Biomedical subjects

M Polette

Publications and source records attributed to M Polette.

At least 19 recordsLinked to original sources

PubMed2006

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression.

ADAM Proteins↗

PubMed2005

Comparison of liquid based cytology and histology for the evaluation of HER-2 status using immunostaining and CISH in breast carcinoma.

BACKGROUND: HER-2 amplification is an important prognostic biomarker and treatment determinant in breast carcinoma. AIMS: To correlate immunocytochemical (ICC) expression of HER-2 and gene amplification determined by chromogenic in situ hybridisation (CISH) using liquid based cytology (LBC) with immunohistochemistry (IHC) and CISH using histological samples of the same breast carcinomas. METHODS: Frozen sections and cytobrushings of 103 breast carcinomas were analysed. Four techniques were performed on each tumour: two on LBC samples (ICC, and CISH, both graded as positive, indeterminate, or negative) and two on histological samples (IHC and CISH). Two cell lines (MCF-7, negative; BT 474, positive) were used as controls for cytological analysis. A complementary fluorescence in situ hybridisation technique was carried out in histological samples with low amplification (4-10 dots/nucleus). RESULTS: Interobserver agreement for the four techniques calculated by the kappa coefficient indicated a substantial agreement. Nine cases failed in cytology because of poor cellularity. Among 94 cases, 19 were amplified; 73, 12, and 9 tumours were scored 0 or 1+, 2+, and 3+, respectively by IHC and 75, 13, and 6, respectively, by ICC. CISH found no amplification in 72 tumours. Correlations between the IHC and CISH results in the histological and cytological samples were always significant. CONCLUSIONS: Her-2 status could be determined in LBC samples and correlated well with reference histological methods using in situ hybridisation. ICC was less reliable because of the presence of the cytoplasmic membrane. However, these results should be confirmed by a large multicentre study.

Adult↗

PubMed2004

Negative human papillomavirus testing in normal smears selects a population at low risk for developing high-grade cervical lesions.

High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas and there is an increasing interest in using HR-HPV DNA detection in adjunction to cytological examination for primary cervical screening. To determine whether women with a normal smear negative for HR-HPV DNA detection with the Hybrid Capture II assay might represent a low-risk population for developing a high-grade squamous intraepithelial lesion (HSIL), 4401 women have been followed in a period of 12-72 months (median=34 months). During this follow-up, four HSIL and one microinvasive carcinoma have been detected in this cohort (three in the cohort of 3526 women >29 years). The global negative predictive value (NPV) of double-negative tests is thus of 99.9% (ninety-five percent confidence interval (95% CI): 99.8-100%), whereas cytology alone gives an NPV of 99.2% (95% CI: 98.9-99.5%). If we obtain a second negative HR-HPV test 1-2 years after the initial test, the NPV is 100%. The NPV is also of 100% in the cohort of women >49 years. We conclude that all these women could be safely screened at longer intervals between 3 and 5 years. This policy will offset the increased costs induced by an additional HR-HPV testing in primary screening.

Adolescent↗

PubMed2001

Quantitative cell dispersion analysis: new test to measure tumor cell aggressiveness.

Tumor progression requires the dispersion of epithelial cells from neoplastic clusters and cell invasion of adjacent stromal connective tissue. Aiming at demonstrating the precise relationships between cell dispersion and cell invasion, related respectively to expression of E-cadherin/catenin complex and matrix metalloproteinases (MMPs), we developed an original in vitro model of cell dispersion analysis. Our study reports the validation of this model that allowed us to analyze and quantify the cell cohesion level by means of time-lapse videomicroscopy and computer analysis based on the observation of spatial and temporal cell distribution. Our model was able to distinguish 2 groups among different human bronchial and mammary epithelial cells previously characterized for the expression of E-cadherin/catenin complex and MMPs and their invasive capacity in the Boyden chamber assay. The first group (16HBE14o(-), MCF-7, T47D) that expressed membranous E-cadherin and beta-catenin, and was negative for MMP-2 expression and non-invasive, displayed a highly cohesive pattern corresponding to a cluster spatial distribution. The second group (Beas2B, BZR, BZR-T33, MDA-MB-231, MDA-MB-435, BT549 and HS578T) that was invasive and showed lack of expression of E-cadherin and a cytoplasmic redistribution of beta-catenin, displayed a dispersed pattern corresponding to a random spatial distribution. Downregulation of E-cadherin by a blocking antibody induced a more random distribution. Conversely, expression of E-cadherin by cDNA transfection induced a cluster distribution. Moreover, tumor cell lines that co-expressed MT1-MMP and MMP-2 (Beas2B, BZR, BZR-T33, MDA-MB-435, BT549 and HS578T) showed a more dispersed pattern than tumor cell lines that did not express MMP-2 (MDA-MB-231). In conclusion, we demonstrated that the spatial group behavior of cell lines, i.e., their cohesion/dispersion ability, reflects their invasive properties. Thus, this model of cell dispersion analysis may represent a new test to measure tumor cell aggressiveness.

Breast↗

PubMed2001

uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration.

To examine the effects of the uPA/plasmin system on cell migration in relation to the activation of MMP-9, we used ex vivo and in vitro wound-repair models of human bronchial epithelial cells and videomicroscopy techniques that make possible cell tracking and quantification of cell migration speeds. We observed that uPA was only detected in migrating cells at the wound edges and located at crucial sites for cell/extracellular matrix interactions. The implication of uPA in human bronchial epithelial cell migration was studied by incubating cultures with a monoclonal antibody raised against uPA and these experiments led to a 70% reduction in cell velocity. To examine the effects of the plasmin system on cell migration, we incubated cultures with increasing concentrations of plasmin or activated MMP-9. We observed a significant dose-dependent increase in cell migration velocity with plasmin (P < 0.001) and MMP-9 (P < 0.001). Moreover, addition of exogenous plasmin led to a twofold increase of activated MMP-9 in migrating cells. We also demonstrated that the addition of anti-uPA IgG led to an inhibition of 43% of activated MMP-9. In conclusion, these results show that uPA is involved in human bronchial epithelial cells migration. This action is mediated by the generation of plasmin, which in turn activates MMP-9, thus making possible cell migration.

Antibodies, Monoclonal↗

PubMed2001

Down-Regulation of MT1-MMP expression by the alpha3 chain of type IV collagen inhibits bronchial tumor cell line invasion.

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surrounded by a remnant or neosynthetized BM material. We have previously reported the presence of a particular alpha chain of type IV collagen, the alpha3(IV) chain, in bronchopulmonary carcinomas. This chain was not detected in the normal bronchial epithelium, but was found around some invasive tumor cluster BM. In the present study, we examined the effects of the alpha3(IV) chain on the invasive properties of bronchial tumor cell lines, with special emphasis on their expression of matrix metalloproteinase-2 (MMP-2) and its activator, membrane type 1-matrix metalloproteinase (MT1-MMP), which is largely involved in tumor progression. Two epithelial bronchial cell lines (16HBE14o- and BZR), showing different invasive abilities, were evaluated. Using the Boyden chamber invasion assay, we demonstrated that the alpha3(IV) chain inhibits the invasive properties of BZR cells and modifies their morphology by inducing an epithelial cell shape. In the presence of the recombinant NC1 domain of the alpha3(IV) chain, the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) was not modified in either cell line. The NC1 alpha3(IV) domain did not modulate the MT1-MMP expression of noninvasive 16HBE14o- cells, whereas a 50% decrease of MT1-MMP mRNA was observed in invasive BZR cells. Accordingly, Western blot analyses showed a disappearance of the 45-kd MT1-MMP form when BZR cells were treated with the recombinant NC1 alpha3(IV) domain. These findings suggest that the alpha3 chain of type IV collagen may play a role in tumor invasion, at least by decreasing the expression and synthesis of MT1-MMP.

Bronchi↗

PubMed2001

Respective contribution of neutrophil elastase and matrix metalloproteinase 9 in the degradation of BP180 (type XVII collagen) in human bullous pemphigoid.

Bullous pemphigoid is a blistering disorder associated with autoantibodies directed against two components of hemidesmosomes, BP180 and BP230. Autoantibodies to the extracellular collagenous domain of BP180 are thought to play a key role in the pathogenesis of the disease. In a murine model of bullous pemphigoid, neutrophil elastase and 92 kDa gelatinase (matrix metalloproteinase 9) have been implicated in subepidermal blister formation via proteolytic degradation of BP180. In this study we sought to elucidate the contribution of these two enzymes to subepidermal blister formation by assessing the expression, localization, and activity of the two proteases in lesional skin, serum samples, and blister fluids obtained from 17 patients with bullous pemphigoid. The results indicate that (i) neutrophil elastase is found in skin biopsy specimens from bullous pemphigoid lesions and is recovered as active enzyme in blister fluids, and (ii) although proform of matrix metalloproteinase 9 is present in lesional skin, it is present only as proenzyme in blister fluids, which also contain high levels of tissue inhibitor of metalloproteinase-1. Next, the capacity of matrix metalloproteinase 9 and neutrophil elastase to degrade a recombinant protein corresponding to the extracellular collagenous domain of the BP180 was studied. Our data illustrate that (i) recombinant matrix metalloproteinase 9, neutrophil elastase, and blister fluid from bullous pemphigoid patients are all able to hydrolyze recombinant BP180; (ii) the pattern of recombinant BP180 proteolysis with blister fluid was similar to that obtained with neutrophil elastase; and (iii) recombinant BP180 degradation by blister fluid could be inhibited by chloromethylketone, a specific elastase inhibitor, but not by batimastat, a wide spectrum matrix metalloproteinase inhibitor. Our results confirm the importance of neutrophil elastase but not matrix metalloproteinase 9 in the direct cleavage of BP180 autoantigen and subepidermal blister formation in human bullous pemphigoid.

Aged↗

PubMed2001

Contribution of MT1-MMP and of human laminin-5 gamma2 chain degradation to mammary epithelial cell migration.

Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-anchored matrix metalloproteinase (MMP) that is frequently associated with processes involving tissue remodelling and cell migration. We have examined MT1-MMP expression and subcellular distribution as a function of MCF10A mammary epithelial cell migration using an in vitro outgrowth migration assay. Stronger expression of MT1-MMP was observed at the mRNA and at the protein level in cells at the periphery of the outgrowth. As shown by videomicroscopy, these cells were involved in an orientated cell migration, in contrast to stationary cells distant from the periphery. Furthermore, MT1-MMP was mainly distributed in lamellipodia of migratory cells, as well as at their basal surface in contact with the substrate. Laminin-5 (Ln-5), a recently described substrate for MT1-MMP, was deposited preferentially in the matrix by migratory cells. Fragments of the gamma2 subunit of Ln-5 were also identified in migratory cultures of MCF10A cells, attesting to its proteolytic degradation. These fragments corresponded in size to those we observed after incubation of purified human Ln-5 with the recombinant catalytic domain of human MT1-MMP. We also show that anti-Ln5 blocking antibodies, MMP inhibitors (BB94 and TIMP-2) and MT1-MMP antisense oligonucleotides significantly decreased MCF10A cell migration. Taken together, these observations demonstrate that MT1-MMP is spatially and temporally regulated during MCF10A cell migration, and suggest that MT1-MMP-mediated pericellular proteolysis of Ln-5 gamma2 chain could contribute to this process.

Blotting, Western↗

PubMed2000

Pseudomonas aeruginosa virulence factors delay airway epithelial wound repair by altering the actin cytoskeleton and inducing overactivation of epithelial matrix metalloproteinase-2.

To investigate the role of P. aeruginosa virulence factors in the repair of human airway epithelial cells (HAEC) in culture, we evaluated the effect of stationary-phase supernatants from the wild-type strain PAO1 on cell migration, actin cytoskeleton distribution, epithelial integrity during and after repair of induced wounds, and the balance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP). PAO1 supernatant altered wound repair by slowing the migration velocity in association with altered actin cytoskeleton polymerization in the lamellipodia of migrating airway epithelial cells and delaying or inhibiting the restoration of epithelial integrity after wound closure. PAO1 virulence factors overactivated two of the gelatinolytic enzymes, MMP-2 and MMP-9, produced by HAEC during repair. During HAEC repair in the presence of PAO1 virulence factors, enhanced MMP-2 activation was associated with decreased rates of its specific inhibitor TIMP-2, whereas enhanced MMP-9 activation was independent of changes of its specific inhibitor TIMP-1. These inhibitory effects were specific to P. aeruginosa elastase-producing strains (PAO1 and lipopolysaccharide-deficient AK43 strain); supernatants from P. aeruginosa strain elastase-deficient PDO240 and Escherichia coli strain DH5alpha had no inhibitory effect. To mimic the effects of P. aeruginosa, we further analyzed HAEC wound closure in the presence of increasing concentrations of activated MMP-9 or MMP-2. Whereas increasing concentrations of active MMP-9 accelerated repair, excess activated MMP-2 generated a lower migration velocity. All these data demonstrate that P. aeruginosa virulence factors, especially elastase, may impede airway epithelial wound closure by altering cell motility and causing an imbalance between pro- and activated forms of MMP-2.

Actins↗

PubMed2000

Modified basement membrane composition during bronchopulmonary tumor progression.

During tumor progression, the extracellular matrix (ECM) and particularly the basement membrane (BM) appear to be dynamic structures that are not only degraded but also deposited around tumor clusters. In this study we examined by immunohistochemistry the localization of three chains of Type IV collagen (alpha1, alpha3 and alpha5), Type VII collagen, and laminin 5 at different stages of bronchopulmonary cancers. In normal tissues, alpha1(IV) chain was detected in all BMs (bronchial, vascular, alveolar, and glandular), alpha5(IV) chain was present only in vascular BM, and laminin 5 and Type VII collagen were co-localized in bronchial and glandular BMs, whereas alpha3(IV) immunolabeling was totally absent from normal bronchi. In well-differentiated carcinomas, alpha3(IV) chain staining was found in some neosynthetized BMs interfacing the tumor cell and the stromal compartment, contrasting with the total absence of labeling in normal tissues. alpha1(IV) chain showed strong reactivity in all BM. Laminin 5 and Type VII collagen were also detected in neosynthetized BM. In poorly differentiated invasive cancers, alpha3(IV) chain and Type VII collagen were not found, whereas laminin 5 and alpha1(IV) chain persisted. The most important modifications in BM composition during tumor progression therefore appear to be the appearance of the alpha3 (IV) chain in well-differentiated carcinomas and its subsequent disappearance in poorly differentiated carcinomas, together with the loss of type VII collagen. alpha5(IV) chain distribution was restricted in vascular BM of well- and poorly differentiated carcinomas. These results show that the composition of BM is modified during the progression of bronchopulmonary tumor, emphasizing that the BM represents a dynamic element in tumor progression and has an important role in tumor cell invasiveness.

Adenocarcinoma↗

PubMed1999

Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling.

Cell spreading and migration associated with the expression of the 92-kD gelatinase (matrix metalloproteinase 9 or MMP-9) are important mechanisms involved in the repair of the respiratory epithelium. We investigated the location of MMP-9 and its potential role in migrating human bronchial epithelial cells (HBEC). In vivo and in vitro, MMP-9 accumulated in migrating HBEC located at the leading edge of a wound and MMP-9 expression paralleled cell migration speed. MMP-9 accumulated through an actin-dependent pathway in the advancing lamellipodia of migrating cells and was subsequently found active in the extracellular matrix (ECM). Lamellipodia became anchored through primordial contacts established with type IV collagen. MMP-9 became amassed behind collagen IV where there were fewer cell-ECM contacts. Both collagen IV and MMP-9 were involved in cell migration because when cell-collagen IV interaction was blocked, cells spread slightly but did not migrate; and when MMP-9 activation was prevented, cells remained fixed on primordial contacts and did not advance at all. These observations suggest that MMP-9 controls the migration of repairing HBEC by remodeling the provisional ECM implicated in primordial contacts.

Actins↗

PubMed1999

Influence of oleic acid on the expression, activation and activity of gelatinase A produced by oncogene-transformed human bronchial epithelial cells.

Invasiveness and metastatic capacity of tumor cells have been related to increased expression and activation of gelatinase-A (MMP-2). 9-octadecenoic acid (oleic acid, OA), a long-chain cis-unsaturated fatty acid, has been shown to partially inhibit the formation of lung metastatic colonies in an ex vivo model of implantation of metastatic cells into nude mice. Reduction of metastasis formation was suggested to be due to a decrease of MMP-2 activity in tumor tissue extracts. Since regulation of MMP-2 activity occurs at different levels, including gene expression, pro-enzyme activation and finally active enzyme inhibition, we here investigated the precise level of the inhibitory effect of OA on MMP-2 activity by oncogene-transformed human bronchial epithelial cells (BZR cells). OA, at the dose of 5 x 10(-5) M, was shown to inhibit by 50% MMP-2 activity released from BZR cells. Northern-blot analysis of mRNA encoding MMP-2, MT1-MMP, the physiological activator of MMP-2, and TIMP-2, the natural inhibitor of MMP-2, revealed that OA did not alter the steady-state levels of MMP-2, MT1-MMP and TIMP-2 mRNA. Also, gelatin zymography demonstrated that the extent of MMP-2 activation was not modified by OA treatment. On the contrary, OA could inhibit the fluorogenic quenching substrate (7-methoxycoumarin-4-yl)acetyl-L-Pro-Leu-Gly-Leu-[N-3-(2,4-dinitrophenyl)-L-2, 3-diaminopropionyl]-Ala-Arg-NH2 (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2) hydrolysis by recombinant MMP-2 with Ki = 4.3 microM. These data suggest that the beneficial influence of OA on the formation of lung metastatic colonies was independent of its influence on MMP-2 expression and/or activation, but could be attributed to inhibition of MMP-2 activity.

Animals↗

PubMed1999

Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase-2 in bronchopulmonary and breast lesions.

Tumor cells interact with stromal cells via soluble or cell-bound factors stimulating the production of matrix metalloproteinases (MMPs), a group of enzymes largely involved in the extracellular matrix (ECM) remodeling in tumor invasion. Among these factors, extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to stimulate in vitro the fibroblast production of various MMPs such as interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), and gelatinase A (MMP-2). In this study, the EMMPRIN protein was detected by immunohistochemistry prominently in malignant proliferations of the breast and the lung. It was present at the surface of both tumor epithelial and peritumor stromal cells. Because previous studies have reported that stromal cells do not express EMMPRIN mRNAs, it is very likely that EMMPRIN is bound to stromal cells via a specific receptor. Moreover, our observations also demonstrated that the same peritumor stromal cells strongly express MMP-2. Our results show that EMMPRIN is an important factor in tumor progression by causing tumor-associated stromal cells to increase their MMP-2 production, thus facilitating tumor invasion and neoangiogenesis. (J Histochem Cytochem 47: 1575-1580, 1999)

Adenocarcinoma↗

PubMed1999

Vimentin contributes to human mammary epithelial cell migration.

Vimentin expression in human mammary epithelial MCF10A cells was examined as a function of their migratory status using an in vitro wound-healing model. Analysis of the trajectories of the cells and their migratory speeds by time lapse-video microscopy revealed that vimentin mRNA and protein expression were exclusively induced in cells at the wound's edge which were actively migrating towards the center of the lesion. Actin labeling showed the reorganization of actin filaments in cells at the wound's edge which confirmed the migratory phenotype of this cell subpopulation. Moreover, the vimentin protein disappeared when the cells became stationary after wound closure. Using cells transfected with the vimentin promoter controlling the green fluorescent protein gene, we also demonstrated the specific activation of the vimentin promoter in the migratory cells at the wound's edge. Transfection of the antisense vimentin cDNA into MCF10A cells clearly reduced both their ability to express vimentin and their migratory speed. Taken together, these observations demonstrate that vimentin is transiently associated with, and could be functionally involved in, the migratory status of human epithelial cells.

Actins↗

PubMed1999

Expression of gelatinase A and its activator MT1-MMP in the inflammatory periprosthetic response to polyethylene.

Wear debris of polyethylene prosthetic components is known to induce a host granulomatous reaction which recruits numerous macrophages and multinucleated giant cells. By releasing cellular mediators of a nonspecific inflammatory reaction, activated phagocytic cells are thought to play a key role in osteolysis leading to aseptic loosening of the prosthesis. Matrix metalloproteinases (MMPs) have been implicated in this destructive process by their ability to degrade extracellular matrix components of bone and adjacent connective tissue. To investigate the roles of gelatinase A, its activator MT1-MMP, and the MMP inhibitors TIMP-1 and TIMP-2 in aseptic loosening of polyethylene prostheses, immunohistochemistry (IHC) and in situ hybridization (ISH) were performed on periprosthetic pseudosynovial interface tissues. Gelatinase A and MT1-MMP were strongly detected immunohistochemically in macrophages and multinucleated giant cells in contact with polyethylene wear debris. In contrast to MT1-MMP, gelatinase A mRNAs were not found in phagocytic cells but in surrounding fibroblasts, thereby suggesting cooperation between macrophages and fibroblasts in this process. While TIMP-1 was expressed essentially in hyperplastic pseudosynoviocytes as assessed by IHC and ISH, TIMP-2, MT1-MMP, and gelatinase A were colocalized in phagocytic cells. These data support the concept of progelatinase A activation involving a trimolecular complex (MT1-MMP-TIMP-2-gelatinase A) mechanism. Thus, this study demonstrated that gelatinase A and its activator might contribute to the aseptic loosening of polyethylene prostheses.

Adult↗

PubMed1999

Matrix-metalloproteinases in bronchopulmonary carcinomas.

Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the extracellular matrix and therefore participate in tumoural invasion. MMPs, especially gelatinases A and B, MT1-MMP, the activator of gelatinase A, and stromelysin-3 were found overexpressed in many cancers including bronchopulmonary carcinomas. In vivo observations revealed that fibroblasts are the principal source of production of MMPs. Some of these enzymes such as MT1-MMP and stromelysin 3, displayed a focal stromal localisation near preinvasive and invasive tumour clusters. Furthermore, some tumour cell lines were shown to stimulate the expression of MT1-MMP by fibroblasts. All these in vivo and in vitro results suggest that certain tumour cells produce diffusible factors which could influence the MMP stromal expression. Among these factors, the TCSF (Tumor Collagenase Stimulatory Factor) which is known to upregulate some MMPs in vitro could be a good candidate for this stromal regulation, since it is produced by bronchial tumour cells in vivo. In this review, we address such a cooperation between tumour and stromal cells for the production of MMPs and emphasize their necessity for tumoural progression in bronchopulmonary carcinomas.

Bronchial Neoplasms↗

PubMed1998

Cytoplasmic redistribution of E-cadherin-catenin adhesion complex is associated with down-regulated tyrosine phosphorylation of E-cadherin in human bronchopulmonary carcinomas.

The E-cadherin-catenin complex, by mediating intercellular adhesion, regulates the architectural integrity of epithelia. Down-regulation of its expression is thought to contribute to invasion of carcinoma cells. To investigate the involvement of the E-cadherin-catenin adhesion system in the progression of human bronchopulmonary carcinomas, we compared the immunohistochemical distribution of E-cadherin, alpha-catenin, and beta-catenin in four human bronchial cancer cell lines with different invasive abilities and in 44 primary bronchopulmonary tumors. Although invasive bronchial cell lines did not express E-cadherin and alpha-catenin, complete down-regulation of cadherin-catenin complex expression was a rare event in vivo in bronchopulmonary carcinomas. Nevertheless, a spotty and cytoplasmic pattern of E-cadherin and catenins was observed in 32 primary tumors, only in invasive tumor clusters. Immunoprecipitation experiments showed that this redistribution was not related to a disruption of cadherin-catenin interaction but to down-regulated tyrosine phosphorylation of E-cadherin. We conclude that loss of E-cadherin and/or catenins is not a prominent early event in the invasive progression of human bronchopulmonary carcinomas in vivo. The decreased tyrosine phosphorylation of E-cadherin may reflect a loss of functionality of the complex and implicates a major role in tumor invasion.

Adenocarcinoma↗

PubMed1998

Membrane-type metalloproteinases in tumor invasion.

Matrix metalloproteinases (MMPs) are members of a multigene family of zinc-dependent enzymes involved in the degradation of numerous extracellular matrix (ECM) components. Among these enzymes, membrane-type MMPs (MT-MMPs) play a major role in the activation of progelatinase A (MMP-2). The molecular structure of these enzymes is characterized by a transmembrane domain and the presence of an insertion of 11 amino-acids between the pro-peptide and the catalytic domains, which may be cleaved by furin-like enzymes leading to the activated form of the enzymes. MT1-MMP appears to play a dual role in extracellular matrix remodeling through activation of progelatinase A and procollagenase 3 and direct cleavage of some ECM macromolecules such as gelatin, type I collagen and fibronectin. Tissue inhibitor of MMPs-2 (TIMP-2) serves as an intermediate in progelatinase A activation by binding to MT1-MMP and progelatinase A on the plasma membrane. In vivo, MT1-MMP is overexpressed in malignant tumor tissues in which it was mainly localized in stromal cells surrounding the neoplastic tissue. These peritumoral fibroblasts, under particular stimuli, would be induced to overexpress MT1-MMP and consequently activate gelatinase A leading to ECM degradation. The expression of MT1-MMP is however observed in vitro in the invasive tumor cells which might represent an late stage of tumor progression. All these data confirm the important role of MT-MMPs in tumor invasion and highlight a cooperation between tumor and stromal cells for the production of these enzymes. The contribution of MMPs in a metastatic process leads to the development of novel therapies using inhibitors of these enzymes. Among a multitude of synthetic inhibitors generated, Marimastat is already clinically employed in cancer treatment.

Animals↗