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PubMedDate not supplied

beta 1-Integrin expression and function in human bladder cancer cells: modulation by TNF alpha.

Cytofluorimetric and biochemical analysis in two different grade human bladder cancer cell lines showed that G3 EJ cells exhibited higher levels of alpha5beta1 and alpha6beta1 heterodimers, and the G2 RT112 cell line higher levels of alpha2beta1. Alpha6/beta4 receptor was detected only in RT112 cells. Adhesion assays with extracellular matrix proteins indicated that both cells bound to fibronectin, laminin and collagen 1, the adhesive properties being related to the integrin profile. Inhibition tests revealed that alpha5beta1 mediated adhesion to fibronectin, alpha3beta1 and alpha6beta1 to laminin, and that alpha2beta1 was the main mediator of adhesion to collagen I in both cell lines. In EJ but not in RT112 cells, tumor necrosis factor-alpha induced the upregulation of alpha2, which mediated increased adhesion to collagen I. The different effects of TNFalpha on the two cell lines were not attributable to differences in tumor necrosis factor responsiveness, as both cells expressed comparable levels of tumor necrosis factor receptor-1 and the tumor necrosis factor-inducible intercellular adhesion molecule-1.

Carcinoma, Transitional Cell↗
PubMed2006

Urokinase receptors are required for alpha 5 beta 1 integrin-mediated signaling in tumor cells.

Up-regulation of urokinase receptors is common during tumor progression and thought to promote invasion and metastasis. Urokinase receptors bind urokinase and a set of beta1 integrins, but it remains unclear to what degree urokinase receptor/integrin binding is important to beta1 integrin signaling. Using site-directed mutagenesis, single amino acid mutants of the urokinase receptor were identified that fail to associate with either alpha3beta1 (D262A) or alpha5beta1 (H249A) but associate normally with urokinase. To study the effects of these mutations on beta1 integrin function, endogenous urokinase receptors were first stably silenced in tumor cell lines HT1080 and H1299, and then wild type or mutant receptors were expressed. Knockdown of urokinase receptors resulted in markedly reduced fibronectin and alpha5beta1-dependent ERK activation and metalloproteinase MMP-9 expression. Re-expression of wild type or D262A mutant receptors but not the alpha5beta1 binding-deficient H249A mutant reconstituted fibronectin responses. Because urokinase receptor.alpha5beta1 complexes bind in the fibronectin heparin-binding domain (Type III 12-14) whereas alpha5beta1 primarily binds in the RGD-containing domain (Type III 7-10), signaling pathways leading to ERK and MMP-9 responses were dissected. Binding to III 7-10 led to Src/focal adhesion kinase activation, whereas binding to III 7-14 caused Rac 1 activation. Tumor cells engaging fibronectin required both Type III 7-10- and 12-14-initiated signals to activate ERK and up-regulate MMP-9. Thus urokinase receptor binding to alpha5beta1 is required for maximal responses to fibronectin and tumor cell invasion, and this operates through an enhanced Src/Rac/ERK signaling pathway.

Cell Line, Tumor↗
PubMed2005

Rhodostomin inhibits thrombin-enhanced adhesion of ROS 17/2.8 cells through the blockade of alphavbeta3 integrin.

Osteosarcoma is a very malignant bone tumor which has a high metastatic potential and usually lead to poor prognosis. The adhesion of tumor cells to the endothelium or extracellular matrix (ECM) is an essential step in the metastatic cascade. We investigated the effect of thrombin on the adhesion activity of the osteosarcoma cell line, ROS 17/2.8. Incubation with the low concentrations of thrombin (0.01-5 U/ml, 5 min to 24 h) elevated the adhesion activity of ROS 17/2.8 to both human umbilical vein endothelial cells (HUVEC) and extracellular matrix, with the peak effect at the concentration of 0.5 U/ml for 30 min at 37 degrees C. The ROS 17/2.8 cells responded to thrombin by a peak effect of increased adhesion to HUVEC (5.5 folds vs. control) and fibronectin (4.8 folds) after thrombin pretreatment (0.5 U/ml, 30 min, 37 degrees C). Pretreatment with monoclonal antibodies against beta3 integrins, including anti-alphavbeta3, 10E5 and 7E3, effectively antagonized the thrombin-enhanced cell adhesion activity, whereas anti-alpha3beta1 and anti-alpha5beta1 did not antagonize the enhanced cell adhesion. Rhodostomin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, and synthetic peptide RGDS also blocked the thrombin-enhanced ROS 17/2.8 cell adhesion. This study demonstrated that thrombin enhanced the cell adhesion of ROS 17/2.8 cells to HUVEC or ECM through an upregulation of beta3 integrins, and rhodostomin was a strong inhibitor on thrombin-enhanced cell adhesion, either to HUVEC or fibronectin substratum.

Animals↗
PubMed2002

Gallium nitrate accelerates partial thickness wound repair and alters keratinocyte integrin expression to favor a motile phenotype.

The nitrate form of the Group III transitional element gallium (GN) increases expression of specific structural components of the provisional wound matrix (i.e., collagen type I, fibronectin) in human dermal fibroblasts. To evaluate the potential of GN as a therapeutic option in management of cutaneous trauma, GN-treated partial thickness porcine wounds and experimentally "injured" human keratinocyte (NHK) monolayer cultures were compared with mirror image control (i.e., saline-treated) sites. GN suppressed cell proliferation in both models, as determined by reduced Ki-67 reactivity and significant lengthening of keratinocyte cell cycle transit times, while effectively promoting reepithelialization. The primary effect of GN was apparently to promote cell migration, as neither epidermal thickness nor epidermal differentiation was altered as a result of GN exposure in vivo or in vitro. Significantly enhanced epidermal reepithelialization was associated with alterations in expression of several keratinocyte integrin subunits. GN induced a significant increase in alpha5 expression. alpha5beta1 switching is a characteristic of the motile phenotype in the setting of cutaneous injury. Concomitantly, GN treatment also induced a dramatic (70%) decrease in the expression of the alpha3 subunit; alpha3beta1 binds laminin 5 and is associated with hemidesmosome formation and reestablishment of a nonmotile phenotype. Taken together, the GN-induced changes in integrin expression favor acellular migration. While the molecular mechanism of GN action on resident cells of the skin remains to be defined, these data suggest that GN administration which represses MMP activity in the wound and increases matrix synthesis also accelerates NHK motility and, thereby, may be a useful therapeutic agent for wound repair.

Animals↗
PubMed2004

Binding of alpha2 monoclonal antibody to human cervical tumor cell (SiHa) surface alpha2beta1 integrin modulates MMP-2 activity.

OBJECTIVE(S): The purpose was to study the interrelationship between cell surface integrin receptor (alpha2beta1) and matrixmetalloproteinases. METHODS: Immunoprecipitation and cell adhesion assay were done to assay alpha2beta1 and alpha3beta1 on SiHa cell surface. Zymogram was developed to assay secreted MMP activity of cells grown in presence of alpha2 monoclonal antibody. Immunoblot was developed to assay expression of MMP-2, FAK, and p-FAK. Plasma membrane-dependent activation of MMP2 was performed by incubating pure MMP-2 with membrane-enriched fraction isolated from SiHa cells. RESULTS: Immunoprecipitation and cell adhesion assay results confirmed the presence of alpha2beta1 receptor on SiHa cells. Zymographic analysis of serum-free media collected at different time points from SiHa cells grown on alpha2 monoclonal antibody-coated culture dishes showed the expression and activation of MMP-2 within 2-4 h, confirmed by immunoblot. Western blot of cells grown on alpha2-coated dishes for 30 min-4 h showed increased phosphorylation of FAK. Membrane-enriched fraction isolated from SiHa cells was found to specifically activate proMMP-2 to its activated forms within 30 min. CONCLUSION(S): The experimental findings strongly indicate that SiHa cell surface alpha2beta1 regulates MMP-2 expression. Increased phosphorylation of focal adhesion kinase (FAK) strongly indicates the possible role of FAK in signaling cascade. Incubation of SiHa cell membrane fraction with pure MMP-2 strongly confirms the cell membrane-dependent activation of proMMP2.

Antibodies, Monoclonal↗
PubMed1997

Integrin binding to immobilized collagen and fibronectin stimulates the proliferation of human thyroid cells in culture.

The expression of integrins of the beta1 family and their possible biological effects were investigated in normal human thyroid cells in monolayer culture. The expression of beta1 and alpha(1-6) integrin subunits was determined by flow cytofluorometry with specific antibodies. Follicular cells of subconfluent monolayer cultures expressed alpha2beta1 and alpha3beta1 at high levels, while alpha1beta1 was only slightly expressed, and alpha4beta1, alpha5beta1, and alpha6beta1 were never detected. Cell attachment assays were performed in fibronectin-, type I collagen-, and laminin-coated microtiter plates. Thyroid cells, while adherent to collagen and fibronectin, showed poor attachment to laminin despite the abundance of their putative receptors alpha2beta1 and alpha3beta1. In serum-free medium, collagen and fibronectin induced cytoskeletal organization, change of cell shape from round to flat, and cell spreading. [3H]Thymidine incorporation and proliferation assays were used to evaluate the effects of collagen and fibronectin on DNA synthesis and cell growth in the absence of a change in spreading or cell shape. Both substrates, in low serum-containing medium, induced a concentration-dependent increase in [3H]thymidine incorporation partially inhibited by RGD-containing peptides that blocked the cell attachment. Thyrocytes cultured in low serum-containing medium on immobilized fibronectin or collagen showed a dose-dependent stimulation of proliferation. These data indicate that fibronectin and collagen can regulate the cytoskeletal organization and cell shape and stimulate the proliferation of normal human thyroid cells in culture and that integrins mediate these effects of extracellular matrix proteins.

Cell Adhesion↗
PubMed2005

Hypoxia stimulates carcinoma invasion by stabilizing microtubules and promoting the Rab11 trafficking of the alpha6beta4 integrin.

Hypoxia plays a key role in tumor cell survival, invasion, and metastasis. Here we show that hypoxia increases tumor cell invasion by the modulation of Rab11, an important molecule for vesicular trafficking, especially membrane protein recycling and translocation of proteins from trans-Golgi network to plasma membrane. Dominant-negative Rab11 dramatically decreased hypoxia-induced invasion of MDA-MB-231 breast carcinoma cells without affecting cell apoptosis. Hypoxia-induced Rab11 trafficking is regulated by microtubule stability, as evidenced by the findings that hypoxia increases Glu tubulin and that colchicine blocks Rab11 trafficking and invasion. Inhibition of GSK-3beta activity by hypoxia seems to be central to microtubule stabilization and invasion. In fact, expression of a dominant-negative GSK-3beta was sufficient to stimulate invasion in normoxia. One target of Rab11-mediated trafficking that contributes to invasion is the integrin alpha6beta4. Hypoxia induced a significant increase in alpha6beta4 surface expression but it had no effect on the surface expression of alpha3beta1. This increase is dependent on Rab11 and stable microtubules. In summary, we identify vesicle trafficking as a novel target of hypoxic stimulation that is important for tumor invasion.

Animals↗
PubMed2006

Galectin-8 binds specific beta1 integrins and induces polarized spreading highlighted by asymmetric lamellipodia in Jurkat T cells.

Integrin-mediated encounters of T cells with extracellular cues lead these cells to adhere to a variety of substrates and acquire a spread phenotype needed for their tissue incursions. We studied the effects of galectin-8 (Gal-8), a beta-galactoside binding lectin, on Jurkat T cells. Immobilized Gal-8 bound alpha1beta1, alpha3beta1 and alpha5beta1 but not alpha2beta1 and alpha4beta1 and adhered these cells with similar kinetics to immobilized fibronectin (FN). Function-blocking experiments with monoclonal anti-integrin antibodies suggested that alpha5beta1 is the main mediator of cell adhesion to this lectin. Gal-8, but not FN, induced extensive cell spreading frequently leading to a polarized phenotype characterized by an asymmetric lamellipodial protrusion. These morphological changes involved actin cytoskeletal rearrangements controlled by PI3K, Rac-1 and ERK1/2 activity. Gal-8-induced Rac-1 activation and binding to alpha1 and alpha5 integrins have not been described in any other cellular system. Strikingly, Gal-8 was also a strong stimulus on Jurkat cells in suspension, triggering ERK1/2 activation that in most adherent cells is instead dependent on cell attachment. In addition, we found that patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disorder, produce Gal-8 autoantibodies that impede both its binding to integrins and cell adhesion. These are the first function-blocking autoantibodies reported for a member of the galectin family. These results indicate that Gal-8 constitutes a novel extracellular stimulus for T cells, able to bind specific beta1 integrins and to trigger signaling pathways conducive to cell spreading. Gal-8 could modulate a wide range of T cell-driven immune processes that eventually become altered in autoimmune disorders.

Androstadienes↗
PubMed1999

Laminin receptors in differentiated thyroid tumors: restricted expression of the 67-kilodalton laminin receptor in follicular carcinoma cells.

The expression of integrin laminin receptors was investigated in normal thyroid primary cultures; immortalized normal thyroid cells (TAD-2); papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid tumor cell lines; seven thyroid tumors (four papillary and three follicular carcinomas); and normal thyroid glands. The expression of alpha1beta1, alpha2beta1, alpha3beta1, alpha6beta1, and alpha6beta4 was found in all tumor specimens and in tumor cell lines, whereas normal thyroid cells and TAD-2 cells lacked the expression of alpha6beta4. Despite the presence of several integrin laminin receptors, adhesion of TAD-2, NPA, and ARO cells to immobilized laminin-1 was poor, whereas WRO cells and follicular carcinoma-derived cells displayed a strong adhesion. Indeed, WRO and follicular carcinoma-derived cells showed expression of a nonintegrin laminin receptor, the 67-kDa high affinity laminin receptor (67LR). TAD-2, NPA, and ARO cells as well as nodular goiter, toxic adenoma, follicular adenoma, and papillary carcinoma-derived cells did not express the 67LR. Adhesion of WRO and follicular carcinoma-derived cells to laminin-1 was specifically inhibited by a recombinant polypeptide containing laminin-binding domains of 67LR, demonstrating that this receptor confers to follicular carcinoma cells attachment capacity to laminin. Moreover, tissue specimens from follicular carcinomas expressed the 67LR, whereas follicular adenomas and normal thyroid tissues were negative. In thyroid tumors, integrin receptors, although abundant, participate weakly in adhesion to laminin. The expression in follicular carcinoma cells of a functional, high affinity 67LR together with nonfunctional integrin LM receptors could be responsible for the tendency of follicular carcinoma cells to metastasize by mediating stable contacts with basal membranes.

Adenocarcinoma, Follicular↗
PubMed2002

Effects of collagen IV on neuroblastoma cell matrix-related functions.

Integrin-mediated interactions with collagen IV and its domains were examined in a human neuroblastoma cell line (SK-N-SH). By adhesion assays we demonstrated that neuroblastoma cells bound to solid-phase intact collagen IV and synthetic cell-binding peptide HEP-III, derived from the collagenous part of the molecule, but not to the main noncollagenous NC1 domain or to the synthetic cell-binding peptide HEP-I, derived from this domain. Monoclonal antibodies against beta1, alpha3, and alpha(v)beta3 integrins resulted in inhibition of cell binding to collagenous substrates by 95, 30, and 35%, respectively. By flow cytometry and immunoblotting it was shown that culture of SK-N-SH cells on collagen IV resulted in alteration in the expression of major neuroblastoma cell integrins. Binding to collagen IV induced the expression and activation of matrix metalloproteinases A and B (MMP-2, MMP-9), with a concomitant increase at the protein level of tissue-specific inhibitors of metalloproteinases (TIMP-1, TIMP-2). Finally, the expression of MMP-2 was significantly up-regulated by anti-alpha3beta1 antibodies, whereas ligation of anti-alpha(v)beta3 antibodies resulted in a modest down-regulation of MMP-2. Our results indicate that the presence of collagen IV modulates the expression of integrins, which are used for binding to this glycoprotein, and MMP-2 secreted by SK-N-SH cells.

Azides↗
PubMed1998

Epidermal differentiation and basement membrane formation by HaCaT cells in surface transplants.

The immortal human keratinocyte line HaCaT has been employed in many studies as paradigm for epidermal keratinocytes. In order to demonstrate its potential to form stable epidermal structures in response to connective tissue, this was challenged in surface transplants on nude mice, where normal keratinocytes rebuild a typical epidermis within two weeks. During the initial regeneration phase (day 1-4) multilayered but poorly organized epithelia formed with proliferating cells in all layers in analogy to normal keratinocytes. Similarly, with tissue consolidation (around day 7) proliferation was reduced and restricted to cells in basal position marked by keratin K14 and beta1-integrin immunostaining. The strong suprabasal reaction for K1 and K10, the appearance of the late markers K2e, filaggrin and loricrin as well as the polarized distribution of alpha2beta1 and alpha3beta1 indicated advancing tissue normalization (day 14). Keratinization further improved at around three weeks switching from the initial parakeratotic to the regular orthokeratotic type which was prominent at six weeks. Accordingly, most ultrastructural features typical for epidermis or normal keratinocyte grafts were detectable including a complete basement membrane (BM) with regular attachment structures. Matrix- and BM-components appeared sequentially with marked linear deposition of laminin-5 (day 4) followed by accumulation of collagen-IV and 'classical' BM-laminin between one and two weeks. With the general codistribution of integrin alpha6beta4 and BM-molecules (day 14) collagen-VII lining of BM became prominent, while epithelium and host connective tissue were still separated by the collagen matrix. In accordance with the delayed orthokeratinization, wound-matrix molecules (fibronectin, tenascin) persisted longer than in normal keratinocyte transplants. Finally, grafts of long-term passaged (no. 310) cells demonstrated a remarkable stability in the expression of epidermal markers. Thus, the immortalized HaCaT cells reveal a generally high competence to realize an epidermal phenotype in a natural environment and appear therefore qualified for in vitro studies on structural and regulatory aspects of keratinocyte physiology and pathology.

Animals↗
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↗
PubMed2006

Current insights into the formation and breakdown of hemidesmosomes.

Hemidesmosomes are multiprotein adhesion complexes that promote epithelial stromal attachment in stratified and complex epithelia. Modulation of their function is of crucial importance in a variety of biological processes, such as differentiation and migration of keratinocytes during wound healing and carcinoma invasion, in which cells become detached from the substrate and acquire a motile phenotype. Although much is known about the signaling potential of the alpha6beta4 integrin in carcinoma cells, the events that coordinate the disassembly of hemidesmosomes during differentiation and wound healing remain unclear. The binding of alpha6beta4 to plectin has a central role in hemidesmosome assembly and it is becoming clear that disrupting this interaction is a crucial event in hemidesmosome disassembly. In addition, further insight into the functional interplay between alpha3beta1 and alpha6beta4 has contributed to our understanding of hemidesmosome disassembly and cell migration.

Animals↗
PubMed2000

alpha5 integrin distribution and TGFbeta1 gene expression in supraglottic carcinoma: their role in neoplastic local invasion and metastasis.

BACKGROUND: Head and neck carcinomas are characterized by tumor-infiltrating lymphocytes (TIL) producing cytokines. Adhesion molecules, extracellular matrix proteins (ECMPs), and cytokines regulate cell-cell and cell-ECMPs interactions. We investigated the distribution of these proteins to contribute to better understanding of their role in local tumor invasion and metastasis. METHODS: Distribution of integrins, laminin, type IV collagen, tenascin, and fibronectin was immunohistochemically evaluated in 13 supraglottis carcinomas. Cytokines gene expression was assessed by reverse-transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Neoplastic cells were alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1 and alpha6beta1 positive. Normal and metaplastic epithelium was alpha5beta1 negative; the stroma of primary and metastatic tumors was tenascin and fibronectin positive. TGFbeta1 and IFNgamma gene expression was observed in the majority of tumors. CONCLUSIONS: Because TGFbeta1 is known to down-modulate immune processes and to increase alpha2beta1, alpha5beta1, and tenascin distribution, we propose that their expression in neoplastic cells of supraglottis carcinoma might represent an immune-related process able to help tumor growth and progression.

Antigens, CD↗
PubMed2001

beta1 Integrin-extracellular matrix protein interaction modulates the migratory response to chemokine stimulation.

It is well established that chemokines have a major role in the stimulation of cell movement on extracellular matrix (ECM) substrates. However, it is also clear that ECM substrates may influence the ability of cells to undergo migration. Using the migration chamber method, we assessed the migratory response of human embryonic kidney-293 (HEK) transfectant cells expressing the CC chemokine receptor 5 (CCR5) (HEK-CCR5) to stimulation by chemokines (macrophage inflamatory protein (MIP)-1alpha, MIP-1beta, and regulated on activation normal-T cell expressed and secreted (RANTES)) on ECM substrates (collagen type I and fibronectin). Using filters coated with collagen (20 microg/mL), results showed that the chemokines differed in their ability to elicit cell movement according to the order MIP-1beta > RANTES MIP-1alpha. In contrast, using filters coated with fibronectin (20 microg/mL), all three chemokines were similar in their ability to stimulate migration of HEK-CCR5 cells. In addition, the migratory response with respect to the concentrations of ECM substrates appeared biphasic: thus, chemokine-stimulated cell movement was inhibited at high ECM concentrations (100 microg/mL). To determine the involvement of beta1 integrins, results showed that the migratory response to chemokine stimulation on collagen was largely inhibited by monoclonal antibody (mAb) to alpha2beta1; however, complete inhibition required a combination of mAbs to alpha1beta1 and alpha2beta1. In comparison, migration on fibronectin was inhibited by mAb to alpha3beta1 and alpha5beta1. Our results suggest that the migratory response to CCR5 stimulation may vary quantitatively with both the CCR5 ligand (MIP-1alpha, MIP-1beta, and RANTES), as well as the nature and concentration of the ECM substrate involved.

Cell Line↗
PubMed2000

Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells.

Integrins participate in controlling proliferation and migration. Therefore, changes in integrin expression might be responsible for unrestrained proliferation and invasiveness of tumor cells. Alterations of integrin subunit expression have been observed in human colon carcinoma, especially loss or reduction of the alpha5 subunit, which was observed consistently. The mechanisms responsible for reduction of alpha5 expression and alteration of expression of other integrins are not fully understood. Circumstantial evidence from previous investigations points to an involvement of activated ras oncogenes in repression of integrin expression. The K-ras protooncogene is activated by point mutation in 50% of human colon carcinomas. Thus, we choose an antisense approach for specific inactivation of activated K-ras in the human colon carcinoma cell line SW 480 in order to test whether activated K-ras contributes to changes in integrin expression on colon carcinoma cells. Cell surface expression of the alpha1 and the alpha5 subunit was increased in K-ras antisense transfected clones, cell surface expression of the alpha3 subunit and the alphav subunit was decreased. This shows, in a human system, that activated K-ras is involved in diminishing cell surface expression of the alpha1beta1 collagen/laminin receptor and the alpha5beta1 fibronectin receptor, both of which are implicated in maintenance of a non-transformed phenotype. Moreover, activated K-ras contributes to increased cell surface expression of the alpha3beta1 laminin/collagen/fibronectin receptor and the alphavbeta5 vitronectin receptor, which might play a role in metastatic behavior of tumor cells.

Adenocarcinoma↗
PubMed1997

Regulated expression of fibronectin, laminin and related integrin receptors during the early chondrocyte differentiation.

We have investigated the expression and localization of fibronectin, laminin, and their receptors, and we used an in vitro chick chondrocyte differentiation model to define a time hierarchy for their appearance in early chondro-genesis and to determine their role in the cell condensation process. By serum fibronectin depletion/reconstitution, or GRGDSP peptide competition experiments, we show that fibronectin contributes to the initial cell-cell interactions that occur during condensation. In later stages, a down-regulation of both fibronectin and of its alpha5beta1 integrin receptor occur, as demonstrated by mRNA and protein kinetics. Immunolocalisation studies suggest that the reduction of fibronectin in discrete areas is involved in local activation of the cell differentiation program. Furthermore, we show that laminin is expressed during the in vitro cell condensation process in areas that are negative for fibronectin staining. The types of laminin as well as the timing of expression have been determined by northern blot and RT-PCR analyses. The highest levels of expression are coincident with maximal cell aggregation. The alpha3beta1 laminin receptor, highly expressed in dedifferentiated cells, follows later on the ligand trend. During in vitro chondrogenesis, a down-regulation in the B isoform, and an up-regulation of the A isoform, of the alpha subunit of the alpha6beta1 laminin receptor occurs. Immunolocalisation studies suggest that laminin is involved in the definition of differentiating areas as opposed to non differentiating areas of the condensed region, i.e. the periphery, which eventually gives rise to the perichondrium.

Animals↗
PubMed2002

Quantitative analysis of adhesion molecules on cellular constituents of the human uterine microenvironment under the influence of estrogen and progesterone.

The uterus contains all the components of a tertiary lymphoid compartment. We hypothesize that specific leukocyte recruitment to the endometrium during the secretory phase of the menstrual cycle and early pregnancy limits the type of immunocyte that gains access. The present study utilized flow cytometry to define and quantify adhesion molecules possibly used by decidual infiltrating lymphocytes (DIL) as homing receptors, uterine microvascular myometrial endothelial cells (UtMVE-Myo) as addressins, and secretory endometrial stroma cells (STO) as retainment factors. Human umbilical cord vein endothelial cells and peripheral blood lymphocytes were used as control cells for comparison studies. DIL were composed of predominantly lymphocyte function-associated antigen (LFA)-1+, intercellular adhesion molecule (ICAM)-1+, LFA-2+, LFA-3+, gp150,95+, alpha1beta1+, Hermes cell adhesion molecule (H-CAM)+, and neural cell adhesion molecule (N-CAM)+ (CD56(bright)) memory/effector natural killer cells. A significant number of UtMVEC-Myo expressed platelet endothelial cell adhesion molecule (PECAM)-1, a percentage were uniquely LFA-3+, and alpha4 integrin expression was uniquely high. An increased number of STO uniquely expressed alpha3, beta3, and LFA-3, whereas alpha2, alpha4, alphaVbeta3, and H-CAM were significantly increased. Possible unique adhesions of DIL:UtMVEC-Myo included SLe(x):PECAM, vascular cell adhesion molecule-1:alpha4, and LFA-2:LFA-3, whereas DIL:STO included LFA-2:LFA-3 and N-CAM:N-CAM. Unique molecules on DIL may also associate with extracellular matrix (ECM) or complement on UtMVEC-Myo or STO to form gp150,95:fibrinogen/iC3b/C3dg, alpha1beta1:laminin (LM)/collagen (CO), and ICAM-1:fibronectin (FN) interactions. Bridges of ECM may also form between DIL and UtMVEC-Myo adhesion molecules including ICAM-1:FN:ICAM-1 and alpha4beta1:FN:alpha4beta1. DIL:ECM:STO interactions may involve alpha2beta1:CO:alpha2beta1, alpha3beta1:LM/CO/FN:alpha3beta1, alphaVbeta3:VN:alphaVbeta3, and H-CAM:hyaluronate:H-CAM. It is likely that many adhesion molecules play a role in the recruitment and retainment of specialized lymphocytes within the uterine microenvironment. (Mackay et al., 1990).

Adult↗