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Results for “Integrin alpha6”

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PubMed2004

Collagen type IV, laminin, alpha-smooth muscle actin (alphaSMA), alpha1 and alpha6 integrins expression in the liver with metastases from malignant gastrointestinal tumours.

Basement membrane proteins and integrins can profoundly affect the biological behaviour of metastasic tumour cells. Using light and ultrastructural immunohistochemistry, we showed the presence of alterations in the occurrence of collagen type IV and laminin, and the expression of alpha1 and alpha6 integrin chains in the livers of patients with metastases from gastric, colorectal and pancreatic cancers. The myofibroblast-like cells in the metastatic stroma were studied. Parallel expressions of alpha-SMA, collagen type IV and alpha1 integrin chain, and appearance of laminin and alpha6 integrin chain immunoreactivity in the extratumoral liver tissue were markedly increased in sinusoids associated with metastases. Furthermore, ultrastructural immunohistochemistry detected tumour cells adhered to amorphous laminin deposits in the metastases. Laminin occurrence in liver sinusoids was visible as fine amorphous deposits in the space of Disse. The similarity between alpha-SMA-positive stromal cells in metastatic stroma and hepatic stellate cells (HSCs) was established by the presence of lipid droplets in their cytoplasm. The immune deposits of alpha1 and alpha6 integrin chains were observed on the hepatocyte microvilli and on the membrane of sinusoidal endothelial cells. These findings suggest that metastatic cells produce stimuli that induce HSCs activation and sinusoidal changes. In addition, the enhanced parallel expression of alphaSMA, collagen type IV, laminin and of alpha1 and alpha6 integrin chains in sinusoids associated with metastases, might potentiate the further dissemination of tumour cells in new liver areas.

Actins↗

PubMed2005

PECAM-1, alpha6 integrins and neutrophil elastase cooperate in mediating neutrophil transmigration.

The heterogeneous nature of the perivascular basement membrane (composed primarily of laminin and collagen type IV) suggests the existence of an elaborate array of adhesive interactions and possibly proteolytic events in leukocyte migration through this barrier. In this context, blockade of alpha6 integrins (laminin receptors), neutrophil elastase (NE) or both inhibited neutrophil migration through interleukin-1beta (IL-1beta)-stimulated mouse cremasteric venules, as observed by intravital microscopy. Furthermore, analysis of tissues by confocal microscopy indicated a synergistic role for alpha6 integrins and NE in mediating neutrophil migration through the perivascular basement membrane. Using a combined in vitro and in vivo experimental approach, the findings of this study also suggest that alpha6 integrins and NE are mobilized from intracellular stores to the cell surface of transmigrating mouse neutrophils, although these events occur via mechanisms dependent on and independent of platelet/endothelial-cell adhesion molecule 1 (PECAM-1, CD31), respectively. Despite different regulatory mechanisms, blockade of alpha6 integrins or NE inhibited migration of murine neutrophils through laminin-coated filters in vitro. Collectively, the findings suggest that, whereas regulation of the expression of alpha6 integrins and NE occur via different adhesive mechanisms, these molecules might act in a cooperative manner in mediating neutrophil migration through venular walls, in particular the perivascular basement membrane.

Animals↗

PubMed2005

Alpha6 integrin subunit mediates laminin enhancement of cisplatin-induced apoptosis in testicular tumor germ cells.

Our study demonstrates that laminin potentiates cisplatin-induced apoptosis in NCCIT, a testicular tumor germ cell line. When cultured on laminin, NCCIT cells displayed a significantly higher susceptibility to cisplatin-induced apoptosis than on plastic or on other ECM components including fibronectin, Type IV collagen and vitronectin. This high cisplatin sensitivity observed on NCCIT cell cultured on laminin was mediated by the alpha6-integrin signaling. The knockdown of the alpha6-integrin subunit by small interfering RNAs suppressed the higher cisplatin-sensitivity supporting the existence of a crosstalk between laminin-alpha6-integrin signaling and cisplatin-induced apoptosis. Our findings indicate that in cisplatin-treated NCCIT cells, the laminin-alpha6-integrin signaling induces the activation of executioner procaspase-3 and -6 as well as apoptosis-inducing factor (AIF) transcription and expression. The ability of integrin-mediated specific stroma-tumor cell interactions to modulate the chemosensitive phenotype of a tumor cell might provide new insights to overcome cisplatin resistance of tumor cells.

Apoptosis↗

PubMed2004

Alpha6-integrin is expressed on germinal centre B cells and modifies growth of a B-cell line.

The production of high-affinity antibodies requires diversification of the antibody repertoire by somatic hypermutation followed by selection of those B cells bearing the highest affinity antibodies. Whilst many surface molecules that mediate the cell-cell interactions required for germinal centre formation have been identified, little is known of the importance of interactions with components of the extracellular matrix, i.e. fibronectin, collagen and laminin. We demonstrate that the laminin-binding alpha6-integrin is expressed on germinal centre B cells and is induced during the in vitro activation of naïve splenic B cells. A laminin network is demonstrated within the germinal centre. Analysis of an alpha6-integrin-expressing mouse B-cell line, A20, demonstrates that this molecule is essential for binding to laminin, and that blocking by anti-alpha6-integrin immunoglobulin causes loss of adhesion associated with an increase in proliferation. There is no correlation with changes in BCL-6 or Blimp-1 expression, suggesting that alpha6-integrin does not play a role in differentiation.

Animals↗

PubMed2001

Regulation of laminin 1-induced pancreatic beta-cell differentiation by alpha6 integrin and alpha-dystroglycan.

BACKGROUND: The ability to manipulate the development of pancreatic insulin-producing beta cells has implications for the treatment of type 1 diabetes. Previously, we found that laminin-1, a basement membrane trimeric glycoprotein, promotes beta-cell differentiation. We have investigated the mechanism of this effect, using agents that block the receptors for laminin-1, alpha6 integrin, and alpha-dystroglycan (alpha-DG). MATERIALS AND METHODS: Dissociated cells from 13.5-day postcoitum (dpc) fetal mouse pancreas were cultured for 4 days with laminin-1, with and without monoclonal antibodies and other agents known to block integrins or alpha-DG. Fetuses fixed in Bouin's solution or fetal pancreas cells fixed in 4% paraformaldehyde were processed for routine histology and for immunohistology to detect hormone expression and bromodeoxyuridine (BrdU) uptake. RESULTS: Blocking the binding of laminin-1 to alpha6 integrin with a monoclonal antibody, GoH3, abolished cell proliferation (BrdU uptake) and doubled the number of beta cells. Inhibition of molecules involved in alpha6 integrin signaling (phosphotidylinositol 3-kinase, F-actin, or mitogen-activated protein kinase) had a similar effect. Nevertheless, beta cells appeared to develop normally in alpha6 integrin-deficient fetuses. Blocking the binding of laminin-1 to alpha-DG with a monoclonal antibody, IIH6, dramatically decreased the number of beta cells. Heparin, also known to inhibit laminin-1 binding to alpha-DG, had a similar effect. In the presence of heparin, the increase in beta cells in response to blocking alpha integrin with GoH3 was abolished. CONCLUSIONS: These findings reveal an interplay between alpha6 integrin and alpha-DG to regulate laminin-1-induced beta-cell development. Laminin-I had a dominant effect via alpha-DG to promote cell survival and beta-cell differentiation, which was modestly inhibited by alpha6 signaling.

Animals↗

PubMed2005

The alpha6 integrin subunit in the developing mouse olfactory bulb.

Integrins are heterodimeric cell surface receptors that mediate developmental events by binding extracellular matrix ligands. Several lines of evidence suggest a role for integrins, specifically the alpha 6 subunit, in neuronal migration, neurite outgrowth, and axon guidance during olfactory development. Therefore, we undertook an analysis of the expression of the alpha 6 subunit in the olfactory system of the embryonic and early postnatal mouse to understand the role it may play during neural development. In addition, as a functional assay we examined the developmental effects of the loss of this subunit on olfactory development by analyzing an alpha 6 knockout (alpha 6-/-). Immunohistochemical analyses and confocal microscopy were used to examine alpha 6 expression in the CD-1 embryonic and early postnatal olfactory system and also to examine the organization of the olfactory system in the alpha 6-/- mouse. In CD-1 mice from E13 to E17, alpha 6 localizes in radial patterns extending from the core of the olfactory bulb to the nerve layer and colocalizes with RC2, an antibody specific for radial glia. By the day of birth (P0; approximately E19), expression is limited to the external plexiform layer and the olfactory nerve layer, where it colocalizes with laminin and p75. In the alpha 6-/- mouse, areas of ectopic granule cells were observed in the mitral cell layer of the olfactory bulb. These ectopias coincided with areas of disorganization of the radial glial processes and breaks in the mitral cell layer. These observations suggest a role for alpha 6 integrin in neural migration during olfactory development, likely secondary to organization of the radial glial scaffold.

Animals↗

PubMed1998

Interaction of BP180 (type XVII collagen) and alpha6 integrin is necessary for stabilization of hemidesmosome structure.

The hemidesmosome is a multimolecular complex that integrates the extracellular matrix with the keratin cytoskeleton and that stabilizes epithelial attachment to connective tissue. A 180 kDa protein (BP180, type XVII collagen), first identified by its reactivity with autoantibodies in the serum of patients with a blistering skin disease called bullous pemphigoid (BP), is a transmembrane component of the hemidesmosome with a collagen-like extracellular domain. Here, using recombinantly expressed molecules and the yeast two-hybrid assay, we have identified alpha6 integrin as a BP180-binding partner. The association between specific domains of the BP180 and alpha6 integrin molecules is inhibited by a 14 mer peptide, whose sequence is identical to amino acid residues 506-519 in the noncollagenous region of the ectodomain of the BP180 molecule, as well as by antibodies raised against this peptide. The 14 mer peptide sequence is part of an epitope recognized by autoantibodies that are pathogenic in BP. In vivo, when 804G cells are plated into medium containing the same peptide, they fail to assemble hemidesmosomes. Furthermore, although BP180 and certain cytoplasmic components of the hemidesmosome colocalize in the peptide-treated cells, they are aberrantly distributed and fail to show extensive association with (alpha6beta4 integrin. Taken together, our results indicate that BP180 is a novel transmembrane ligand of the alpha6beta4 integrin heterodimer. In addition, our data provide support for the possibility that BP180 and alpha6 integrin interaction is not only mediated by the BP epitope but is necessary for hemidesmosome formation.

Antigens, CD↗

PubMed1996

Abrogation of lung metastasis of human fibrosarcoma cells by ribozyme-mediated suppression of integrin alpha6 subunit expression.

The interaction of tumor cells with the basement membrane plays a crucial role in tumor metastasis. VLA-6 (alpha6beta1) integrin is one of the major surface receptors for the basement membrane, specifically recognizing laminin. To study the role of VLA-6 integrin in tumor invasion and metastasis, we synthesized a ribozyme that selectively degrades the integrin alpha6 subunit mRNA. The catalytic activity of the ribozyme was verified by in vitro cleavage of alpha6 subunit mRNA. Introduction of the anti-alpha6 ribozyme gene into the human fibrosarcoma cell line HT1080 yielded stable transfectants, which expressed a significantly reduced level of integrin alpha6 mRNA. Flow cytometric analysis showed that the surface expression of VLA-6, but not other integrins, was reduced by approximately 70% in transfected cells. Ribozyme-transfected cells were less adherent to laminin-coated substrata and less invasive into reconstituted basement membrane than mock-transfected cells. When injected i.v. into nude mice, ribozyme-transfected cells produced no lung metastasis in all except 1 of 35 mice, though mock-transfected cells produced multiple lung metastases in 22 of 29 mice. Our results indicate that VLA-6 integrin plays a critical role in tumor invasion and metastasis and may serve as a potential target for eradication of tumor metastasis in the lung.

Animals↗

PubMed2002

Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titres to human alpha6 integrin.

SUMMARY: Oral pemphigoid (OP) is a chronic autoimmune disease, involving the oral cavity, characterized by a homogenous linear deposition of immunoglobulins, complement, or both along the basement membrane zone (BMZ) and a subepithelial blister formation. The alpha6/beta4 heterodimer is an integrin family of adhesion receptors, which mediates basal cell to matrix interactions. Recent evidence suggests a pathophysiologic role for antibodies against human alpha6 integrin in blister formation in OP, in organ culture studies. Fifty percent of OP patients have been reported to experience disease progression to involve other mucosal tissues, including the eye and larynx. To prevent this extension of disease, systemic therapy with systemic corticosteroids, dapsone, and immunosuppressive agents has been recommended. The use of intravenous immunoglobulin (IVIg) in the treatment of pemphigoid has been recently described. In this study, we present the use of IVIg, in a group of seven patients, with severe OP, in whom systemic conventional treatment was contraindicated. To determine the influence of treatment on antibodies to human alpha6 integrin in OP, seven patients with OP treated with IVIg therapy and a comparable control group of seven patients with OP, treated with conventional therapy, were evaluated at monthly intervals, for a 12 consecutive month treatment period. An effective clinical response was observed in all seven patients treated with IVIg therapy, after a mean treatment period of 4.5 months. IVIg therapy induced a prolonged and sustained clinical remission in all seven patients after a mean treatment period of 26.9 months. A statistically significant difference was observed in the quality of life pre- and post-IVIg therapy (P < 0.001). Both the study and the control groups had a very similar initial serological response to treatment. A statistically significant reduction in the antibody titres was observed after four months of treatment, in both groups (P = 0.015). Thereafter, patients treated with IVIg therapy had a faster rate of decline in the antibody titres, and the difference in the rate of decline between the study and control groups became statistically significant after six months of treatment (P = 0.03). The use of IVIg therapy resulted in reduction of antialpha6 antibody titres and in inducing and maintaining both a sustained, clinical and serological remission.

Adult↗

PubMed2001

Down-regulation of alpha6 integrin, an anti-oncogene product, by functional cooperation of H-Ras and c-Myc.

BACKGROUND: The molecular basis of cooperation of H-Ras and c-Myc in regulating cellular behaviour, such as cell adhesiveness, is still poorly understood. To investigate the role of H-Ras and c-Myc in cell adhesiveness, a constitutively active H-RasV12 (H-RasV12) and c-Myc were stably expressed, singly or in combination in a haematopoietic cell line, and the expression and activity of cell adhesion molecules were monitored. RESULTS: We have shown that the ectopic expression of H-RasV12, but not c-Myc alone, in a haematopoietic cell line, induces the activation of very late antigen-6 (VLA-6, alpha6beta1) integrin. Co-expression of H-RasV12 and c-Myc in the same cells further resulted in the induction of expression of vascular cell adhesion molecule-1 (VCAM-1) and the inhibition of expression of alpha6 integrin, a candidate anti-oncogene product, leading to a loss of adhesiveness to laminin (Lm), a ligand for VLA-6. CONCLUSIONS: Cooperation of H-Ras and c-Myc reciprocally regulates expression of the adhesion molecules, alpha6 integrin and VCAM-1. Our results represent an unprecedented account of the cooperation of the oncogene products, H-Ras and c-Myc, to inhibit expression of an anti-oncogene product, alpha6 integrin.

Animals↗

PubMed1997

Homozygous alpha6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia.

Junctional epidermolysis bullosa with congenital pyloric or duodenal atresia is a distinct variant within this group of autosomal recessive blistering skin diseases. In this study we demonstrate, for the first time, a homozygous mutation in the alpha6 integrin gene (ITGA6) in a family with three affected individuals. For this purpose, we first determined the genomic organization of ITGA6, and placed the gene on chromosome 2q by high resolution radiation hybrid mapping. Heteroduplex analysis of PCR products containing the individual exons of ITGA6, followed by direct nucleotide sequencing, revealed that the proband was homozygous for a G-to-T transversion in the +1 position of intron 12. This mutation, 1856+1G-->T, affects an invariant base of the 5' donor splice site predicting aberrant splicing involving exon 12. The mutation was verified in the proband's DNA by restriction enzyme digestion which also confirmed that the parents were heterozygous carriers of this mutation. Altered expression of alpha6 integrin, which forms a heterodimer with the beta4 subunit at the dermal-epidermal junction, would explain fragility and blistering as a result of minor trauma to the skin.

Antigens, CD↗

PubMed2004

Contributions of the alpha6 integrins to breast carcinoma survival and progression.

This review summarizes recent findings that support a key role for the alpha6 integrins (alpha6beta1 and alpha6beta4) in the progression of breast carcinoma. The hypothesis that emerges from the existing data is that both of these integrins have the ability to sustain the survival of breast carcinoma cells, especially in stress conditions such as those that exist in the tumor microenvironment. The mechanisms by which these integrins promote survival appear to involve their ability to regulate the expression of vascular endothelial growth factor (VEGF), either at the level of transcription or translation. VEGF produced by breast carcinoma cells in response to alpha6 integrin regulation can function in an autocrine manner to promote survival signaling.

Breast Neoplasms↗

PubMed1999

beta1- and alpha6-integrin are surface markers on mouse spermatogonial stem cells.

Although spermatogenesis is essential for reproduction, little is known about spermatogonial stem cells. These cells provide the basis for spermatogenesis throughout adult life by undergoing self-renewal and by providing progeny that differentiate into spermatozoa. A major impediment to our understanding of the biology of these stem cells is the inability to distinguish them from spermatogonia that are committed to differentiation. We made use of the known association of stem cells with basement membranes and our spermatogonial transplantation assay system to identify specific molecular markers on the stem cell surface. Selection of mouse testis cells with anti-beta1- or anti-alpha6-integrin antibody, but not anti-c-kit antibody, produced cell populations with a significantly enhanced ability to colonize recipient testes and generate donor cell-derived spermatogenesis. We demonstrate spermatogonial stem cell-associated antigens by using an assay system based on biological function. Furthermore, the presence of surface integrins on spermatogonial stem cells suggests that these cells share elements of a common molecular machinery with stem cells in other tissues.

Animals↗

PubMed2005

The telomerase activity of adult mouse testis resides in the spermatogonial alpha6-integrin-positive side population enriched in germinal stem cells.

Testis is one of the organs with the most telomerase activity in the adult. This activity protects chromosomes from telomere attrition and ensures the transmission of full-length chromosomes to progeny. Little is known about telomerase activity during adult germ cell differentiation, however. We demonstrate here that the telomerase activity of adult mouse testis resides in the alpha6-integrin-positive Side Population containing spermatogonia and enriched in spermatogonial stem cells. The telomerase activity of these cells fell upon entry into meiosis and during the subsequent spermiogenesis. In addition, the telomerase activity of cells in various stages of differentiation was unaffected by aging and, notably, remained high in the alpha6-integrin-positive Side Population.

Age Factors↗

PubMed1997

Increased expression of alpha6-integrin receptors and of mRNA encoding the putative 37 kDa laminin receptor precursor in pancreatic carcinoma.

The expression of alpha6-integrin receptors (VLA-alpha6) and of mRNA encoding the putative 37 kDa laminin receptor precursor (37 LRP) was determined in ductal pancreatic adenocarcinoma and normal pancreatic tissue from the same patient. VLA-alpha6 expression was enhanced and redistributed in pancreatic carcinoma, and 37 LRP mRNA levels were elevated in carcinomatous pancreatic tissue as well as in five pancreatic tumor cell lines. The molecular weight of the major RNA species detected was higher in carcinoma tissue (1.9 kb) as opposed to cell lines (1.2 kb), possibly reflecting alternative splicing of 37 LRP mRNA in the primary tumor.

Adenocarcinoma↗

PubMed2007

Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin.

BACKGROUND: Mucous membrane pemphigoid is an autoimmune mucocutaneous blistering disease. A subset, known as anti-epiligrin cicatricial pemphigoid is associated with a high risk for malignancy. Oral pemphigoid (OP) is limited to the oral cavity. The purpose of this study was to determine the association between malignancy and patients with OP with antibodies to alpha6-integrin subunit. METHODS: We determined the incidence of cancer in 72 patients with OP and compared it to the expected incidence using age and sex-specific rates of malignancy in the National Cancer Institute's Surveillance, Epidemiology, and End Results (NCI SEER) Registry. RESULTS: During a mean observation period of 9.1 years (range: 2.8-40), for 70, three OP patients developed malignancies. The expected number of cancers based on the NCI SEER Registry was 8.83. The relative risk for cancer in OP patients, with autoantibodies to alpha6-integrin, was 0.34 (95% CI, 0.07-0.99, P < 0.05). CONCLUSION: It appears that patients with OP, with antibodies to alpha6, may have a possible reduced relative risk for developing cancer.

Adult↗

PubMedDate not supplied

Differential expression of two cell adhesion molecules, Ephrin-A5 and Integrin alpha6, during cranial neurulation in the chick embryo.

The formation of the neural tube (neurulation) depends on the physical properties of the cells and tissues both inside and outside the neural plate. One such important physical property is cell adhesion. Theoretical and biological evidence support a role for cell adhesion in neurulation, but few specific cell adhesion molecules have been identified during this process. Ephrin-A5 and Integrin alpha6 are two of the known genes encoding cell adhesion molecules that are likely to be directly involved in neurulation because neural tube defects result when they are knocked out in mice. Yet it remains unclear how they can act on the cell and tissue behaviors of neurulation, because their domains of expression in neurulating tissues have not been reported. We report here the detailed pattern of expression of these two cell adhesion molecules in the chick embryo throughout the stages of neurulation at the mRNA and protein level. We show that Ephrin-A5 and Integrin alpha6 are differentially expressed in the ectoderm, outside and inside the neural plate, respectively, and that they are both restricted to neurulation at cranial (brain) levels. We discuss the potential contribution of this differential expression to the cell adhesion mechanisms involved in cranial neurulation and anencephaly.

Animals↗

PubMed1998

Retroviral transfer of antisense integrin alpha6 or alpha8 sequences results in laminar redistribution or clonal cell death in developing brain.

To assess the roles of two integrin alpha subunits (alpha6 and alpha8) in the developing chicken optic tectum, progenitors were infected with retroviral vectors that contained the marker gene lacZ plus antisense sequences from either the alpha6 or alpha8 integrin subunit cDNAs. On embryonic day 3 (E3), the vector was injected into tectal ventricles of chicken embryos. On E6, E7.5, E9, or later, chicken embryos were killed, and optic tecta were dissected and processed for histochemical detection of lacZ-positive cells. The antisense-bearing cell clones (descendants of a single infected progenitor) were analyzed for proliferation and migration patterns and were compared with lacZ-only vector-infected control clones. At E6, both alpha6 and alpha8 integrin antisense-containing cell clones were similar to controls. At E7.5, integrin alpha8 antisense-containing clones exhibited a cell number reduction in upper laminae (intermediate zone and tectal plate), and at E9, they exhibited a reduction in the ventricular zone as well. Integrin alpha6 antisense-containing cell clones exhibited no difference in total cell number at E9 but had a net laminar redistribution of more cells in the ventricular zone and less cells in the tectal plate. Our data show that different integrins play different roles during brain development: alpha6 integrin is essential for migration of tectal cells into specific laminae, and alpha8 integrin is essential for the survival of optic tectum cells. Also alpha8 integrin-substrate interactions may suppress early programmed cell death in premigratory and migratory neuroblasts.

Animals↗