SEARCH · PubMed Health

Results for “Integrin alpha3”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 433 records · Page 24Linked to original sources

PubMed2005

Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility.

PURPOSE: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha6beta4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. EXPERIMENTAL DESIGN: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. RESULTS: The majority of pancreatic and colorectal tumors expressed the alpha2, alpha3, alpha6, beta1, and beta4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha6beta4 and CO-029 was restricted to tumor cells, whereas alpha1, alpha2, alpha3, alpha6, beta1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha3beta1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha6beta4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. CONCLUSION: alpha6beta4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha6beta4 with CD151 and CO-029 correlates with increased tumor cell motility.

Adenocarcinoma↗

PubMed1997

Adhesion molecule expression in normal skin and melanocytic lesions. Role of UV-irradiation and architectural characteristics in nevi.

Cell adhesion between surfaces of cells and to extracellular matrices represents a fundamental mechanism in tissue organization and influences the biological behaviour and the architecture of tumors. We investigated the expression of various adhesion molecules in normal skin (n=5), nevi (n=29), and malignant melanoma (n=10) by immunohistochemistry. Special attention was paid to the correlation between adhesion molecule expression and the respective architectural features, e.g. UV-induced morphological changes, and the arrangement of melanocytes in congenital nevi. In nevi, a single erythemagenic dose of UV-light did not influence the integrin expression of melanocytes, but results in an upregulation of alpha3 beta1- and alpha6 beta1-integrin within the suprabasal layers of the epidermis. This suprabasal labelling was associated with an increased number of suprabasal melanocytes in UV-irradiated nevi which were detected with HMB-45 antibody. Nine of 10 congenital nevi demonstrated a labelling of alpha4 beta1-integrin only in melanocytes of the deeper dermis. This integrin previously has been associated with high tumor thickness and the clinical outcome in melanomas. The integrin profile observed in melanomas differed in part from that seen in nevi with expression of beta2- and beta3-integrins in some cases. The results may indicate a correlation between adhesion molecule expression and histopathological findings in melanocytic lesions.

Cell Adhesion Molecules↗

PubMed2000

Proliferation and differentiation in the human breast during pregnancy.

Using multiple immunofluorescence labelling on human breast tissues obtained and freshly frozen at the 12th, 15th, and 18th weeks of pregnancy, we have shown that markers of mammary functional differentiation, milk proteins (beta-casein and kappa-casein), are synthesised by actively cycling (Ki67 positive) as well as non-cycling (Ki67 negative) cells. These results demonstrate that functional differentiation/maturation does not coincide with loss of proliferative potential in human mammary luminal epithelial cells. In addition, we have examined expression patterns of integrin subunits (alpha1, alpha2, alpha3, alpha6, beta1, and beta4) and extracellular matrix components (laminin, fibronectin, collagen I, and collagen IV), since they have been shown to exert influences on mammary differentiation and morphogenesis in vitro. Compared to human breast tissues obtained from non-pregnant women, a decrease in alpha2 labelling on luminal epithelial cells was observed, particularly in expanding acini that showed abundant Ki67 positivity. The expression patterns of other integrin subunits, however, did not change, indicating that the expression patterns of most integrins existing prior to pregnancy are sufficient to support the morphological and functional development associated with milk protein synthesis.

Adult↗

PubMedDate not supplied

Hepatocyte growth factor upregulates alpha2beta1 integrin in Madin-Darby canine kidney cells: implications in tubulogenesis.

It has been well established that hepatocyte growth factor (HGF) induces branching tubule formation of Madin-Darby canine kidney (MDCK) cells cultured in collagen gel. Tubulogenesis per se requires the involvement of cell proliferation, migration, focalization proteolysis, cell-cell interaction and differentiation. However, signaling pathways and proteins involved in HGF-induced tubulogenesis by MDCK cells have not been thoroughly studied. Because cell-matrix interactions play important roles in tubulogenesis, we analyzed whether HGF altered the expression of extracellular matrix receptor (alpha2, alpha3, beta1 and alphavbeta3 integrin). We found that among those proteins examined, alpha2beta1 integrin levels were enhanced by HGF. HGF-induced upregulation of alpha2beta1 integrin was mediated via upregulation of alpha2 integrin mRNA abundance. Cycloheximide blocked the HGF-induced increase in alpha2 integrin mRNA expression. To understand the signaling pathways leading to an HGF-induced increase in alpha2beta1 integrin levels, PD98059 (MEK1 inhibitor), LY294002 (PI3-kinase inhibitor), and GF109203X (PKC inhibitor) were used. We found that PD98059 blocked the HGF-induced increase in alpha2beta1 integrin expression. Furthermore, 5E8 (specific anti-alpha2beta1 integrin antibody) was employed to elucidate the potential role of HGF-induced upregulation of alpha2beta1 integrin in branching morphogenesis. 5E8 did not alter HGF-induced scattering effects but disrupted HGF-induced branching tubulogenesis in collagen gel via inhibition of cell-cell interactions and growth. Taken together, HGF upregulates alpha2beta1 integrin expression via an indirect pathway, the results of which contribute to the regulation of cell-cell interactions and cell growth during branching morphogenesis in collagen gel.

Animals↗

PubMed2005

Molecules mediating cell-ECM and cell-cell communication in human heart valves.

The specific phenotype of different tissues depends on the interactions of cells with neighboring cells and the surrounding extracellular matrix, which is mediated by cell adhesion receptors including integrins, immunoglobulin family members, syndecans, and selectins. The aim of this study was to investigate the adhesion profile of native human valve interstitial cells (ICs) in situ and in vitro by analyzing these adhesion receptors. Flow cytometry and immunocytochemistry was used to quantify the expression of the specific receptors on ICs cultured from all human cardiac valves, and immunohistochemistry were used to profile their distribution pattern in valve tissue sections. The valve leaflets and cultured ICs from all valves expressed alpha1, alpha2, alpha3, alpha4, and alpha5 integrins to varying degrees and percentages with very little expression of alpha6 and alphaV. Valve leaflet ICs from all valves, expressed predominantly beta1 integrin but no beta3 or beta4 integrin. Syndecan-1 and Syndecan-4 were not detected. Intercellular adhesion molecule-1 was weakly detected, whereas vascular adhesion molecule-1 was barely detectable and E-selectin was not detected. This study has delineated the identity of some of the integrins synthesized and expressed by human valve ICs and the specificity of adhesion molecules with which the valve ICs interact with the extracellular matrix and mediate intercellular interactions. This pattern of expression of cell surface adhesion molecules may be considered as a basis for a fingerprint on which to base future cell alternatives and would provide useful information for valve tissue engineering.

Cell Adhesion↗

PubMed1996

In vitro modulation of tumor progression-associated properties of hormone refractory prostate carcinoma cell lines by cytokines.

BACKGROUND: Cytokines exert cytostatic and immunomodulatory effects on carcinoma cells. Growth inhibition of human prostate carcinoma by cytokines has been demonstrated both in vitro and in vivo, whereas the cellular and molecular changes in prostate carcinoma properties after cytokine treatment have never been characterized. We have thus investigated whether the intrinsic properties of prostate carcinoma cells that are associated with tumor development and progression can be altered by direct cytokine treatment. METHODS: LNCaP, DU-145, and PC-3 cell lines were treated with tumor necrosis factor-alpha (TNF-alpha) (200 U/mL), interferon-gamma (IFN-gamma) (500 U/mL), human leukocyte interferon (IFN-alpha) (500 U/mL), and interleukin-2 (IL-2) (400 U/mL). The expression of (prostate-specific antigen [PSA] and prostate-specific membrane [PSM]), androgen receptor (AR), growth factors, oncogenes, collagenase, cell adhesion molecules, HLA antigens, cell adhesion to human bone marrow stroma, and cell growth were determined by quantitative polymerase chain reaction (PCR) analysis, fluorescence-activated cell sorter (FACS) analysis, and cell attachment and proliferation assays, and were compared with non-treated cells. RESULTS: PCR analysis indicated that only LNCaP cells expressed PSA, PSM, and AR mRNA. Cytokine treatment did not alter PSM mRNA expression, whereas a 15-fold decrease in PSA and a 5-fold reduction in AR mRNA expression was detected in TNF-alpha-treated cells. The down regulation of PSA production was also demonstrated at the protein level in a dose-dependent fashion. A fivefold decrease in PSA mRNA was also detected in IL-2-treated LNCaP cells but without a reduction in AR. Down regulated epidermal growth factor receptor (EGF-R) and basic fibroblast growth factor (b-FGF) mRNA expressions were detected in TNF-alpha- and IFN-alpha-treated DU-145 and PC-3 cells, whereas, only reduced EGF-R expression was observed in LNCaP cells. IFN-gamma and IL-2 treatment down regulated the expression of collagenase Type IV mRNA in DU-145 and PC-3 cells, whereas tumor transforming growth factor-beta (TGF-beta) and IL-6 mRNA expressions did not exhibit any essential changes after cytokine treatment. A reduction in c-myc mRNA expression was observed in TNF-alpha- and IFN-alpha-treated cells, whereas no change in HER-2 expression was noted in any cytokine treated cells. Up regulated P-cadherin, but not E-cadherin, mRNA expression was detected in TNF-alpha- and IFN-gamma-treated PC-3 cells. FACS analysis revealed that all but IL-2-treated cells had enhanced HLA Class I expression, with the maximum effect seen in TNF-alpha-treated LNCaP cells (threefold increase). Up regulated HLA Class II expression was seen only in IFN-gamma-treated cells. All cytokine-treated DU-145 and PC-3 cells expressed reduced levels of alpha3, but not beta1, integrin. Up regulated of ICAM-1 expression was seen in all cytokine treated DU-145 and PC-3 cells, whereas no change in CD44 occurred. Cytokine treatment reduced the binding affinity of LNCaP and DU-145, but not of PC-3 cells, to human bone marrow stromal cells, and all cytokines but IL-2 showed a mild to moderate growth inhibition to prostate cancer cells, with a marked inhibition only observed in TNF-alpha-treated LNCaP cells. CONCLUSIONS: Cytokine treatment can effectively alter several prostate carcinoma properties that are closely associated with tumor invasion and a metastatic phenotype, suggesting that immunotherapy via the local delivery of cytokines may have a potentially therapeutic role in the treatment of hormone-refractory prostate cancer through both direct and indirect antitumor mechanisms.

Antigens, Neoplasm↗

PubMed1998

Immunohistochemical and urinary markers of podocyte injury.

Renal podocytes play an important role in glomerular filtration. We estimated podocyte injury by light microscopic examination of kidney specimens or by urinary excretion of substances related to podocytes. Fresh kidney sections from 69 patients and urinary sediments from 84 patients with various renal diseases were examined immunohistochemically using fluorescent labelling. Four kinds of monoclonal antibodies which recognize podocytes were used: (1) anti-podocalyxin (anti-PCX) antibody, (2) anti-C3b receptor (anti-C3bR) antibody, (3) anti-podocyte protein, 44 kilodalton, (anti-pp44) antibody, and (4) anti-alpha 3 integrin (anti-Int alpha3) antibody. Labelling of kidney sections by anti-C3bR (k-C3bR) was reduced in cases of severe glomerular injury, although there were no changes in k-PCX, k-pp44, or k-Int alpha3 labelling. PCX labelling of urinary sediments (u-PCX) was detected in nearly all cases of glomerulonephritis, u-C3bR was seen in some cases of glomerular injury, u-Int alpha3 was seen in only a small number of cases of severe glomerular injury, and u-pp44 was not detected in any urinary samples. u-PCX, u-C3bR, u-Int alpha3, and k-C3bR correlated with the degree of pathological change, the degree of proteinuria and hematuria. These results suggest that immunostaining kidney sections with anti-C3bR antibody and urinary sediments with anti-PCX, anti-C3bR, and anti-Int alpha3 antibodies might be useful in detecting podocyte injury.

Adolescent↗

PubMed1999

Chemokines induce the cellular migration of MCF-7 human breast carcinoma cells: subpopulations of tumour cells display positive and negative chemotaxis and differential in vivo growth potentials.

We previously reported that chemotactic cytokines (chemokines) induce the directional migration of cells derived from the breast carcinoma cell line MCF-7 in vitro, however it was apparent that only a small percentage of cells displayed the ability to migrate upon stimulation. In the present study three sub-lines derived from the parental MCF-7 cell line were selected for their ability to migrate in response to MIP-1alpha, MIP-1beta or RANTES across Transwell filters of 8 microm pore size. The first round selection of migratory cells resulted in sub-populations which demonstrated an increased chemotactic response compared with parental cells. Cells migrating to MIP-1beta were subjected to four further rounds of positive or negative selection, resulting in two sub-lines, MCF-7L4 and MCF-7U4 which displayed an increased and decreased chemotactic response respectively to MIP-1alpha MIP-1beta and RANTES. No difference in chemokine receptor RNA message expression between these sub-lines and the parental MCF-7 line were detected, although increased levels of alpha3, alpha6 and alphav integrin sub-units were shown for MCF-7L4 (positively selected sub-line) compared with MCF-7U4 cells. Moreover, the in vivo growth of cells derived from the two MCF-7 sub-lines was inversely correlated with their chemotactic response. The results of this study depict further the inherent heterogeneity in cancer, suggesting that the chemotactic response may influence the migratory traits of sub-populations within the tumour and potentially contribute to their in vivo behavior, growth and survival.

Breast Neoplasms↗

PubMed1997

Phenotypic characterization of keratinocytes migrated from polymer support - in vitro study.

The keratinocytes are able to migrate from the poly (2- hydroxyethylmethacrylate) disc if it is transferred to the new Petri-dish colonized with irradiated 3T3 mouse fibroblasts, and form a ring-shaped colony around the disc. The phenotypic characterization of human keratinocytes migrated from these discs was studied using a group of monoclonal antibodies. The keratinocytes in the external periphery of the colony of cells which migrated from the disc express the proliferating cell nuclear antigen (PCNA), alpha2, alpha3 chains and alpha5beta1 integrin receptor. A protein of the desmosome complex, desmoplakin-1, was also expressed. Involucrin and cytokeratin-10 were expressed after prolonged cultivation. These results suggest that the migrated keratinocytes are able to proliferate, recognize extracellular matrix molecules important in the process of the re-epitelization of the wound, and terminally differentiate in vitro. They are encouraging for further experiments with respect to the development of a support for keratinocyte cultivation and for grafting in clinical practice.

Journal Article↗

PubMed1999

Identification of antigens on porcine pulmonary microvascular endothelial cells recognized by human xenoreactive natural antibodies.

Transplantation of organs between species is prevented in part by humoral immune responses triggered by xenoreactive natural antibodies. Although the immune barrier to xenotransplantation of the lung is thought to be qualitatively and quantitatively different than the immune barrier to xenotransplantation of the kidney or heart, the antibody-antigen reactions responsible for rejection of pulmonary xenografts have not been characterized. To begin to address this issue for porcine lungs transplanted into humans, we analyzed the porcine pulmonary endothelial antigens recognized by human xenoreactive natural antibodies. Human and baboon natural antibodies recognized glycoprotein and glycolipid antigens isolated from the membranes of porcine pulmonary microvascular endothelial cells. The antigens included the integrin chains alpha1, alpha2, alpha3, alpha5, alpha(v), beta1, beta 3, the von Willebrand Factor, and fibronectin. These glycoproteins seemed to be recognized by the same antibodies that bind to porcine kidney or cardiac xenografts. Natural antibodies also recognized at least four glycolipids containing from one to five sugar residues, although at a lower level per unit number of cells than glycoprotein antigens. The epitope recognized by natural antibodies was predominantly Gal alpha1-3Gal, a structure expressed by lower mammals but not by humans and baboons. The antigens recognized by human antibodies in the porcine lung may provide insight into the pathogenesis of the rejection reaction. Moreover, the similarity of porcine lung antigens to porcine kidney and heart antigens suggests that differences in the rejection reactions between these organs reflects the distinct responses of the organs to humoral immunity.

Animals↗

PubMed2005

Tumor cell invasiveness correlates with changes in integrin expression and localization.

In nontumorigenic mammary epithelial cells (EpH4), transforming growth factor-beta (TGFbeta1) causes cell cycle arrest/apoptosis, but induces epitheliomesenchymal transition (EMT) in Ha-Ras-transformed EpH4 cells (EpRas). EMT is closely correlated with late-stage tumor progression and results in fibroblastic, migratory cells displaying a mesenchymal gene expression program (FibRas). EpRas and FibRas cells showed strongly increased cell substrate adhesion to fibronectin, collagens I/IV and laminin 1. Furthermore, Ras transformation caused enhanced or de-novo expression of the integrin subunits beta1, alpha2 and alpha3, or alpha5 and alpha6, respectively, the latter subunits being even more strongly expressed in FibRas cells. Importantly, polarized EpRas cells expressed integrin subunits beta1 and alpha6 at distinct (apical and lateral) membrane domains, while FibRas cells coexpressed these integrins and alpha5 at the entire plasma membrane. During EMT, EpRas cells formed an alpha5beta1 complex and deposited its ligand fibronectin into the extracellular matrix. Function-blocking alpha5 antibodies attenuated migration, and caused massive apoptosis in EpRas cells undergoing TGFbeta1-induced EMT in collagen gels, but failed to affect EpRas- or FibRas-derived structures. We conclude that functional alpha5beta1 integrin is centrally implicated in EMT induction. Importantly, FibRas cells also failed to deposit the alpha6beta4 ligand laminin 5, suggesting that alpha6beta4 is no longer functional after EMT and replaced by mesenchymal integrins such as alpha5beta1.

Breast↗

PubMed1999

Alpha8 integrin in glomerular mesangial cells and in experimental glomerulonephritis.

BACKGROUND: Mesangial cell (MC) proliferation and extracellular matrix accumulation are typical responses of renal glomeruli to injury. Extracellular matrix components are known to affect MC behavior, which is mediated primarily via integrin receptors of the beta1 family. In addition to alpha1, alpha3, alpha5, and alpha6 chains of beta1 integrins, recent studies have shown the alpha8 chain to be expressed in glomeruli and renal vasculature. alpha8beta1 can serve as a receptor for fibronectin, which is abundant in the mesangium. We investigated the glomerular expression pattern of the alpha8 chain in renal tissues of mouse, rat, and humans as well as in cultured MCs. In addition, the regulation of alpha8 expression in MCs was studied in culture and in nephritic rats. METHODS: The expression of alpha8 protein in kidney tissue and cultured MCs was investigated by immunohistochemistry, immunocytochemistry, and Western blotting. The effects of TGF-beta1 on alpha8 mRNA levels in MCs were studied by Northern blot analysis. In addition, time course studies of glomerular abundance and localization of alpha8 were performed in rats with mesangioproliferative anti-Thy1.1 nephritis. RESULTS: In tissue sections of normal human, rat, and mouse kidney, we found strong immunohistochemical staining for alpha8 in the mesangium and in the media of renal arterioles. Double staining for alpha8 and Thy1.1, a surface antigen of rat MCs, showed alpha8 to be specifically expressed in MCs but not in glomerular endothelial and epithelial cells. In anti-Thy1.1 nephritis of rats, the glomerular abundance of alpha8 protein was reduced in the early mesangiolytic phase but was increased greatly with subsequent MC proliferation, peaking at day 6 of disease. At later stages of this reversible form of nephritis, the number of MCs and the extent mesangial alpha8 staining declined to control levels. Cell culture experiments revealed that freshly plated MCs organize alpha8 into focal contacts within one hour after attachment to fibronectin and vitronectin substrata, showing colocalization with focal contact proteins vinculin and talin. Stimulation of MCs with transforming growth factor-beta1 led to increases of alpha8 mRNA and protein levels. CONCLUSIONS: These results show that in human, rat, and mouse glomeruli, alpha8 integrin is strongly and exclusively expressed in MCs. Gene expression of alpha8 is regulated in cultured MCs, and alpha8 protein abundance is regulated in vivo and in MC culture. It is currently unclear what functional properties this integrin receptor protein has with regard to MC anchorage to extracellular matrix and modulation of the MC phenotype in normal and diseased glomeruli. However, in view of its abundance in the mesangium, alpha8beta1 integrin could be an important MC receptor of matrix ligands and may play a role in the embryology, physiology, and pathophysiology of the glomerular capillary tuft.

Animals↗

PubMed1999

In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese.

Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.

Cells, Cultured↗

PubMed2004

Adhesion of HT-29 colon carcinoma cells to endothelial cells requires sequential events involving E-selectin and integrin beta4.

HT-29 colon carcinoma cells attach to TNFalpha-activated human umbilical vein endothelial cells (HUVECs) by their specific binding to E-selectin. This interaction activates, in the cancer cells, the MAPK SAPK2/p38, which leads to their transendothelial migration (Laferrière et al., J Biol Chem 2001; 276: 33762). In this study, we investigated the role of E-selectin in activating integrins to modulate adhesion and regulate integrin-mediated events. Blocking the integrins from HT-29 cells (alpha2, alpha3, alpha6, alphav/beta5, beta1 and beta4) with specific antibodies revealed a role for beta4 integrin in their adhesion to TNFalpha-treated HUVEC. The beta4 integrin-dependent adhesion was maximal after 30 min, whereas the-E-selectin-dependent adhesion was maximal after 15 min. Integrin beta4 became quickly phosphorylated upon addition of HT-29 cells to endothelial cells and the effect was independent of the expression of E-selectin. Moreover, a recombinant E-selectin/Fc chimera did not induce the phosphorylation of beta4. The phosphorylation of beta4 is not required for adhesion since adhesion was not affected in HT-29 cells that express a truncated form of beta4 that is deleted from its cytoplasmic phosphorylatable domain. However, the expression of the non-phosphorylatable deletant of beta4 was associated with decreased transendothelial cell migration underscoring the key role for the cytoplasmic domain of beta4 in cell migration. We suggest: 1) that the adhesion of HT-29 cells to activated endothelial cells follows at least two essential sequential steps involving the binding of E-selectin to its receptor on carcinoma cells and then the binding of beta4 to its own receptor on endothelial cells; 2) that the phosphorylation of integrin beta4 contributes to enhance the motile potential of cancer cells and increase their trans-endothelial migration. Overall, our results indicate that the interaction of metastatic cancer cells with endothelial cells implies a specific sequence of signaling events that ultimately leads to an increase in their efficient transendothelial migration.

Cell Adhesion↗

PubMed1997

Primary prostatic epithelial cell binding to human bone marrow stroma and the role of alpha2beta1 integrin.

Prostate cancer selectively metastasises to the bone. To investigate the importance of prostate epithelial cell adhesion to bone marrow cells in this process we examined the binding of human primary prostatic epithelial cells (PEC) to human bone marrow stromal cultures (BMS). We found that PEC derived from both malignant and benign tissue showed greater adhesion to BMS than to benign prostatic fibroblasts (median difference was 340% and 200% respectively), skin fibroblasts or plastic tissue culture plates. Adhesion to BMS grown from the bone marrow of patients with prostatic skeletal metastases was no different from those grown from normal bone marrow. The role of integrin molecules in these cell interactions was determined. Collagen type I and fibronectin were found to increase PEC adhesion whereas vitronectin and laminin did not. Inhibition studies demonstrated that although there was heterogeneity between samples, antibodies against the integrins alpha2 and beta1 consistently inhibited PEC binding to BMS. This result was more marked for PEC derived from malignant tissue. However studies investigating the effects of disintegrins and anti-alpha3 and anti-alpha5 integrins indicated that for a percentage of patients these integrins and RGD (arginine, glycine, aspartamine)-dependent binding pathways were also involved. In summary, the results indicate that BMS are adherent to primary PEC derived from both malignant and benign tissue. The integrin alpha2beta1 is a major contributor to this interaction.

Animals↗

PubMed2000

Conditional ablation of beta1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination.

The major epidermal integrins are alpha3beta1 and hemidesmosome-specific alpha6beta4; both share laminin 5 as ligand. Keratinocyte culture studies implicate both integrins in adhesion, proliferation, and stem cell maintenance and suggest unique roles for alphabeta1 integrins in migration and terminal differentiation. In mice, however, whereas ablation of alpha6 or beta4 results in loss of hemidesmosomes, epidermal polarity, and basement membrane (BM) attachment, ablation of alpha3 only generates microblistering due to localized internal shearing of BM. Using conditional knockout technology to ablate beta1 in skin epithelium, we have uncovered biological roles for alphabeta1 integrins not predicted from either the alpha3 knockout or from in vitro studies. In contrast to alpha3 null mice, beta1 mutant mice exhibit severe skin blistering and hair defects, accompanied by massive failure of BM assembly/organization, hemidesmosome instability, and a failure of hair follicle keratinocytes to remodel BM and invaginate into the dermis. Although epidermal proliferation is impaired, a spatial and temporal program of terminal differentiation is executed. These results indicate that beta1's minor partners in skin are important, and together, alphabeta1 integrins are required not only for extracellular matrix assembly but also for BM formation. This, in turn, is required for hemidesmosome stability, epidermal proliferation, and hair follicle morphogenesis. However, beta1 downregulation does not provide the trigger to terminally differentiate.

Animals↗

PubMed1998

Expression of the VLA family of integrins in coeliac intestinal mucosa.

The integrins, a family of cell surface proteins, mediate cell adhesion and may influence within the intestinal mucosa processes such as migration and/or proliferation and differentiation of enterocytes and lymphocytes. The aim of this study was to examine the distribution pattern of integrin subunits (VLA alpha1, alpha2, alpha3, alpha4, alpha5, alpha6, beta1 chains) in normal intestinal mucosa and in that of patients with active coeliac disease (CD) and CD in remission. Immunohistochemical techniques and double immunostainings with monoclonal antibodies were used for investigation of the VLA alpha family of integrins and beta1 chain distribution. While the majority of the findings are consistent with the few data previously reported in the literature, surprising is the finding of a lack of expression of VLAalpha1 on the intraepithelial lymphocytes in the coeliac mucosa. The deficient VLA alpha1 expression on IEL in coeliac but not in normal mucosa may imply a genetic variation or a specific deficiency of gene expression during T cell differentiation and activation.

Antibodies, Monoclonal↗

PubMed2001

Extracellular matrix molecules improve periodontal ligament cell adhesion to anorganic bone matrix.

Bone replacement graft (BRG) materials are used in periodontal therapy to encourage new bone formation. Extracellular matrix proteins may improve periodontal ligament fibroblast (PDLF) attachment to these materials. We demonstrate that PDLFs adhere well to the extracellular matrix (ECM) proteins fibronectin, vitronectin, laminin, and collagen types I and IV. PDLFs express numerous ECM-receptor integrin subunit transcripts (alpha1, alpha2, alpha3, alpha4, alpha5, alpha11, beta1, beta5, and beta8) at high levels, while others (alpha6, alpha9, alphaV, beta3, beta6, and beta7) are expressed at reduced levels. Despite the fact that PDLFs adhere well to fibronectin and collagen type IV bound to plastic, and express integrins that recognize these ECM proteins, they do not attach well to anorganic bovine bone matrix (ABM) coated with these same proteins. However, the addition of vitronectin, laminin, or collagen type I to these same ABMs substantially increased PDL cell attachment. Thus, selective use of ECM proteins may be clinically useful in promoting cell attachment to ABM and bone regrowth.

Adsorption↗