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ABSTRACT: BACKGROUND: With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic.Content:The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix.Summary:A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix.
Clinical Chemistry 11/2012; · 7.91 Impact Factor
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ABSTRACT: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.
The Journal of Immunology 09/2012; 189(8):4135-43. · 5.79 Impact Factor
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ABSTRACT: Rationale: Interleukin-13 (IL-13) is a prototypic Th2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis, bronchial hyperresponsiveness, mucus hypersecretion, subepithelial fibrosis and eosinophil infiltration. Objectives: We assessed the potential efficacy of inhaled anti-IL-13 monoclonal antibody Fab' fragment on allergen-induced airway inflammation, hyperresponsiveness and remodeling in an experimental model of allergic asthma. Anti-IL-13 Fab' was administered to mice as a liquid aerosol generated by inExpose® inhalation system in a tower allowing a nose-only exposure. Methods: BALB/c mice were treated by PBS, anti-IL-13 Fab' or A33 Fab' fragment and subjected to ovalbumin (OVA) exposure for 1 and 5 weeks (short term (ST) and long term (LT) protocols). Measurements and Main Results: Our data demonstrate a significant anti-asthma effect following nebulization of anti-IL-13 Fab' in a model of asthma driven by allergen exposure as compared to saline and non-immune Fab fragments. In short and long terms protocols, administration of the anti-IL-13 Fab' by inhalation significantly decreased bronchial responsiveness to methacholine, BALF eosinophilia, inflammatory cell infiltration in lung tissue, and many features of airway remodeling. Levels of pro-inflammatory mediators and matrix metalloprotease levels were significantly lower in lung parenchyma of mice treated with anti-IL-13 Fab'. Conclusions: These data demonstrate that an inhaled anti-IL-13 Fab' significantly reduces airway inflammation, hyperresponsiveness and remodeling. Specific neutralization of IL-13 in the lungs using an inhaled anti-IL-13 Fab' could represent a novel and effective therapy for the treatment of asthma.
American Journal of Respiratory Cell and Molecular Biology 08/2012; · 5.13 Impact Factor
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ABSTRACT: Membrane-type 4 matrix metalloprotease (MT4-MMP) expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However, whether these pro-tumorigenic and pro-metastatic effects of MT4-MMP are related to a proteolytic action is not yet known. Through site directed mutagenesis MT4-MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4-MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in recombination activating gene-1-deficient mice. All these effects were abrogated upon MT4-MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor-derived MT4-MMP, but not host-derived MT4-MMP contributes to angiogenesis. A genetic approach using MT4-MMP-deficient mice revealed that the status of MT4-MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4-MMP requires a permissive microenvironment. Indeed, tumor-derived MT4-MMP failed to circumvent the lack of an host angio-promoting factor such as plasminogen activator inhibitor-1. Overall, our study demonstrates the key contribution of MT4-MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4-MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic dissemination.
International Journal of Cancer 01/2012; 131(7):1537-48. · 5.44 Impact Factor
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Julie Lecomte,
Krystel Louis,
Benoit Detry,
Silvia Blacher,
Vincent Lambert,
Sandrine Bekaert,
Carine Munaut,
Jenny Paupert,
Pierre Blaise,
Jean-Michel Foidart,
Jean-Marie Rakic,
Stephen M Krane, Agnès Noel
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ABSTRACT: In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ( -/- ) mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV.
Cellular and Molecular Life Sciences CMLS 02/2011; 68(4):677-86. · 6.57 Impact Factor
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Geneviève Paulissen,
Natacha Rocks,
Maud M Guéders,
Denis Bedoret,
Céline Crahay,
Florence Quesada-Calvo,
Jonathan Hacha,
Sandrine Bekaert,
Christophe Desmet,
Jean-Michel Foidart,
Fabrice Bureau, Agnès Noel,
Didier D Cataldo
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ABSTRACT: Asthma is a complex disease linked to various pathophysiological events including the activity of proteinases. The multifunctional A disintegrin and metalloproteinases (ADAMs) displaying the ability to cleave membrane-bound mediators or cytokines appear to be key mediators in various inflammatory processes. In the present study, we investigated ADAM-8 expression and production in a mouse model of allergen-induced airway inflammation. In allergen-exposed animals, increased expression of ADAM-8 was found in the lung parenchyma and in DC purified from the lungs. The potential role of ADAM-8 in the development of allergen-induced airway inflammation was further investigated by the use of an anti-ADAM-8 antibody and ADAM-8 knockout animals. We observed a decrease in allergen-induced acute inflammation both in BALF and the peribronchial area in anti-ADAM-8 antibody-treated mice and in ADAM-8-deficient mice (ADAM-8(-/-) ) after allergen exposure. ADAM-8 depletion led to a significant decrease of the CD11c(+) lung DC. We also report lower levels of CCL11 and CCL22 production in antibody-treated mice and ADAM-8- deficient mice that might be explained by decreased eosinophilic inflammation and lower numbers of DC, respectively. In conclusion, ADAM-8 appears to favour allergen-induced acute airway inflammation by promoting DC recruitment and CCL11 and CCL22 production.
European Journal of Immunology 02/2011; 41(2):380-91. · 5.10 Impact Factor
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Vincent Chabottaux,
Stéphanie Ricaud,
Laurent Host,
Silvia Blacher,
Alexandra Paye,
Marc Thiry,
Anikitos Garofalakis,
Carine Pestourie,
Karine Gombert,
Françoise Bruyere,
Daniel Lewandowsky,
Bertrand Tavitian,
Jean-Michel Foidart,
Frédéric Duconge, Agnès Noel
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ABSTRACT: The present study aims at investigating the mechanism by which membrane-type 4 matrix metalloproteinase (MT4-MMP), a membrane-anchored MMP expressed by human breast tumour cells promotes the metastatic dissemination into lung. We applied experimental (intravenous) and spontaneous (subcutaneous) models of lung metastasis using human breast adenocarcinoma MDA-MB-231 cells overexpressing or not MT4-MMP. We found that MT4-MMP does not affect lymph node colonization nor extravasation of cells from the bloodstream, but increases the intravasation step leading to metastasis. Ultrastructural and fluorescent microscopic observations coupled with automatic computer-assisted quantifications revealed that MT4-MMP expression induces blood vessel enlargement and promotes the detachment of mural cells from the vascular tree, thus causing an increased tumour vascular leak. On this basis, we propose that MT4-MMP promotes lung metastasis by disturbing the tumour vessel integrity and thereby facilitating tumour cell intravasation.
Journal of Cellular and Molecular Medicine 06/2009; 13(9B):4002-13. · 4.13 Impact Factor
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Natacha Rocks,
Geneviève Paulissen,
Florence Quesada-Calvo,
Carine Munaut,
Maria-Luz Alvarez Gonzalez,
Maud Gueders,
Jonathan Hacha,
Christine Gilles,
Jean-Michel Foidart, Agnès Noel,
Didier D Cataldo
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ABSTRACT: ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1-overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor beta (TGF-beta), and interleukin-1beta (IL-1beta). Neutralizing antibodies against TGF-beta and IL-1beta blocked the chemotactic effect of medium conditioned by ADAMTS-1-expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1-induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling.
Cancer Research 12/2008; 68(22):9541-50. · 7.86 Impact Factor
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Maud M Gueders,
Pascal Bertholet,
Fabienne Perin,
Natacha Rocks,
Raphaël Maree,
Vincent Botta,
Renaud Louis,
Jean-Michel Foidart, Agnès Noel,
Brigitte Evrard,
Didier D Cataldo
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ABSTRACT: In this study, we assess the effectiveness of inhaled doxycycline, a tetracycline antibiotic displaying matrix metalloproteinases (MMP) inhibitory effects to prevent allergen-induced inflammation, hyperresponsiveness and remodeling. MMPs play key roles in the complex cascade of events leading to asthmatic phenotype.
Doxycycline was administered by aerosols by the mean of a novel formulation as a complex with hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD) used as an excipient. BALB/c mice (n=16-24 in each group) were sensitized and exposed to aerosolized ovalbumin (OVA) from day 21 to 27 (short-term exposure protocol) or 5 days/odd weeks from day 22 to 96 (long-term exposure protocol).
In the short-term exposure model, inhaled doxycycline decreased allergen-induced eosinophilic inflammation in bronchoalveolar lavage (BAL) and in peribronchial areas, as well as airway hyperresponsiveness. In lung tissue, exposure to doxycycline via inhaled route induced a fourfold increase in IL-10 levels, a twofold decrease in IL-5, IL-13 levels and diminished MMP-related proteolysis and the proportion of activated MMP-9 as compared to placebo. In the long-term exposure model, inhaled doxycycline significantly decreased the extent of glandular hyperplasia, airway wall thickening, smooth muscle hyperplasia and subepithelial collagen deposition which are well recognized features of airway remodeling.
Doxycycline administered by aerosols decreases the allergen-induced airway inflammation and hyperresponsiveness and inhibits the development of bronchial remodeling in a mouse model of asthma by modulation of cytokines production and MMP activity.
Biochemical Pharmacology 02/2008; 75(2):514-26. · 4.70 Impact Factor
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ABSTRACT: In addition to their direct antimicrobial activity, defensins might also influence adaptive immunity by attracting immature dendritic cells (DC). As these cells have been shown to be deficient in uterine cervix carcinogenesis, we evaluated the ability of alpha-defensin (HNP-2, human neutrophil defensin 2) and beta-defensin (HbetaD2, human beta defensin 2) to stimulate their migration in human papillomavirus (HPV)-associated (pre)cancers. We first observed, using RT-PCR and immunohistology, that HbetaD2 is absent in HPV-transformed keratinocytes and that it is weakly expressed in cervical (pre)neoplastic lesions in comparison with normal keratinocytes. We next demonstrated that defensins exert a chemotactic activity for DC in a Boyden Chamber assay and stimulate their infiltration in an in vitro-formed (pre)neoplastic epithelium (organotypic culture of HPV-transformed keratinocytes). To evaluate the ability of defensins also to recruit DC in vivo, we developed a model of immunodeficient mice grafted with organotypic cultures of HPV+ keratinocytes, which form an epithelium similar to a high-grade neoplastic lesion, with tumoral invasion and neovascularization. Intravenously injected human DC were able to infiltrate grafts of HPV+ keratinocytes after administration of HNP-2 in the transplantation chamber. Taken together, these results suggest that defensins could reverse a frequent immune alteration observed in cancer development.
The FASEB Journal 10/2007; 21(11):2765-75. · 5.71 Impact Factor
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ABSTRACT: The restricted view of matrix metalloproteinases (MMPs) as simple destroyers of extracellular matrix components has largely ignored their substantial contribution in many aspects of cancer development and metastatic dissemination. Over the last few years, the relevance of MMPs in the processing of a large array of extracellular and cell surface-associated proteins has grown considerably. Our knowledge about the complex functions of MMPs and how their contribution may differ throughout cancer progression is rapidly expanding. These new findings provide several explanations for the lack of success of MMP inhibition in clinical trials. A complete understanding of MMP biology is needed before considering them, their substrates or their products as therapeutic targets. In this review, we explore the different faces of MMP implication in breast cancer progression by considering both clinical and fundamental aspects.
Clinical and Experimental Metastasis 02/2007; 24(8):647-56. · 3.52 Impact Factor
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Catherine Maillard,
Maud Jost,
Maria Unni Rømer,
Nils Brunner,
Xavier Houard,
Annabelle Lejeune,
Carine Munaut,
Khalid Bajou,
Laurence Melen,
Keld Dano,
Peter Carmeliet,
Norbert E Fusenig,
Jean Michel Foidart, Agnès Noel
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ABSTRACT: Angiogenesis and tumor expansion are associated with extracellular matrix remodeling and involve various proteases such as the plasminogen (Plg)/plasminogen activator (PA) system. Recently, several experimental data have implicated the plasminogen activator inhibitor-1 (PAI-1) in tumor angiogenesis in murine systems. However, little is known about PAI-1 functions in human skin carcinoma progression. By generating immunodeficient mice (in Rag-1-/- or nude background) deleted for PAI-1 gene (PAI-1-/-), we have evaluated the impact of host PAI-1 deficiency on the tumorigenicity of two malignant human skin keratinocyte cell lines HaCaT II-4 and HaCaT A5-RT3 forming low-grade and high-grade carcinomas, respectively. When using the surface transplantation model, angiogenesis and tumor invasion of these two cell lines are strongly reduced in PAI-1-deficient mice as compared to the wild-type control animals. After subcutaneous injection in PAI-1-/- mice, the tumor incidence is reduced for HaCaT II-4 cells, but not for those formed by HaCaT A5-RT3 cells. These data indicate that PAI-1 produced by host cells is an important contributor to earlier stages of human skin carcinoma progression. It exerts its tumor-promoting effect in a tumor stage-dependent manner, but PAI-1 deficiency is not sufficient to prevent neoplastic growth of aggressive tumors of the human skin.
Neoplasia 02/2005; 7(1):57-66. · 5.95 Impact Factor
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ABSTRACT: Plasminogen activator inhibitor type 1 (PAI-1) plays a key role in tumor progression and is believed to control proteolytic activity and cell migration during angiogenesis. We report here that host PAI-1, at physiological concentration, promotes in vivo tumor invasion and angiogenesis. In sharp contrast, inhibition of tumor vascularization was observed when PAI-1 was produced at supraphysiologic levels, either by host cells (transgenic mice overexpressing PAI-1) or by tumor cells (after transfection with murine PAI-1 cDNA). This study provides for the first time in vivo evidence for a dose-dependent effect of PAI-1 on tumor angiogenesis. Of great interest is the finding that PAI-1 produced by tumor cells, even at high concentration, did not overcome the absence of PAI-1 in the host, emphasizing the importance of the cellular source of PAI-1.
Oncogene 10/2004; 23(41):6986-90. · 6.37 Impact Factor
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Nor Eddine Sounni,
Christian Roghi,
Vincent Chabottaux,
Mathias Janssen,
Carine Munaut,
Erik Maquoi,
Beatriz G Galvez,
Christine Gilles,
Francis Frankenne,
Gillian Murphy,
Jean-Michel Foidart, Agnès Noel
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ABSTRACT: Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) are two key molecules involved in pericellular proteolysis and cell proliferation during tumor growth and angiogenesis. Our previous data showed that MT1-MMP overexpression in human breast carcinoma MCF7 cells induced an up-regulation of VEGF expression. This effect was associated in vivo with accelerated tumor growth and angiogenesis. We now provide evidence that MT1-MMP overexpression specifically affected VEGF-A production and failed to influence that of other VEGF family members (VEGF, B, C, D, or PlGF) or their receptors. The up-regulation of VEGF-A by MT1-MMP was related to an increased transcriptional activation rather than to a modification of mRNA stability. It was blocked by synthetic MMP inhibitors, TIMP2, but not TIMP-1 and abolished by a partial deletion of the catalytic domain or the cytoplasmic tail of MT1-MMP. Analysis of the signal transduction mechanisms demonstrated that MT1-MMP acts through a signaling pathway involving Src tyrosine kinases. Thus, our results provide new insight into the mechanisms of action of MT1-MMP during angiogenesis and suggest that the full enzymatic activity of MT1-MMP is required for a specific up-regulation of VEGF-A through an activation of Src tyrosine kinase pathways.
Journal of Biological Chemistry 05/2004; 279(14):13564-74. · 4.77 Impact Factor
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Christèle Bisson,
Silvia Blacher,
Myriam Polette,
Jean-Frédéric Blanc,
Florence Kebers,
Joëlle Desreux,
Bernard Tetu,
Jean Rosenbaum,
Jean-Michel Foidart,
Philippe Birembaut, Agnès Noel
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ABSTRACT: The membrane type-1 matrix metalloproteinase (MT1-MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP-2 and MMP-13) and to degrade extracellular matrix. Our study was undertaken to localize and identify the MT1-MMP expressing cells in human breast adenocarcinomas. A textural analysis of images obtained by immunohistochemistry and in situ hybridization showed precisely the co-expression of alpha smooth muscle actin (alphaSM actin) and MT1-MMP in myofibroblasts. MT1-MMP expression is confined to myofibroblasts in close contact with tumor cells. In sharp contrast, the expression of MMP-2 was more widely distributed in both alphaSM actin positive and negative cells close to and at distance from cancer cell clusters. Our in vitro observations are consistent with the higher level of MT1-MMP expression and of MMP-2 activation observed in alphaSM actin positive fibroblasts derived from breast tumors, as compared to normal breast fibroblasts. Collectively, these results implicate myofibroblasts as major producer of MT1-MMP in breast cancer and emphasize the importance of stromal-epithelial cell interactions in their progression.
International Journal of Cancer 06/2003; 105(1):7-13. · 5.44 Impact Factor
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ABSTRACT: ADAMs (a disintegrin and metalloprotease) constitute a family of cell surface proteins containing disintegrin and metalloprotease domains which associate features of adhesion molecules and proteases. ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs) bear thrombospondin type I motifs in C-terminal extremity, and most of them are secreted proteins. Because genetic studies have shown that ADAM-33 gene polymorphisms are associated with asthma, we designed this study to assess mRNA expression profile of several ADAM and ADAMTS proteases in sputum from patients with asthma and to investigate the relationship between expression of these proteases and asthma-associated inflammation and airway obstruction. mRNA expression profile of selected ADAM and ADAMTS proteinases (ADAM-8, -9, -10, -12, -15, -17, and -33; ADAMTS-1, -2, -15, -16, -17, -18, and -19), their physiological inhibitors TIMP-1 and TIMP-3, and RECK, a membrane-anchored MMP activity regulator, was obtained by RT-PCR analysis performed on cells collected by sputum induction from 21 patients with mild to moderate asthma and 17 healthy individuals. mRNA levels of ADAM-8, ADAM-9, ADAM-12, TIMP-1, and TIMP-3 were significantly increased, whereas mRNA levels coding for ADAMTS-1, ADAMTS-15, and RECK were significantly decreased in patients with asthma compared with control patients. ADAM-8 expression was negatively correlated with the forced expiratory volume at the first second (FEV(1)) (r = -0.57, P < 0.01), whereas ADAMTS-1 and RECK expressions were positively correlated to FEV(1) (r = 0.45, P < 0.05, and r = 0.55, P = 0.01, respectively). We conclude that expression of ADAMs and ADAMTSs and their inhibitors is modulated in airways from patients with asthma and that these molecules may play a role in the pathogenesis of asthma.
Molecular Medicine 12(7-8):171-9. · 3.76 Impact Factor
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Corinne Martinella-Catusse,
Myriam Polette, Agnès Noel,
Christine Gilles,
Pierre Dehan,
Carine Munaut,
Alain Colige,
Laurette Volders,
Jean-Claude Monboisse,
Jean-Michel Foidart,
Philippe Birembaut
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ABSTRACT: 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.
Laboratory Investigation.
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ABSTRACT: 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.
Br J Cancer.
