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At least 217 records · Page 12Linked to original sources
PubMed2004

Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs.

The active migration of tumor cells, a crucial requirement for metastasis development and cancer progression, is regulated by signal substances including neurotransmitters. We investigated the migration of tumor cells within a three-dimensional collagen matrix using time-lapse videomicroscopy and computer-assisted analysis of the migration path. Tumor cell migration is induced by norepinephrine, dopamine and substance P. We show that this induced migration, using MDA-MB-468 breast and PC-3 prostate carcinoma cells, can be inhibited by using specific, clinically established receptor antagonists to the beta2-adrenoceptor, the D2 receptor, or the neurokinin-1 receptor, respectively. All of the investigated neurotransmitters significantly activated the cyclic adenosine-monophosphate response element binding protein (CREB). Furthermore, microarray analysis revealed changes of gene expression toward a highly motile tumor cell type, including an upregulation of the alpha2 integrin, which is an essential adhesion receptor for collagen in migration. The gene for the tumor suppressor gelsolin was downregulated. These 2 critical alterations were confirmed on the protein level by flow-cytometry and immunoblotting, respectively. Neurotransmitters thus induce a metastatogenic tumor cell type by directly regulating gene expression and increased migratory activity, which can be prevented by established neurotransmitter antagonists.

Breast Neoplasms↗
PubMed2003

Variation in enterovirus receptor genes.

The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG) --> Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG) --> Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the alpha2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and beta3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. =

Autoimmune Diseases↗
PubMed1995

Upregulation of integrin expression in benign vulvar warts.

Benign anogenital warts demonstrate features both of hyperproliferation and of aberrant differentiation associated with human papillomavirus (HPV) infection. The expression of integrins has been examined in normal vulvar epithelium and benign vulvar warts to determine whether HPV infection is associated with changes in integrin expression, either during terminal differentiation or among the proliferating cell population. The expression of integrins in normal vulvar epithelium was similar to that seen in the epidermis, with little expression of alpha 1 and expression of alpha 2, alpha 3, and beta 1 at the periphery of basal cells. In vulvar wart epithelium, alpha 1 was not significantly expressed, but upregulation of alpha 2, alpha 3, and beta 1 was seen at the periphery of cells throughout the basal and spinous layers. In addition, alpha 2 staining was greater at foci along the basal layer of normal vulva, whilst such heterogeneity was not detected in wart sections. Expression of beta 4 and alpha V was confined to the basal and lateral aspects of normal basal cells, but expressed at the periphery of basal cells and to a lesser extent in epibasal and spinous layers of warts. The observed differences in integrin expression are consistent with those reported in other hyperproliferative epithelia.

Condylomata Acuminata↗
PubMed2002

FGFR3 isoforms have distinct functions in the regulation of growth and cell morphology.

We have previously cloned the alternatively spliced isoform of fibroblast growth factor receptor 3 (FGFR3DeltaAB) that lacks the acid box in the extracellular region. To understand the biological functions and signal transduction of these FGFR3 isoforms, we analyzed the effect of FGF1 in ATDC5 cells, chondroprogenitor cell lines overexpressing these isoforms. In response to FGF1, FGFR3 induced a marked cell-morphology change to a round shape, while FGFR3DeltaAB did not. Furthermore, FGFR3 induced complete growth arrest, whereas FGFR3DeltaAB induced only moderate growth inhibition. Both receptors induced the expression of the CDK inhibitor p21(CIP1). However, only FGFR3 induced STAT1 phosphorylation that mediates the transcriptional induction of p21(CIP1), although both FGFR3 isoforms could induce a strong activation of mitogen-activated protein (MAP) kinases. Taken together, the different biological responses mediated by FGFR3 and FGFR3DeltaAB appear to be due to a difference in their ability to utilize STAT1 pathway and signals involved in cell rounding.

Alternative Splicing↗
PubMed2001

Environmental modulation of alpha(v), alpha(2) and beta(1) integrin subunit expression in human oesophageal squamous cell carcinomas.

Integrins are cell adhesion molecules pivotal in regulating normal cell behaviour. Ectopic expression of integrins, characteristic of transformed cells, is instrumental in differentiation, proliferation, apoptosis, angiogenesis, matrix degradation and migration. Oesophageal squamous cell carcinoma (SCC) has a propensity to metastasize and hence an extremely poor prognosis. It is shown here that oesophageal SCCs express alpha(v)strongly and that normal oesophageal tissue does not express alpha(v). This makes alpha(v)a significant indicator of the transformed phenotype. alpha(2)and beta(1)integrin subunits are down-regulated in oesophageal SCCs compared to normal oesophagus. Dominance of the alpha(2)beta(1)heterodimer is symptomatic of potential loss of other beta(1)binding integrins in oesophageal SCCs. These results suggest a decrease in rigid cell adhesion possibly increasing migratory potential, whilst simultaneously permitting the adhesion and migration of SCC cells on a large repertoire of ligands due to de novo alpha(v)expression.

Animals↗
PubMed1994

Control of lymphocyte integrin function: evidence for multiple contributing factors.

The control of lymphocyte adhesion is critical for proper cellular functions. The alpha 2 beta 1 integrin complex serves as a receptor for collagen on lymphocytes. The T cell leukemia Jurkat expresses alpha 2 beta 1 in a latent form on the cell surface. Three types of stimuli, antibody to the alpha 2 chain (JBS2), antibody to the beta 1 chain (JB1B), and phorbol ester (PMA), each induce activation of alpha 2 beta 1-dependent Jurkat binding to collagen. A comparison of the JBS2, JB1B, and PMA induction requirements indicated that the JB1B and the JBS2 effects are not sensitive to staurosporine while the PMA response is completely inhibited. Combinations of functionally saturating concentrations of the stimuli displayed an additive effect. Collectively these results suggest that several factors contribute to the generation of full integrin functionality and cellular adhesion, thus providing a possible basis for incrementally controlling the adhesive potential of lymphoid cells.

Alkaloids↗
PubMed2001

alpha11beta1 integrin is a receptor for interstitial collagens involved in cell migration and collagen reorganization on mesenchymal nonmuscle cells.

alpha11beta1 integrin constitutes a recent addition to the integrin family. Here, we present the first in vivo analysis of alpha11 protein and mRNA distribution during human embryonic development. alpha11 protein and mRNA were present in various mesenchymal cells around the cartilage anlage in the developing skeleton in a pattern similar to that described for the transcription factor scleraxis. alpha11 was also expressed by mesenchymal cells in intervertebral discs and in keratocytes in cornea, two sites with highly organized collagen networks. Neither alpha11 mRNA nor alpha11 protein could be detected in myogenic cells in human embryos. The described expression pattern is compatible with alpha11beta1 functioning as a receptor for interstitial collagens in vivo. To test this hypothesis in vitro, full-length human alpha11 cDNA was stably transfected into the mouse satellite cell line C2C12, lacking endogenous collagen receptors. alpha11beta1 mediated cell adhesion to collagens I and IV (with a preference for collagen I) and formed focal contacts on collagens. In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development.

Animals↗
PubMed1994

Platelet-derived growth factor-BB stimulates synthesis of the integrin alpha 2-subunit in human diploid fibroblasts.

Platelet-derived growth factor (PDGF)-BB stimulates fibroblast-mediated contraction of collagen gels, as well as migration of fibroblasts through collagen-coated membranes. In the present study we examined effects of PDGF-BB stimulation on the synthesis of collagen-binding beta 1 integrins by human diploid fibroblasts (AG 1518). PDGF-BB stimulation led to an increase in the rare of integrin alpha 2-subunit synthesis. In contrast, synthesis of the integrin alpha 1- or alpha 3-subunits were not affected by PDGF-BB stimulation. Furthermore, levels of alpha 2-subunit mRNA relative to levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA increased after PDGF-BB stimulation. The latter finding is compatible with PDGF-BB stimulating transcription of the alpha 2-subunit gene. PDGF-BB stimulation did not influence the relation between levels of integrin beta 1-subunit mRNA and GAPDH mRNA. In addition, the rate of synthesis or post-translational processing of the integrin beta 1-subunit were not, or only marginally, affected by PDGF-BB stimulation. It is likely that the motility response elicited in fibroblasts by PDGF-BB involves such alterations in the synthesis of the alpha 2-subunit of the alpha 2 beta 1 collagen-binding integrin.

Becaplermin↗
PubMed1995

Cell-to-cell contact modulates the expression of the beta 1 family of integrins in primary cultures of thyroid cells.

The expression of the beta 1 family of integrins was studied in normal thyroid tissue cultures and monolayer cell cultures. The expression of the various subunits was measured by flow cytofluorometry with specific monoclonal antibodies and by Northern analysis. In monolayer cell cultures but not in tissue cultures, the expression of the alpha 3 subunit on the cell membrane progressively increased soon after plating, reaching a 30-fold higher intensity. The alpha 2 subunit, not detectable in native follicular cells, was expressed de novo and reached a remarkable high level. Up-regulation of alpha 2 and alpha 3 in monolayer cell cultures was serum-independent and preceded the expression of proliferating cell nuclear antigen, [3H]thymidine incorporation, and cell replication. Northern analysis demonstrated an increased level of beta 1 integrin mRNA. The increase of alpha 2 and alpha 3 was readily reversible since the expression of these molecules returned to a lower level when cultures reached a high cell density. Down-regulation did not occur until cell cultures were confluent. When cells from high cell density and low integrin expression were harvested and sparsely seeded in culture, up-regulation of integrins was observed again, while rapid reaggregation of isolated cells inhibited this phenomenon. Altogether these data suggest that cell-to-cell contact may regulate the expression of beta 1 integrins in thyroid primary cultures.

Antigens, CD↗
PubMed1996

Modulation of expression and assembly of vinculin during in vitro fibrillar collagen-induced angiogenesis and its reversal.

A model of collagen-induced in vitro angiogenesis was used to investigate the modulation of expression and assembly of focal adhesion plaque-associated proteins during the process of differentiation. Human umbilical vein endothelial cells (HUVEC), first attached on an adhesive substratum (gelatin-, fibronectin-, or laminin-coated dish) or adherent collagen gel and then covered by an overlaying collagen get, organized within 3-4 days in tube-like structures (TLS). Removing the overlaying collagen gel from fully differentiated HUVEC induced a reversion of the process and HUVEC returned to a monolayer pattern. Modulations of focal adhesion-associated proteins occurring in HUVEC during the in vitro differentiation process and its reversal were investigated by Western blot analysis. A significant decrease of expression of vinculin, the integrin alpha2 subunit, talin, alpha-actinin, and actin was observed in TLS whereas the amount of FVIII-related antigen did not vary as compared to control monolayer cultures. During reversal, all the reduced proteins were markedly reexpressed. Human skin fibroblasts (HSF), submitted to the same experimental conditions, did not form TLS. Most of the focal adhesion proteins in HSF were similarly modulated by an overlaying collagen gel with the exception of vinculin, which was not modified. This particular protein was therefore more thoroughly investigated. In a nondifferentiated monolayer of HUVEC, a significant proportion of vinculin was organized into a detergent-resistant juxtamembranous structure (focal adhesion plaque) which disassembled early in TLS formation and reassembled during the reversal of the process. The reduction of vinculin during TLS formation was preceded by a downregulation of its mRNA while this mRNA was upregulated during reversal of the morphotype. These results suggest that the modulations of the cytoskeletal and focal adhesion proteins and more specifically of vinculin coupled to its subcellular redistribution are critical and early events in the cascade of mechanochemical signaling during in vitro angiogenesis induced by fibrillar collagen.

Actins↗
PubMed1999

The effects of extracellular matrix on cell attachment, proliferation and migration in a human lens epithelial cell line.

Lens capsule consists of several kinds of extracellular matrix (ECM) which may play an important role in cell attachment, migration and proliferation of lens epithelial cells as a basement membrane. We have investigated the effects of ECM on cell attachment, proliferation and migration in a human lens epithelial (HLE) cell line. The HLE cell line, SRA 01/04, which was transfected with large T-antigen of SV40 was cultured in the absence of serum. Culture plates were coated with human type IV collagen, laminin or fibronectin. The number of cells were counted at 30-180 min and 3, 5 and 7 days of culture. The rate of BrdU incorporation was measured to study the cell proliferation. The cell migration was measured 1, 3, 5 and 7 days after seeding cells. Integrins, the receptors of ECM, were also detected using antibodies for the cell membrane antigens (CD49b, CD49c, CD49e) by an immunohistochemical method. Although less than 10% of cells attached to the non-coated plate and 50-60% of cells attached to the ECM-coated plates, there was no difference of cell attachment among each ECM used. The cell attachment was almost complete during the first 30 min of culture. Cell proliferation was not enhanced, but cell survival was aided by culture on the ECM components for up to 7 days. The area of cell attachment enlarged on the ECM-coated plates, whereas no migration was observed on the non-coated plate. These data indicate that ECM is the essential factor for cell attachment and increases migration of HLE cells.

Antigens, CD↗
PubMed1997

Invasive potentials of gastric carcinoma cell lines: role of alpha 2 and alpha 6 integrins in invasion.

The potentials of the two major histological types of gastric carcinoma to invade through extracellular matrices were studied with cell lines. We found that the invasive potential of intestinal-type carcinoma cells (MKN-28 and MKN-74) were higher than those of diffuse-type carcinoma cells (MKN-45 and KATO-III). To investigate whether the alpha 2 and alpha 6 integrin adhesion molecules are responsible for, or involved in carcinoma invasion. We further studied alpha 2 and alpha 6 expression patterns in these two types of cell line. Although fluorescence-activated cell sorting analysis revealed that all cells examined invariably expressed these integrin molecules, their expressional patterns were different among different cell lines. The intestinal-type carcinoma cells expressed integrins mainly along the cell-cell contact region, whereas the diffuse-type carcinoma cells showed a diffuse cytoplasmic pattern of integrin expression. Invasion by MKN-28, MKN-74 and MKN-45 cells through reconstituted basement membrane or type I collagen gel was significantly inhibited (P < 0.05) by 50 micrograms/ml anti-(alpha 2 integrin) or anti-(alpha 6 integrin) monoclonal antibodies. Our results suggest that active invasiveness is stronger in the intestinal-type than in the diffuse-type carcinoma cells and that alpha 2 and alpha 6 integrins play important roles in invasion of both types of gastric carcinoma cell lines.

Antigens, CD↗
PubMed2001

Localization of alpha integrin subunits in the neural retina of the tiger salamander.

BACKGROUND: Integrin receptors mediate cell-extracellular matrix interactions and regulate many events, including cell growth, proliferation, and differentiation. Retinal integrins are incompletely understood, although these receptors are potentially important factors in normal retinal function and pathology. METHODS: Immunocytochemistry was used to localize alpha integrin subunits 1-6 in the neural retina. RESULTS: Each alpha integrin subunit had a unique distribution in the retina, although there was considerable overlap among subunits. The alpha 1 subunit was broadly distributed throughout the retina, with some presumptive ganglion cells showing enriched labeling. The alpha 2 subunit was present on all retinal cell bodies, but was reduced in synaptic layers. The alpha 3 subunit was present in synaptic layers, Müller cells, and some cone and amacrine cells. The alpha 4 subunit was broadly distributed in the nuclear layers but was reduced in synaptic layers. The alpha 5 subunit was broadly expressed in the nuclear and synaptic layers with enriched labeling in the outer plexiform layer. Labeling for the alpha 6 subunit was restricted to the outer limiting membrane and some cone outer segments. Double-labeling studies indicated that photoreceptor terminals may exhibit alpha 1 and alpha 5 subunits, while processes from second-order neurons may exhibit alpha 1, alpha 3, and alpha 5 subunits. CONCLUSION: Integrin receptors containing the alpha 1, alpha 3, and alpha 5 subunits may have important functions at retinal synapses, in addition to roles in the nuclear layers. Integrin receptors containing alpha 2, alpha 4, and alpha 6 subunits probably serve non-synaptic functions.

Ambystoma↗
PubMed2001

Characterization of cultured human prostatic epithelial cells by cluster designation antigen expression.

Cultured prostatic epithelial cells have been extensively studied as a model of prostate biology. What is the lineage relationship of the cultured cells to the epithelial cell types in tissue? How different are cultured cells derived from tumor tissue to those derived from benign tissue? Expression of cluster designation (CD) cell surface molecules has been shown to be useful in characterizing cells according to lineage. A CD profile was therefore generated for cultured human prostatic epithelial cells and compared with those previously established for basal and luminal epithelial cells in the prostate. Presence of CD44, CD49b, CD49f, and CD104 and absence of CD57 suggests that cultured cells were derived from basal cells of prostatic tissues. However, expression of certain CD antigens characteristic of luminal epithelial cells was also observed in subpopulations of cultured cells. The pattern of CD antigens in cultured cells reflects a phenotype similar to that of transit-amplifying cells that have been described in the prostate. Several CD antigens were found expressed by both cultured prostatic epithelial and stromal cells, and are probably associated with cell proliferation. The CD profiles of cultured epithelial cell strains derived from normal compared with malignant tissues were notably similar to each other and to that of the prostate cancer cell line PC-3. We conclude that cells in culture retain expression of certain lineage-characteristic CD antigens. Furthermore, CD antigens can define subpopulations of cells with differential gene expression.

Aged↗
PubMed2006

Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk.

Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. alpha(V)beta(3), alpha(IIb)beta(3) and alpha(2)beta(1), have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the alpha(2) component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin alpha(2)beta(1). The 176T>C polymorphism in the ITGB3 gene, encoding the beta(3) subunit of integrins alpha(IIb)beta(3) and alpha(V)beta(3), modifies a variety of traits of beta(3) expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11-8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, 'wildtype') were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53-0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3-4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.

Breast↗
PubMed1995

Immunohistochemical analysis of alpha 1-integrins in cervical cancer.

OBJECTIVE: The purpose of this study was to determine and compare the expression of the alpha 2-, alpha 3-, alpha 4- and alpha 5-subunits of the beta 1-family of integrins in both the normal and the carcinomatous cervix. STUDY DESIGN: A total of 22 solid tissue specimens (18 cancer and 4 normal) were analyzed immunohistochemically. The double-stain technique used an avidin-biotin complex kit to identify the various integrins and alkaline phosphatase-anti-alkaline phosphatase kit to identify the epithelial cells. Staining intensity, the main outcome measured, was graded as absent, weak, moderate, or strong. Statistical analysis was performed with the Wilcoxon rank sum test for nonparametric data. RESULTS: The alpha 2- and alpha 3-integrins stained the normal cervix epithelium more intensely than the stroma (p = 0.03). The alpha 4- and alpha 5-integrins stained both the stroma and the normal epithelium similarly. The alpha 2-integrin was absent in the stroma of all 18 cancer specimens despite being present in the epithelial regions of 14 to 18 cancers. The alpha 3-integrin had a greater staining intensity in the stroma of the cancers than in the epithelial regions (p = 0.002). Both alpha 4- and alpha 5-integrins were absent in the epithelial regions of the cancers but present in the stroma. CONCLUSIONS: The distribution and intensity of integrin expression in cervical cancer differ from their expression in the normal cervix. In particular, the fibronectin receptors, alpha 4 and alpha 5, were absent in the epithelial regions of the cervical cancers, and alpha 3 also had diminished expression in the malignant epithelium. These changes correlate well with the changes expected in malignant transformation.

Antigens, CD↗