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PubMedDate not supplied

[Inhibition of the motility of melanoma cells using interference RNA against CD9].

INTRODUCTION: Although 65 % of the deaths caused by skin cancer are due to melanomas, the possible causes that may explain the aggressiveness of this type of tumor are still unknown. Different approaches have been used to try to find an effective treatment, but they have been unsuccessful. Interference RNA (iRNA) is an essential technique for this research. With this technique, we can selectively "knock down" or silence protein expression. The tetraspanins CD9 and CD151 are molecules involved in cell motility, including melanoma cells. MATERIAL AND METHODS: A375 melanoma cell line, anti-CD9 and anti-CD151 monoclonal antibodies, and iRNA against CD9 and CD151. Immunofluorescence techniques, flow cytometry, cell transfection, cell selection with magnetic beads and evaluation of cell migration in a wound-healing model. RESULTS: The A375 cells express CD9 and CD151. By using iRNA against CD9 and CD151, we managed to inhibit the expression of these proteins. The cells transfected with iRNA against CD9 showed significant inhibition of their motility. DISCUSSION: We managed to silence the expression of CD9 and CD151 using iRNA techniques in the A375 melanoma cell line. The reduction in CD9 caused the inhibition of cell motility, while the interference with CD151 expression had a more moderate effect. This data indicates that the knockdown of tetraspanins may be a future target for the treatment of melanoma.

Antigens, CD↗
PubMed2003

Effect of a single dose aspirin on platelets in humans with multiple risk factors for coronary artery disease.

We sought to assess how one tablet of non-enteric coated aspirin (325 mg) affects human platelets in subjects with risk factors for coronary artery disease. Data from 63 individuals with multiple cardiac risk factors were analyzed. Platelets were assessed twice at baseline (pre-aspirin), and after 3-4 h (post-aspirin). We employed 5 microM epinephrine-induced conventional aggregometry, closure time with epinephrine/collagen cartridge by PFA-100(R) (Dade-Behring), and aspirin response units (ARU) stimulated by propyl gallat with Ultegra (Accumetrics, San Diego, CA, USA) for measuring platelet function. In addition, the expression of platelet receptors was determined by using the following monoclonal antibodies: anti-CD31, CD41, CD42b, CD51/CD61, CD62p, CD63, CD107a, and CD151. Platelet-leukocyte formation was detected utilizing dual antibodies for a pan-platelet marker CD151, and CD14, a monocyte/macrophage marker. PAC-1 was used to measure fibrinogen-platelet binding. One pill of aspirin significantly decreased platelet-rich plasma (PRP) aggregation (74.18+/-16.75% vs. 24.92+/-8.64%; p<0.0001) and resulted in reduction of the aspirin response units (ARU) (662.24+/-65.65 vs. 451.05+/-69.31; p<0.0001). There was also prolongation of the closure time (194.4+/-25.3 vs. 258.63+/-55.61 s; p<0.0001). High correlation (r(2)=0.73-0.86) between platelet analyzer readings and aggregation was observed. One tablet of aspirin moderately inhibited expression of most surface platelet receptors measured, and such inhibition reached significance (p<0.05) for PAC-1, CD31, CD41, CD42, CD62p, and CD151. We conclude that a single dose of aspirin affects major platelet receptors, presumably directly or indirectly through the inhibition of prostanoids via platelet cyclooxygenase-1 blockade. The Ultegra Analyzer with a novel cartridge seems to be reliable in reflecting aspirins' effects on platelets and could be used in the future in clinical practice for monitoring aspirin therapy.

Adult↗
PubMed2002

Expression of transmembrane 4 superfamily (TM4SF) proteins and their role in hepatic stellate cell motility and wound healing migration.

BACKGROUND/AIMS: Migration of activated hepatic stellate cells (HSC) is a key event in the progression of liver fibrosis. Little is known about transmembrane proteins involved in HSC motility. Tetraspanins (TM4SF) have been implicated in cell development, differentiation, motility and tumor cell invasion. We evaluated the expression and function of four TM4SF, namely CD9, CD81, CD63 and CD151, and their involvement in HSC migration, adhesion, and proliferation. METHODS/RESULTS: All TM4SF investigated were highly expressed at the human HSC surface with different patterns of intracellular distribution. Monoclonal antibodies directed against the four TM4SF inhibited HSC migration induced by extracellular matrix proteins in both wound healing and haptotaxis assays. This inhibition was independent of the ECM substrates employed (collagen type I or IV, laminin), and was comparable to that obtained by incubating the cells with an anti-beta1 blocking mAb. Importantly, cell adhesion was unaffected by the incubation with the same antibodies. Co-immunoprecipitation studies revealed different patterns of association between the four TM4SF studied and beta1 integrin. Finally, anti-TM4SF antibodies did not affect HSC growth. CONCLUSIONS: These findings provide the first characterization of tetraspanins expression and of their role in HSC migration, a key event in liver tissue wound healing and fibrogenesis.

Antibodies, Monoclonal↗
PubMed2000

Tetraspanins are localized at motility-related structures and involved in normal human keratinocyte wound healing migration.

We have described previously that beta1 integrins, which mediate keratinocyte cell adhesion and migration, are in ligand-occupied conformation at the basal surface but not at the lateral and apical surfaces of keratinocytes. This led us to study the cellular localization and function of tetraspanin molecules, which have been postulated to modulate integrin activity. We found that CD9 and CD81 are highly expressed by keratinocytes clearly delineating filopodia at lateral and apical surfaces. CD63 and CD151 are largely expressed in the intracellular compartment, although some membrane expression is observed. We found accumulation of CD9, CD81, and CD151 together with alpha3 and beta1 integrins at intercellular junctions. In low calcium medium, this intercellular space is crossed by a zipper of filopodia enriched in alpha3beta1 and tetraspanin proteins. Interestingly, the expression of CD9, CD81, and beta1 and alpha3 integrins was detected in the footprints and rippings of motile keratinocytes, suggesting their role in both adhesion to extracellular matrix and keratinocyte motility. beta1 integrins were only partially activated in the rips, whereas cytoskeleton-linking proteins such as talin were completely absent. On the other hand, antitetraspanin antibodies did not stain focal adhesions, which contain talin. The involvement of tetraspanins in keratinocyte motility was assessed in a wound healing migration assay. Inhibition of cell migration was observed with antibodies to CD9, CD81, beta1, and alpha3, and, to a lesser extent, to CD151. Together these results indicate that tetraspanin-integrin complexes might be involved in transient adhesion and integrin recycling during keratinocyte migration, as well as in intercellular recognition.

Antigens, CD↗
PubMed2001

Transmembrane-4 superfamily proteins associate with activated protein kinase C (PKC) and link PKC to specific beta(1) integrins.

Translocation of conventional protein kinases C (PKCs) to the plasma membrane leads to their specific association with transmembrane-4 superfamily (TM4SF; tetraspanin) proteins (CD9, CD53, CD81, CD82, and CD151), as demonstrated by reciprocal co-immunoprecipitation and covalent cross-linking experiments. Although formation and maintenance of TM4SF-PKC complexes are not dependent on integrins, TM4SF proteins can act as linker molecules, recruiting PKC into proximity with specific integrins. Previous studies showed that the extracellular large loop of TM4SF proteins determines integrin associations. In contrast, specificity for PKC association probably resides within cytoplasmic tails or the first two transmembrane domains of TM4SF proteins, as seen from studies with chimeric CD9 molecules. Consistent with a TM4SF linker function, only those integrins (alpha(3)beta(1), alpha(6)beta(1), and a chimeric "X3TC5" alpha(3) mutant) that associated strongly with tetraspanins were found in association with PKC. We propose that PKC-TM4SF-integrin structures represent a novel type of signaling complex. The simultaneous binding of TM4SF proteins to the extracellular domains of the integrin alpha(3) subunit and to intracellular PKC helps to explain why the integrin alpha3 extracellular domain is needed for both intracellular PKC recruitment and PKC-dependent phosphorylation of the alpha(3) integrin cytoplasmic tail.

Animals↗
PubMed1998

Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions.

Cell-to-cell junction structures play a key role in cell growth rate control and cell polarization. In endothelial cells (EC), these structures are also involved in regulation of vascular permeability and leukocyte extravasation. To identify novel components in EC intercellular junctions, mAbs against these cells were produced and selected using a morphological screening by immunofluorescence microscopy. Two novel mAbs, LIA1/1 and VJ1/16, specifically recognized a 25-kD protein that was selectively localized at cell-cell junctions of EC, both in the primary formation of cell monolayers and when EC reorganized in the process of wound healing. This antigen corresponded to the recently cloned platelet-endothelial tetraspan antigen CD151/PETA-3 (platelet-endothelial tetraspan antigen-3), and was consistently detected at EC cell-cell contact sites. In addition to CD151/PETA-3, two other members of the tetraspan superfamily, CD9 and CD81/ TAPA-1 (target of antiproliferative antibody-1), localized at endothelial cell-to-cell junctions. Biochemical analysis demonstrated molecular associations among tetraspan molecules themselves and those of CD151/ PETA-3 and CD9 with alpha3 beta1 integrin. Interestingly, mAbs directed to both CD151/PETA-3 and CD81/ TAPA-1 as well as mAb specific for alpha3 integrin, were able to inhibit the migration of ECs in the process of wound healing. The engagement of CD151/PETA-3 and CD81/TAPA-1 inhibited the movement of individual ECs, as determined by quantitative time-lapse video microscopy studies. Furthermore, mAbs against the CD151/PETA-3 molecule diminished the rate of EC invasion into collagen gels. In addition, these mAbs were able to increase the adhesion of EC to extracellular matrix proteins. Together these results indicate that CD81/TAPA-1 and CD151/PETA-3 tetraspan molecules are components of the endothelial lateral junctions implicated in the regulation of cell motility, either directly or by modulation of the function of the associated integrin heterodimers.

Animals↗
PubMed1998

Highly stoichiometric, stable, and specific association of integrin alpha3beta1 with CD151 provides a major link to phosphatidylinositol 4-kinase, and may regulate cell migration.

Here we describe an association between alpha3beta1 integrin and transmembrane-4 superfamily (TM4SF) protein CD151. This association is maintained in relatively stringent detergents and thus is remarkably stable in comparison with previously reported integrin-TM4SF protein associations. Also, the association is highly specific (i.e., observed in vitro in absence of any other cell surface proteins), and highly stoichiometric (nearly 90% of alpha3beta1 associated with CD151). In addition, alpha3beta1 and CD151 appeared in parallel on many cell lines and showed nearly identical skin staining patterns. Compared with other integrins, alpha3beta1 exhibited a considerably higher level of associated phosphatidylinositol-4-kinase (PtdIns 4-kinase) activity, most of which was removed upon immunodepletion of CD151. Specificity for CD151 and PtdIns 4-kinase association resided in the extracellular domain of alpha3beta1, thus establishing a novel paradigm for the specific recruitment of an intracellular signaling molecule. Finally, antibodies to either CD151 or alpha3beta1 caused a approximately 88-92% reduction in neutrophil motility in response to f-Met-Leu-Phe on fibronectin, suggesting an functionally important role of these complexes in cell migration.

1-Phosphatidylinositol 4-Kinase↗
PubMed2000

Endothelial cell and stromal antigens in human periapical granulation tissue.

Periapical granulation tissue consists of vasculature of varying sizes and types, infiltrating cells, and other stromal elements. We examined the differential expression of endothelial and stroma antigens in this tissue to determine their tissue distribution in order to obtain hints on their functions. Some of the antigens examined were present only in the endothelial lining of vasculature, including high endothelial venules (e.g. CD31 and CD105), whereas others were more widely expressed by both vascular and stromal elements (e.g. CD29, CD63, CD44, and CD151). Immunohistochemical analysis using monoclonal antibodies specific to certain tissue compartments revealed the tissue architecture more precisely and the expression of certain antigens in the tissue suggested special roles for these antigens. Tissue distribution of CD63, CD143, CD147, and CD151 in periapical granulation tissue is first reported in the present study.

Antibodies, Monoclonal↗
PubMed2005

Role of tetraspanins CD9 and CD151 in primary melanocyte motility.

Tetraspanins CD9 and CD151 have been implicated in cellular motility and intercellular adhesion in several cellular types. Here, we have studied the subcellular localization and the functional role of these molecules in primary melanocytes. We found that endogenous tetraspanins preferentially clustered in areas of melanocyte homotypic intercellular contacts and at the tips of dendrites. These observations were further confirmed using time-lapse fluorescence confocal microscopy of melanocytes transfected with CD9- and CD151-GFP (green fluorescent protein) constructs, suggesting an involvement of these proteins in cellular contacts and migration. Cell adhesion and migration assays performed using blocking monoclonal antibodies against CD9 and CD151 showed no significant effect on cell-extracellular matrix adhesion, whereas the migration of melanocytes was significantly enhanced. The regulation of the migratory capacity of melanocytes by CD9 and CD151 was further confirmed knocking down the endogenous expression of these tetraspanins with small interference RNA oligonucleotides. Therefore, tetraspanin molecules are localized at motile structures in primary human melanocytes regulating the migratory capacity of these cells.

Antigens, CD↗
PubMed2004

Expression of tetraspanins in peripheral blood leukocytes: a comparison between normal and infectious conditions.

The role of tetraspanins is undefined, despite their detection in diverse cell types and functions. This study addresses the characterization of tetraspanin expression levels in normal peripheral blood leukocytes (PBL) and in patients with bacterial infection. Membranal and cytoplasmic expression of CD9, CD53, CD63, CD81, CD82 and CD151 in polymorphonuclears (PMN), monocytes, B and T lymphocytes was assessed using flow cytometry. Results suggested that for normal PBL, PMN are distinguished by dominant cytoplasmic CD63; monocytes and B cells prevailingly express CD53; CD82 is primarily expressed on T-cell membranes. However, a major trend of downregulation was demonstrated for the examined tetraspanins, except CD63, in all patients' PBL subtypes. Therefore, tetraspanin modulation in infections may be attributed to elevated leukocyte motility in immune reactions and this is compatible with the previous publications of tetraspanins as metastasis suppressors. This work represents the first comprehensive baseline of tetraspanin expression in normal PBL and in infectious disorders.

Adolescent↗
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↗
PubMed2004

Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation.

Tetraspanins associate with several transmembrane proteins forming microdomains involved in intercellular adhesion and migration. Here, we show that endothelial tetraspanins relocalize to the contact site with transmigrating leukocytes and associate laterally with both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Alteration of endothelial tetraspanin microdomains by CD9-large extracellular loop (LEL)-glutathione S-transferase (GST) peptides or CD9/CD151 siRNA oligonucleotides interfered with ICAM-1 and VCAM-1 function, preventing lymphocyte transendothelial migration and increasing lymphocyte detachment under shear flow. Heterotypic intercellular adhesion mediated by VCAM-1 or ICAM-1 was augmented when expressed exogenously in the appropriate tetraspanin environment. Therefore, tetraspanin microdomains have a crucial role in the proper adhesive function of ICAM-1 and VCAM-1 during leukocyte adhesion and transendothelial migration.

Antigens, CD↗
PubMed2006

CD9 controls the formation of clusters that contain tetraspanins and the integrin alpha 6 beta 1, which are involved in human and mouse gamete fusion.

The process of gamete fusion has been largely studied in the mouse and has revealed the crucial role of the tetraspanin CD9. By contrast, human gamete fusion remains largely unknown. We now show that an anti-alpha 6 integrin mAb (GoH3) strongly inhibited human sperm-egg fusion in human zona-free eggs. Furthermore, a mAb directed against CD151, a tetraspanin known to associate with alpha 6 beta1, partially inhibited sperm-egg fusion. By contrast, the addition of an anti-CD9 mAb to zona free eggs had no effect. The integrin alpha 6 beta1, CD151 and CD9 tetraspanins were evenly distributed on human zona-intact oocytes. On zona-free eggs, the integrin alpha 6 beta1 and tetraspanin CD151 patched and co-localized but the tetraspanin CD9 remained unchanged. CD9 mAb prevented alpha 6 beta1 integrin clustering and gamete fusion when added prior to, but not after, zona removal. Antibody-mediated aggregation of integrin alpha 6 beta1 yielded patches that were bigger and more heterogeneous in mouse oocytes lacking CD9. Moreover, a strong labelling of alpha 6 beta1 could be observed at the sperm entry point. Altogether, these data show that CD9 controls the redistribution of some membrane proteins including the alpha 6 beta1 integrin into clusters that may be necessary for gamete fusion.

Animals↗
PubMed1999

PETA-3/CD151, a member of the transmembrane 4 superfamily, is localised to the plasma membrane and endocytic system of endothelial cells, associates with multiple integrins and modulates cell function.

The Transmembrane 4 Superfamily member, PETA-3/CD151, is ubiquitously expressed by endothelial cells in vivo. In cultured human umbilical vein endothelial cells PETA-3 is present on the plasma membrane and predominantly localises to regions of cell-cell contact. Additionally, this protein is abundant within an intracellular compartment which accounts for up to 66% of the total PETA-3 expressed. Intracellular PETA-3 showed colocalisation with transferrin receptor and CD63 suggesting an endosomal/lysosomal localisation which was supported by immuno-electronmicroscopy studies. Co-immunoprecipitation experiments investigating possible interactions of PETA-3 with other molecules demonstrated associations with several integrin chains including beta1, beta3, beta4, (alpha)2, (alpha)3, (alpha)5, (alpha)6 and provide the first report of Transmembrane 4 Superfamily association with the (alpha)6beta4 integrin. Using 2-colour confocal microscopy, we demonstrated similar localisation of PETA-3 and integrin chains within cytoplasmic vesicles and endothelial cell junctions. In order to assess the functional implications of PETA-3/integrin associations, the effect of anti-PETA-3 antibodies on endothelial function was examined. Anti-PETA-3 mAb inhibited endothelial cell migration and modulated in vitro angiogenesis, but had no detectable effect on neutrophil transendothelial migration. The broad range of integrin associations and the presence of PETA-3 with integrins both on the plasma membrane and within intracellular vesicles, suggests a primary role for PETA-3 in regulating integrin trafficking and/or function.

Antigens, CD↗
PubMed2000

Transmembrane-4-superfamily proteins CD151 and CD81 associate with alpha 3 beta 1 integrin, and selectively contribute to alpha 3 beta 1-dependent neurite outgrowth.

Proteins in the transmembrane-4-superfamily (TM4SF) form many different complexes with proteins in the integrin family, but the functional utility of these complexes has not yet been demonstrated. Here we show that TM4SF proteins CD151, CD81, and CD63 co-distribute with alpha3beta1 integrin on neurites and growth cones of human NT2N cells. Also, stable CD151-alpha3beta1 and CD81-alpha3beta1 complexes were recovered in NT2N detergent lysates. Total NT2N neurite outgrowth on laminin-5 (a ligand for alpha3beta1 integrin) was strongly inhibited by anti-CD151 and -CD81 antibodies either together ( approximately 85% inhibition) or alone ( approximately 45% inhibition). Notably, these antibodies had no inhibitory effect on NT2N neurites formed on laminin-1 or fibronectin, when alpha3beta1integrin was not engaged. Neurite number, length, and rate of extension were all affected by anti-TM4SF antibodies. In summary: (1) these substrate-dependent inhibition results strongly suggest that CD151 and CD81 associations with alpha3beta1 are functionally relevant, (2) TM4SF proteins CD151 and CD81 make a strong positive contribution toward neurite number, length, and rate of outgrowth, and (3) NT2N cells, a well-established model of immature central nervous system neurons, can be a powerful system for studies of integrin function in neurite outgrowth and growth cone motility.

Antigens, CD↗
PubMed1999

Selective tetraspan-integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions.

The tetraspans are molecules with four transmembrane domains which are engaged in multimolecular complexes (the tetraspan web) containing a subset of beta1 integrins (in particular alpha3beta1, alpha4beta1 and alpha6beta1), MHC antigens and several unidentified molecules. The molecules associated with tetraspans are readily detected after immunoprecipitation performed in mild detergents such as Brij 97 or CHAPS. In this study we show that another classical mild detergent, digitonin, dissociated most of these associated molecules, including integrins, from the tetraspans CD9, CD37, CD53, CD63, CD82, Co-029, Talla-1 and NAG-2. In contrast, reciprocal immunoprecipitations from various cell lines demonstrated that two other tetraspans, CD81 and CD151, formed complexes with integrins not disrupted by digitonin. These complexes were CD81/alpha4beta1, CD151/alpha3beta1 and CD151/alpha6beta1. Furthermore, a new anti-CD151 monoclonal antibody (mAb), TS151r, was shown to have a restricted pattern of expression, inversely related to the sum of the levels of expression of alpha6beta1 and alpha3beta1. This mAb was unable to co-precipitate integrins in digitonin, suggesting that its epitope is blocked by the association with integrins. Indeed, the binding of TS151r to the cell surface was quantitatively diminished following alpha3beta1 overexpression. Altogether, these data suggest that, among tetraspans, CD81 interacts directly with the integrin alpha4beta1, and CD151 interacts directly with integrins alpha3beta1 and alpha6beta1. Because all tetraspan-tetraspan associations are disrupted by digitonin, it is likely that the other tetraspans interact indirectly with integrins, through interactions with CD81 or CD151.

Animals↗
PubMedDate not supplied

Expression of tetraspanin adaptor proteins below defined threshold values is associated with in vitro invasiveness of mammary carcinoma cells.

Tetraspanins are transmembrane adaptor proteins involved in the regulation of various fundamental cellular processes. For a number of malignant diseases, the level of expression of members of the tetraspanin family was found to correlate with tumor cell invasiveness, ability to form metastases, and poor clinical outcome. We describe the exact quantification of mRNAs coding for the tetraspanins CD9, CD63, CD82 and CD151 expressed by mammary carcinoma-derived cell lines that were classified as invasive or non-invasive according to their ability to penetrate collagen-fibroblast gels in vitro. The mean of beta2-microglobulin-normalized expression of CD9 was about 10-fold higher than the mean calculated for CD63 and about 20-fold higher than expression of CD82 and CD151. Direct comparison of tetraspanin expression of invasive and non-invasive cell lines with the Mann-Whitney test revealed a significant correlation for CD63. Grouping of cell lines in relation to threshold values of expression resulted in significant correlations for CD63 (Fisher's exact test p=0.004) and CD151 (p=0.02) but not for CD82 (p=0.065) and CD9 (p=0.168). Expression of CD9, C63 and CD151 was found to be coupled whereas CD82 was expressed independently. This highly significant association points to common mechanisms of gene regulation for this subgroup of tetraspanins. We showed that on basis of absolute amounts of tetraspanin mRNAs, at least in vitro invasiveness is clearly predictable. Our results support the assumption that downregulation of tetraspanins in breast cancer cells is an important step of tumor progression to more malignant phenotypes and underline their important role as mediators in multimolecular membrane protein complexes regulating cell adhesion and migration.

Antigens, CD↗
PubMed2003

Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial.

BACKGROUND: Despite the common practice of clopidogrel loading for coronary stenting, the time dependence and degree of platelet inhibition after this therapy are not well defined. We sought to establish an optimal clopidogrel dosing regimen for sustained platelet inhibition in stented patients. METHODS AND RESULTS: Platelets were assessed by conventional aggregation with 5 micromol/L adenosine diphosphate (ADP), 1 microg/mL collagen (COLL), and 750 micromol/L arachidonic acid; whole blood aggregation by 1 microg/mL collagen (WBA); shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 100 patients undergoing elective stent placement without glycoprotein (GP) IIb/IIIa receptor antagonists. Blood was obtained at baseline and serially over 5 days poststenting after different clopidogrel loading regimens: 300 mg 24 hours before (Group A), 12 hours before (Group B), 3 to 6 hours before (Group C), and 75 mg at the time of intervention (Group D). Before stenting, ADP, COLL, CT, and WBA were reduced by clopidogrel loading (P <.05). CF was not affected by clopidogrel. Before stenting, GP IIb/IIIa expression increased in groups A through C (P <.05), whereas PECAM-1 and CD107a were reduced (P <.05). At 2 hours and 2 days poststenting, platelets, in general, exhibited an increase in activity that was most inhibited by clopidogrel loading. Clopidogrel inhibited GP Ib, platelet/endothelial cell adhesion molecule-1, CD 107a, CD 151, and GP IIb/IIIa expression at day 5 poststenting. CONCLUSION: A 300 mg clopidogrel load given 3 to 24 hours before stenting inhibits platelets at the time of the procedure and reduces poststent activity more than a 75 mg dose given at the time of the procedure. The inhibition of adhesive molecule expression may also contribute an antithrombotic effect. Poststent activation of platelets may warrant higher periprocedural dosing.

Aged↗