CD18, CD49b, CD49c and CD49e on lens anterior capsules in human cataracts.

PURPOSE: To examine the lens epithelial cells obtained from the anterior lens capsules removed during cataract surgery and detect various subclasses of the cell surface adhesion molecules known as integrins. METHODS: The circular sections of anterior capsules with attached lens epithelial cells (LECs) were obtained during cataract surgery from 28 patients. The lens capsules were immunohistochemically stained. RESULTS: CD49b CD49c, CD49e, and CD18 were detected in varying degrees in specimens obtained from human cataractous lenses. The positive percentages were 33, 75, 33, and 20%, respectively. The most striking feature was the increasing staining profiles towards the edges of the capsules (away from the central part of the lens capsules) for CD49c, suggesting that the LECs showed higher immunoreactivity for this antibody. The immunoreactivity for CD49b and CD49e was weaker. This was absent for CD18 in the central part of the lens capsules. CONCLUSION: The positive expression of antibodies suggests that specific integrin subunits were expressed in LECs of human cataracts. These results suggest that lens epithelial cells expressing CD49b, CD49c, CD49e, and CD18 might be precursors in the process of anterior lens epithelial cell (A cell) adhesion, and hence play a role in anterior capsule opacification or in subsequent migration and a possible role in posterior capsule opacification.

Aged↗
PubMed1999

Expression of coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers.

Recombinant adenoviral vectors are broadly applied in gene therapy protocols. However, adenovector-mediated gene transfer has limitations in vivo. One of these is the low gene transfer rate into organs other than the liver after systemic intravenous vector injection. Local direct injection into the target organ has been used as one possible solution, but increases necessary equipment and methodology and is traumatic to the target. Wild-type adenovirus infection as well as adenovector-mediated gene transfer depends on virus interaction with the Coxsackie adenovirus receptor (CAR) mediating virus attachment to the cell surface, and on interaction with alphavbeta3 and alphavbeta5 integrins mediating virus entry into the cell. In order to assess the receptor-associated potential of different tissues to act as adenovector targets, we have therefore determined CAR and alphav-integrin expression in multiple organs from different species. In addition, we have newly determined several human, rat, pig and dog CAR-mRNA sequences. Sequence comparison and structural analyses of known and of newly determined sequences suggests a potential adenovirus binding site between amino acids 29 and 128 of the CAR. With respect to the virus receptor expression patterns we found that CAR-mRNA expression was extremely variable between different tissues, with the highest levels in the liver, whereas alphav-integrin expression was far more homogenous among different organs. Both CAR and alphav-integrin showed similar expression patterns among different species. There was no correlation, however, between the adenovector expression patterns after intravenous, intracardiac and aortic root injection, respectively, and the virus receptor patterns. In summary, many organs carry both receptors required to make them potential adenovector targets. In sharp contrast, their actual targeting clearly indicates that adenovirus receptor expression is necessary but not sufficient for vector transfer after systemic injection. The apparently very important role of anatomical barriers, in particular the endothelium, requires close attention when developing non-traumatic, organ-specific gene therapy protocols.

Adenoviridae↗
PubMed2001

Expansion of tropism of a feline parvovirus to target a human tumor cell line by display of an alpha(v) integrin binding peptide on the capsid.

The autonomous parvoviruses are small, non-enveloped, single strand DNA viruses. They occur in many species and they have oncolytic properties. We are modifying the capsid of feline panleukopenia virus (FPV), a parvovirus which normally infects feline cells, with the goal of targeting human tumor cells for potential cancer therapy. Using recombinant viruses transducing a luciferase reporter, we show that insertion of a cyclically constrained, integrin-binding peptide at an exposed position on the FPV capsid enables transduction of an alpha(v) integrin-expressing human rhabdomyosarcoma cell line (Rh18A). These cells were not transduced by virus with the unmodified FPV capsid. Transduction of Rh18A was specifically inhibited by an alpha(v) integrin blocking antibody. However, other human tumor lines expressing alpha(v) integrins were not transduced by virus with either the modified or unmodified capsid. We conclude that modification of the FPV capsid to bind alpha(v) integrins can contribute to, but is not generally sufficient for, redirecting infection to human tumor cells. The permissiveness of Rh18A cells presumably involves additional factors unique to this line among various human cell lines tested.

Antigens, CD↗
PubMed2003

Role of nuclear and cytoplasmic localization in the tumour-suppressor activity of the von Hippel-Lindau protein.

Mutations in the von Hippel-Lindau (VHL) tumour-suppressor gene result in several forms of cancer. In the present study, we investigated the role of VHL subcellular localization in its antitumour properties. We generated renal cell carcinoma (RCC) lines stably expressing either exclusively nuclear (RCC/NLS-VHL), cytoplasmic (RCC/NES-VHL) or nucleo-cytoplasmic shuttling (RCC/DeltaNES-VHL or RCC/VHL) forms of VHL and investigated several parameters linked to tumorigenesis and known to be dysregulated in VHL disease. Remarkably, although the expression of wild-type VHL is largely cytoplasmic, all of the antitumour properties of VHL tested could be reconstituted by expressing exclusively nuclear VHL.

Amino Acid Sequence↗
PubMed2003

Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulphide bond engineering.

We report the isolation and amino acid sequences of six novel dimeric disintegrins from the venoms of Vipera lebetina obtusa (VLO), V. berus (VB), V. ammodytes (VA), Echis ocellatus (EO) and Echis multisquamatus (EMS). Disintegrins VLO4, VB7, VA6 and EO4 displayed the RGD motif and inhibited the adhesion of K562 cells, expressing the integrin alpha5beta1 to immobilized fibronectin. A second group of dimeric disintegrins (VLO5 and EO5) had MLD and VGD motifs in their subunits and blocked the adhesion of the alpha4beta1 integrin to vascular cell adhesion molecule 1 with high selectivity. On the other hand, disintegrin EMS11 inhibited both alpha5beta1 and alpha4beta1 integrins with almost the same degree of specificity. Comparison of the amino acid sequences of the dimeric disintegrins with those of other disintegrins by multiple-sequence alignment and phylogenetic analysis, in conjunction with current biochemical and genetic data, supports the view that the different disintegrin subfamilies evolved from a common ADAM (a disintegrin and metalloproteinase-like) scaffold and that structural diversification occurred through disulphide bond engineering.

Amino Acid Motifs↗
PubMed1997

Interleukin 1-induced calcium signalling in chondrocytes requires focal adhesions.

The cytokine interleukin 1 (IL-1) is an important mediator of connective-tissue destruction in arthritic joints but the mechanisms by which IL-1 mediates signal transduction in chondrocytes is poorly understood. Previous results have indicated that IL-1 receptors co-localize with focal adhesions [Qwarnstrom, Page, Gillis and Dower (1988) J. Biol. Chem. 263, 8261-8269], discrete adhesive domains of cells that function in cell attachment and possibly in signal transduction. We have determined whether focal adhesions restrict IL-1-induced Ca2+ signalling in primary cultures of bovine chondrocytes. In cells grown for 24 h on fibronectin, the basal intracellular Ca2+ ion concentration ([Ca2+]i) was 100+/-3 nM. Optimal increases of [Ca2+]i above baseline were induced by 10 nM IL-1 (183+/-30 nM above baseline). There was no significant difference between cells plated on fibronectin or type II collagen (P>0.2; 233+/-90 nM above baseline). Ca2+ transients were significantly decreased by the inclusion of 0.5 mM EGTA in the bathing buffer (74+/-11 nM above baseline), and 1 microM thapsigargin completely blocked Ca2+ transients. Cells plated on poly-(l-lysine) or suspended cells showed no Ca2+ increases, whereas cells grown on fibronectin exhibited IL-1-induced Ca2+ responses that corresponded temporally to the time-dependent cell spreading after plating on fibronectin. Cells plated on poly-(l-lysine) and incubated with fibronectin-coated beads exhibited vinculin staining in association with the beads. In identical cell preparations, IL-1 induced a 136+/-39 nM increase of [Ca2+]i above baseline in response to 10 nM IL-1beta. There were no IL-1-induced Ca2+ increases when cells on poly-(l-lysine) were incubated with fibronectin-coated beads for only 15 min at 37 degrees C, in cells maintained for 3 h at 4 degrees C, in cells incubated with BSA beads for 3 h at 37 degrees C, or in cells pretreated with cytochalasin D. Labelling of IL-1 receptors with 125I-IL-1beta showed 3-fold more specific labelling of focal adhesion complexes in cells incubated with fibronectin-coated beads compared with cells incubated with BSA-coated beads, indicating that IL-1 receptor binding or the number of IL-1 receptors was increased in focal adhesions. These results indicate that, in chondrocytes, IL-1-induced Ca2+ signalling is dependent on focal adhesion formation and that focal adhesions recruit IL-1 receptors by redistribution in the cell membrane.

Animals↗