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PubMed2001

Beta 1-integrins regulate the formation and adhesion of ovarian carcinoma multicellular spheroids.

Ovarian carcinoma multicellular spheroids are an in vitro model of micrometastasis whose adhesive abilities have not been elucidated. In this study, we identified adhesion molecules that mediate the formation of ovarian carcinoma spheroids and their subsequent adhesion to extracellular matrix proteins. The NIH:OVCAR5, but not the SKOV3, ovarian carcinoma cell line formed spheroids similar to multicellular aggregates isolated from patient ascitic fluid. NIH:OVCAR5 spheroid formation was augmented by a beta 1-integrin-stimulating monoclonal antibody or exogenous fibronectin, but was inhibited by blocking monoclonal antibodies against the alpha 5- or beta 1-integrin subunits. By immunohistochemical staining, alpha 2-, alpha 3-, alpha 5-, alpha 6-, and beta 1-integrin subunits, CD44, and fibronectin were detected in NIH:OVCAR5 spheroids. NIH:OVCAR5 spheroids adhered to fibronectin, laminin, and type IV collagen, and this adhesion was partially inhibited by blocking antibodies against the alpha 5-, alpha 6-, and alpha 2-integrin subunits, respectively. A blocking monoclonal antibody against the beta 1-integrin subunit completely inhibited adhesion of the spheroids to all three proteins. These results suggest that interactions between the alpha 5 beta 1-integrin and fibronectin mediate the formation of ovarian carcinoma spheroids and that their adhesion to extracellular matrix proteins at sites of secondary tumor growth may be mediated by a complex interaction between multiple integrins and their ligands.

Antigens, CD↗
PubMed2003

Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors.

Often described as incomplete or absent, the basement membrane of blood vessels in tumors has attracted renewed attention as a source of angiogenic and anti-angiogenic molecules, site of growth factor binding, participant in angiogenesis, and potential target in cancer therapy. This study evaluated the composition, extent, and structural integrity of the basement membrane on blood vessels in three mouse tumor models: spontaneous RIP-Tag2 pancreatic islet tumors, MCa-IV mammary carcinomas, and Lewis lung carcinomas. Tumor vessels were identified by immunohistochemical staining for the endothelial cell markers CD31, endoglin (CD105), vascular endothelial growth factor receptor-2, and integrin alpha5 (CD49e). Confocal microscopic studies revealed that basement membrane identified by type IV collagen immunoreactivity covered >99.9% of the surface of blood vessels in the three tumors, just as in normal pancreatic islets. Laminin, entactin/nidogen, and fibronectin immunoreactivities were similarly ubiquitous on tumor vessels. Holes in the basement membrane, found by analyzing 1- micro m confocal optical sections, were <2.5 micro m in diameter and involved only 0.03% of the vessel surface. Despite the extensive vessel coverage, the basement membrane had conspicuous structural abnormalities, including a loose association with endothelial cells and pericytes, broad extensions away from the vessel wall, and multiple layers visible by electron microscopy. Type IV collagen-immunoreactive sleeves were also present on endothelial sprouts, supporting the idea that basement membrane is present where sprouts grow and regress. These findings indicate that basement membrane covers most tumor vessels but has profound structural abnormalities, consistent with the dynamic nature of endothelial cells and pericytes in tumors.

Animals↗
PubMed2001

Patterns of integrin expression in a human mandibular explant model of osteoblast differentiation.

Cell-matrix interaction is crucial in regulating osteoblast differentiation and function. These interactions are themselves regulated, at least in part, by integrins. Although there are some data from mammalian models, few studies have compared integrin expression at different stages of the osteoblast lineage. Here, primary human mandibular osteoblast cultures were grown in the presence of epidermal growth factor (EGF), giving a proliferative, less differentiated phenotype, or of vitamin D(3) and hydrocortisone (D+Hc), giving a more differentiated phenotype. These cultures were compared with those of cells prepared in the absence of EGF or D+Hc by fluorescence-activated cell sorter using a panel of monoclonal antibodies to specific integrin heterodimers. To provide in vivo correlation, the same panel of antibodies was used to stain fresh-frozen, undemineralised sections of human mandibular bone. Under baseline conditions the alpha(3), alpha(5), alpha(v), alpha(v)beta(3), beta(3) and beta(1) integrin subunits were expressed strongly by the cells, with low-level expression of the alpha(1), alpha(2) and alpha(4) subunits. In the presence of EGF there was increased alpha(2) expression. With D+Hc, alpha(3) and alpha(5) expression was elevated. Immunohistochemical analysis demonstrated alpha(2), alpha(3), alpha(5), alpha(v)beta(3), beta(1) and beta(3) subunits in cells of the osteoblast lineage; alpha(2) staining was restricted to cells close to the bone surface whilst alpha(v)beta(3) and beta(3) were most frequently localised in the osteocytes. The results provide evidence that cells at successive stages of the osteoblast lineage show different patterns of integrin expression. These integrins may be important in cell-matrix interactions leading to osteoblast differentiation.

Antibodies, Monoclonal↗
PubMed2000

Mechanism of action in thalidomide teratogenesis.

In this commentary, we describe a model to explain the mechanism of the embryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) stimulation of the transcription of alphav and beta3 integrin subunit genes. The resulting alphavbeta3 integrin dimer stimulates angiogenesis in the developing limb bud, which promotes outgrowth of the bud. The promoters of the IGF-I and FGF-2 genes, the genes for their binding proteins and receptors, as well as the alphav and beta3 genes, lack typical TATA boxes, but instead contain multiple GC boxes (GGGCGG). Thalidomide, or a breakdown product of thalidomide, specifically binds to these GC promoter sites, decreasing transcription efficiency of the associated genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regions of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity, and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha. On the other hand, the anti-cancer action of thalidomide may be based on its antiangiogenic action, resulting from specific DNA intercalation. The tissue specificity of thalidomide and its effect against only certain neoplasias may be explained by the fact that various developing tissues and neoplasias depend on different angiogenesis or vasculogenesis pathways, only some of which are thalidomide-sensitive.

Animals↗
PubMed1999

Differential expression of alpha 1, alpha 3 and alpha 5 integrin subunits in acute and chronic stages of myocardial infarction in rats.

OBJECTIVE: Anchoring cardiac myocytes to extracellular matrix, which is mediated mainly by integrins on their surfaces, is important for maintaining the architecture of myocardial tissues and transmitting mechanical force. We evaluated the expression of alpha integrin subunits on myocytes and the accumulation of interstitial collagen and fibronectin at acute and chronic stages after myocardial infarction. METHODS: Myocardial infarction was induced by ligation of left coronary arteries in rats. The expression of alpha 1, alpha 3 and alpha 5 integrin subunits, and accumulation of collagen and fibronectin were analyzed with immunohistochemistry or sirius-red staining. RESULTS: In hearts without infarction, moderate expression of the alpha 3 subunit and only slight expression of the alpha 5 subunit were observed on myocytes. In the first week after infarction, the alpha 1 subunit, collagen and fibronectin were increased only in the peri-infarcted area, while the alpha 5 subunit was increased both in peri-infarcted and non-infarcted areas. At day 42, the expression of the alpha 1 subunit and collagen were still increased, although the alpha 5 subunit and fibronectin were decreased. The expression of the alpha 3 subunit was not altered throughout the experimental period. CONCLUSION: These data suggest that integrin subunits play an important role in healing and remodeling processes after myocardial infarction.

Animals↗
PubMed2003

Nischarin inhibits Rac induced migration and invasion of epithelial cells by affecting signaling cascades involving PAK.

Nischarin, a cytosolic protein that binds the alpha5beta1 integrin, plays an important role in fibroblast migration, and in regulation of the actin cytoskeleton. The effect of Nischarin on Rac induced migration and invasion by breast and colon epithelial cell lines has been determined. In these cells, Rac potently induced migration, as well as invasion of matrix; both of these events were strongly inhibited by overexpression of Nischarin. To understand the mechanism of Nischarin's inhibitory role in Rac induced cell migration, several effector domain mutants of Rac1 were employed. Nischarin was able to inhibit migration induced by Rac effector mutants that can activate PAK and JNK, but not migration stimulated by other Rac mutants. Further, Nischarin inhibited PAK induced cell migration, while not affecting migration induced by MEKK1, a Rac effector in the JNK pathway. In addition, Nischarin failed to inhibit migration induced by MEK1, a downstream effector in the Ras-Raf-MEK-Erk signaling cascade. Furthermore, Nischarin does not affect Rac mediated JNK and PI3K activities. However, Rac induced migration and invasion were effectively blocked by pharmacological inhibitors of PI-3 kinase and MEK. These results suggest that several pathways contribute to cell migration, but that Nischarin selectively inhibits Rac driven signaling cascades that affect migration through PAK.

Animals↗
PubMed2001

Immunological dysregulation of lung cells in response to vitamin E deficiency.

Vitamin E supplementation exhibits anti-inflammatory properties. In the lung, the beneficial effects of vitamin E supplementation on inflammation and infections are well documented, but potential consequences of alimentary vitamin E deficiency to the immunological status of lung cells are not known. It is unclear if temporary vitamin E deficiency exhibits deleterious consequences or can be compensated for by other cellular antioxidants. To address this question, the alimentary vitamin E supply to rats was modified. We then investigated the effects on major histocompatibility molecule (MHC) class II, cell adhesion molecules, interleukin (IL)10, tumor necrosis factor (TNF)alpha in various lung cells. The constitutive expression of MHC class II, intercellular adhesion molecule (ICAM)-1, L-selectin, alpha5-integrin, and CD 166, was demonstrated by flow cytometry on type II pneumocytes, alveolar macrophages, and on co-isolated lymphocytes. Vitamin E depletion increased ICAM-1 and CD166 on type II cells and macrophages, whereas the expression of L-selectin increased only on macrophages. Furthermore, the vitamin E depletion increased the cellular content and secretion of IL10 in type II cells, but decreased the content and secretion of TNFalpha. Vitamin E depletion decreased the cellular vitamin E content, but did not change the activity of antioxidant enzymes (catalase, superoxide dismutase) and the glutathion (GSH)/oxidized glutathion (GSSG) ratio in alveolar type II cells. The shift of protein kinase C (PKC) from the cytosol to membranes indicates that a PKC-dependent signaling pathway may be involved in the change of the immunological status of type II cells. All these effects were reversed by vitamin E repletion. In summary, these results are clearly compatible with the view that a temporary vitamin E deficiency induces a reversible immunological dysregulation in alveolar type II cells and lung macrophages. This deficiency might predispose the lung to develop acute or chronic inflammation.

Animals↗
PubMed1997

The expression of VLA integrins in the human tonsilla palatina.

The integrin receptors are a family of transmembrane glycoproteins comprising non-covalent heterodimers. They interact with a wide variety of ligands including extracellular matrix glycoproteins, complement and other cell, while their intracellular domains interact with the cytoskeleton. They participate in cell-matrix and cell-cell adhesion in many physiologically important processes including embryological development, hemostasis, thrombosis, wound healing, immune and nonimmune defense mechanisms, and in oncogenic transformation. This investigation was focused on the histological distribution of the beta 1-integrins in the human tonsil using an indirect immunoperoxidase method. Present data suggest that lymphocyte and antigen presenting cells (FDCs, IDCs, and macrophages) interact with each other following adhesion to extracellular matrix proteins (e.g. fibronectin) through their integrin receptors in order to carry out special immunological functions. In addition, stromal elements and epithelial components were shown to express VLA integrins providing interactions for tissue organization and compartmentalization.

Antibodies, Monoclonal↗
PubMed2000

Visualizing muscle cell migration in situ.

BACKGROUND: Cell migration has been studied extensively by manipulating and observing cells bathed in putative chemotactic or chemokinetic agents on planar substrates. This environment differs from that in vivo and, consequently, the cells can behave abnormally. Embryo slices provide an optically accessible system for studying cellular navigation pathways during development. We extended this system to observe the migration of muscle precursors from the somite into the forelimb, their cellular morphology, and the localization of green fluorescent protein (GFP)-tagged adhesion-related molecules under normal and perturbed conditions. RESULTS: Muscle precursors initiated migration synchronously and migrated in broad, rather than highly defined, regions. Bursts of directed migration were followed by periods of meandering or extension and retraction of cell protrusions. Although paxillin did not localize to discernible intracellular structures, we found that alpha-actinin localized to linear, punctate structures, and the alpha5 integrin to some focal complexes and/or vesicle-like concentrations. Alterations in the expression of adhesion molecules inhibited migration. The muscle precursors migrating in situ formed unusually large, long-lived protrusions that were polarized in the direction of migration. Unlike wild-type Rac, a constitutively active Rac localized continuously around the cell surface and promoted random protrusive activity and migration. CONCLUSIONS: The observation of cellular migration and the dynamics of molecular organization at high temporal and spatial resolution in situ is feasible. Migration from the somite to the wing bud is discontinuous and not highly stereotyped. In situ, local activation of Rac appears to produce large protrusions, which in turn, leads to directed migration. Adhesion can also regulate migration.

Animals↗
PubMed1999

Low doses of ultraviolet A radiation stimulate adhesion of human dermal fibroblasts by integrins in a protein kinase C-dependent pathway.

In this work, we have studied the modulation of fibroblast-extracellular matrix interactions by physiological doses of ultraviolet A (UV-A) radiation using an adhesion assay on collagen. We have shown that low doses of UV-A (20 kJ/m2) stimulate fibroblast adhesion while higher doses (100 and 200 kJ/m2) inhibit it. By measurement of the thiobarbituric acid reactive substances (TBARS) and use of the chain-breaking antioxidant vitamin E, no role of lipid peroxidation can be detected in these effects. By incubating fibroblasts with a specific protein kinase C (PKC) inhibitor, GF109203X, we have demonstrated that the stimulation of the adhesion by low doses of UV-A involves, at least in part, a PKC-dependent mechanism. In addition, using function-blocking antibodies of alpha 1, alpha 2 or alpha 5 integrin chains involved in extracellular matrix anchorage, we have shown that they decrease the stimulation of adhesion following low doses of UV-A radiation, demonstrating the involvement of these three integrin chains in this UV-A effect. In parallel, 20 kJ/M2 of UV-A are found to rapidly stimulate membrane expression of alpha 1, alpha 2 and alpha 5 integrin chains. This work, which underlines the involvement of integrins in UV-A effects, contributes to the evaluation of the mechanisms by which cell-matrix interactions modulate cell behaviour.

Adolescent↗
PubMedDate not supplied

Mesothelium expression of integrins in vivo and in vitro.

OBJECTIVE: To characterize the expression of alpha subunits of integrin adhesion molecules in peritoneal tissue in vivo and in vitro. METHOD: Peritoneum from the anterior abdominal wall (n = 22) and the serosa of the posterior uterus (n = 11) was obtained from women of reproductive age without endometriosis who were undergoing surgery for benign conditions. Immunohistochemical studies were performed on serial sections of peritoneum from the anterior abdominal wall, the uterine serosa, mesothelial monolayer cultures, and peritoneum explants from the abdominal wall using monoclonal antibodies to alpha subunits of integrin adhesion molecules. Electron microscopy was performed to localize these adhesion molecules in the mesothelium. RESULTS: The mesothelial expression of alpha integrin subunits was identical in the anterior peritoneum and uterine serosa. In vivo the mesothelium strongly expressed alpha 2 and alpha 3 and variably expressed alpha 6. In the monolayer cultures there was moderate/strong staining for alpha 2, alpha 3, and alpha 5; there was minimal expression of alpha v. In the explants there was moderate/strong expression of alpha 2, alpha 3, alpha 5, and alpha v; alpha 6 was variably expressed. The ultrastructure of the mesothelium was unique in the anterior peritoneum, uterine serosa, and the monolayer cultures. The integrin subunits were distributed throughout the cytoplasm, were expressed in the plasma membrane, and were present on the surface (i.e., towards the peritoneal cavity) of the mesothelium. CONCLUSION: Integrins are expressed by the mesothelium of the peritoneum. The mesothelium expression of integrins in vivo differs from that of the mesothelium integrin expression in monolayer culture and explant culture.

Antigens, CD↗
PubMed2001

[Quantitative expression of the adhesion receptors VLA-4, VLA-5, L-selectin, MAC-1, and ICAM-1 on the surface of CD34+ cells].

The aim of this work was to quantify by flow cytometry the main adhesion receptors on CD34+ cells. These cells were isolated from bone marrow (BM) or mobilized peripheral blood (PB). The proportions of CD34+/CD49d+ and CD34+/CD49e+ are weaker on PB cells, without quantitative expression variation. This phenotypic variation may induce CD34+ cells exist from BM into circulation, promoting the mobilization. The homing to the BM implicate the CD62L receptor, which expression was found more frequently and stronger on PB cells than on BM. The CD11b, CD18 and CD54 receptors are implicated in CD34+ cells adhesion to BM micro-environment. No significant variation in CD34+/CD11b+ and CD34+/CD18+ cells frequency was noted. Moreover, CD54 receptor was more frequently expressed on PB cells. Quantitative analysis revealed that CD18 was more strongly expressed on BM than on PB cells. This quantitative variation could promote progenitor adhesion by interacting with stromal cells. Finally, quantitative expression of the main receptors on CD34+ cells provides an original option for studying CD34+ cells during the mobilization, the homing or the adhesion to BM micro-environment.

Antigens, CD↗
PubMed1997

Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity.

In order to investigate the biological role of fibronectin in glioma cell invasion, we studied the relation between migratory responses or adhesiveness of glioma cells to fibronectin and the in vitro invasion in three human malignant glioma cell lines, A172, T98G and U373MG. All these cell lines chemotactically migrated in a dose-dependent manner to fibronectin in concentrations ranging from 0.5 to 10 microg/ml, with A172 cells showing the strongest migration and U373 cells the weakest. Checkerboard analyses demonstrated that A172 and T98G cells showed much stronger chemokinetic responses to fibronectin than U373MG cells. In contrast to the migratory responses, A172 and U373MG cells showed an almost equally high adhesion to fibronectin and T98G cells a low adhesion. The degree of expression of the integrin alpha5 subunit correlated well with the strength of glioma cell adhesion to fibronectin rather than that of migration to the molecule. Furthermore, the cell adhesion to fibronectin was almost completely inhibited by arginine-glycine-aspartic acid (RGD)-containing peptides, but the fibronectin-stimulated cell migration was only partially inhibited. An in vitro invasion assay disclosed that U373MG cells invaded the artificial basement membrane barrier the most and A172 cells the least. However, addition of fibronectin to the glioma cells markedly enhanced the invasive activity of A172 and T98G cells but had little effect on that of U373MG cells. These results indicate that fibronectin-stimulated migration can be one of the factors promoting invasiveness of glioma cells and that the chemokinetic activity of fibronectin may play a crucial role in glioma invasion through conferring motor-driving force on the glioma cells.

Cell Adhesion↗
PubMed2002

Role of protein kinase C during insulin mediated skeletal muscle cell spreading.

Protein kinase C (PKC) is known to play important roles in integrin mediated cell spreading. This study investigated the role of PKC during insulin mediated muscle cell spreading, which was independent of integrin alpha5. We found that PKC-alpha becomes active and localise to membrane during insulin mediated cell spreading. We also found that PKC activation is essential for cell spreading stimulated by insulin and this activation enhances the cell spreading. PKC activation increased the tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin as well as tyrosine kinase activity of FAK. We also observed that PKC activation enhanced the FAK associated PI 3-kinase activity and also increased the activation of ERK-1/-2. Moreover, the effect of PKC activation on insulin mediated cell spreading as well as tyrosine phosphorylation of FAK and paxillin depends upon integrity of actin cytoskeleton. Thus, PKC is an important signaling protein during insulin mediated muscle cell spreading.

Actin Cytoskeleton↗
PubMed1999

Soluble Arg-Gly-Asp peptides reduce collagen accumulation in cultured rat hepatic stellate cells.

Hepatic stellate cells play a central role in the pathogenesis of liver fibrosis, both via production of extracellular matrix proteins and through secretion of matrix metalloproteinases. In this study, effects of soluble cell adhesion peptides on collagen type I accumulation and on expression of matrix metalloproteinases were analyzed. First, we revealed the expression of alpha5-integrin on hepatic stellate cells by immunostaining. Treatment with 100 microg/ml of soluble Arg-Gly-Asp (RGD) peptides was found to reduce accumulation of type I collagen without any effects on its transcriptional level in rat hepatic stellate cells, whereas a control peptide Gly-Arg-Gly-Glu-Ser (GRGES) had no such effect. Soluble RGD peptides also increased the secretion of collagenase by stellate cells. These data suggested that reduced accumulation of type I collagen caused by the RGD peptide ligation to integrins on hepatic stellate cells was partly due to stimulated expression of collagenase by stellate cells.

Animals↗
PubMed1997

Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness.

Migration of cells in higher organisms is mediated by adhesion receptors, such as integrins, that link the cell to extracellular-matrix ligands, transmitting forces and signals necessary for locomotion. Whether cells will migrate or not on a given substratum, and also their speed, depends on several variables related to integrin-ligand interactions, including ligand levels, integrin levels, and integrin-ligand binding affinities. These and other factors affect the way molecular systems integrate to effect and regulate cell migration. Here we show that changes in cell migration speed resulting from three separate variables-substratum ligand level, cell integrin expression level, and integrin-ligand binding affinity-are all quantitatively predictable through the changes they cause in a single unifying parameter: short-term cell-substratum adhesion strength. This finding is consistent with predictions of a mathematical model for cell migration. The ligand concentration promoting maximum migration speed decreases reciprocally as integrin expression increases. Increases in integrin-ligand affinity similarly result in maximal migration at reciprocally lower ligand concentrations. The maximum speed attainable, however, remains unchanged as ligand concentration, integrin expression, or integrin-ligand affinity vary, suggesting that integrin coupling with intracellular motors remains unaltered.

Animals↗
PubMed1997

Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains beta 1, alpha 1 to 6 and alpha V.

Accumulation of extracellular matrix is important in the progression of glomerulonephritis. Since adherent cell types utilize integrins to bind and organize extracellular matrix proteins, we have assessed expression of the beta 1 integrins in sequential sections from 85 human renal biopsies and 4 normal kidneys by immunohistochemical staining. Our results demonstrate strong correlations between expression of the alpha 5 chain within the interstitium, the alpha V chain on proximal and distal tubular epithelium and the presence of chronic histological damage. Moreover, staining for interstitial alpha 5 and proximal and distal tubular alpha V were also strongly associated with expression of certain adhesion molecules (ICAM-1, VCAM-1, E-selectin and L-selectin) and the presence of macrophages within the interstitium, which have been linked, in an earlier study, with the degree of chronic histological damage and disease progression. However, in contrast to our earlier study of adhesion molecules, there were also associations between expression of integrin chains within the glomerulus and tubulointerstitium. For example, there were strong positive associations between staining for alpha 5 on glomerular endothelium and its expression on extraglomerular vascular endothelium and between both mesangial alpha 1 and podocyte alpha 3 and tubular staining for the common beta 1 subunit. While the functional significance of these associations is obscure, they suggest some kind of communication between cells in different sites in the kidney. There were also positive associations between staining for different integrins within the glomerulus, notably mesangial cell staining for alpha 2, glomerular endothelial cells staining for alpha 5 and glomerular epithelial cell alpha 3. These results suggest that there is a coordinated upregulation of integrin expression both within the tubulointerstitium and the glomerulus and that at least some of these integrins (interstitial alpha 5 and distal tubular alpha V) are associated with the expression of other adhesion molecules, macrophage infiltration and the presence of markers of disease progression (interstitial fibrosis and tubular atrophy).

Antigens, CD↗