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See detailMicroenvironment-derived ADAM28 impacts the onset of lung cancer
Hubeau, Céline ULiege; Gérard, Catherine ULiege; Carnet, Oriane ULiege et al

Poster (2019, September)

Background ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. Moreover, in vivo studies have shown that knockdown of ... [more ▼]

Background ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. Moreover, in vivo studies have shown that knockdown of ADAM28 in tumor cells decreased the primary tumor growth and formation of lung metastasis. Besides, ADAM28 is thought to be an important regulator of inflammatory signaling pathways as it sheds the pro-inflammatory cytokine, pro-TNF-alpha. ADAM28 protease also interacts with integrins and the P-selectin glycoprotein ligand-1 leading to inflammatory cell migration. Altogether, these findings suggest that ADAM28 contributes to cellular mechanisms leading to cancer development and progression. Methods This study aims to characterize the effects of microenvironment-derived ADAM28 on lung metastasis formation. To achieve this purpose, we generated ADAM28-/- mice into two different mouse strains (C57BL/6 and BALB/c). Lung metastatic dissemination was assessed in both ADAM28-/- and wild-type (WT) mice after intravenous injection of Lewis Lung Carcinoma cells, B16K1 melanoma cells or 4T1 breast carcinoma cells. As ADAM28 promotes leukocyte transendothelial migration, lymphocyte subtypes implicated in tumor cytotoxicity or in regulation of immune response were studied by flow cytometry. Results An unexpected increased tumor burden was found in lungs of ADAM28-/- mice as compared to WT mice. Flow cytometry analysis revealed that less CD8+ T were infiltrated within lungs of ADAM28-/- tumor-bearing mice. Moreover, a reduced CD8+ T cell population was observed in the spleen of naïve ADAM28-/- mice that is not caused by an impaired T cell maturation in the thymus. Ex vivo assays demonstrated that intrinsic properties of CD8+ T cells from ADAM28-/- mice were not affected by ADAM28 deficiency as their proliferation, migration and activation was similar. Besides, we found no expression of ADAM28 in isolated CD8+ T cells from the spleen of ADAM28-/- and WT mice. Therefore, we hypothesized that ADAM28 indirectly modulates the anti-tumor cytotoxic immune response. We also found that ADAM28 depletion is associated with a reduced infiltration of NK cell within lungs of ADAM28-/- tumor-bearing mice. Conclusion Our results demonstrate a protective effect of microenvironment-derived ADAM28 by regulating the tumor-associated immune response. [less ▲]

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See detailStromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression.
Primac, Irina ULiege; Maquoi, Erik ULiege; Blacher, Silvia ULiege et al

in Journal of Clinical Investigation (2019), 130

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying ... [more ▼]

Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors such as breast cancer (BC). Herein, we identify an integrin alpha11/PDGFRbeta+ CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin alpha11-deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin alpha11 and PDGFRbeta was found at both transcriptional and histological levels in BC specimens. High stromal integrin alpha11/PDGFRbeta expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using five CAF subpopulations (one murine, four human) revealed that integrin alpha11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, integrin alpha11 pro-invasive activity relies on its ability to interact with PDGFRbeta in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a pro-invasive matricellular protein. Pharmacological inhibition of PDGFRbeta and JNK impaired tumor cell invasion induced by integrin alpha11-positive CAFs. Collectively, our study uncovers an integrin alpha11-positive subset of pro-tumoral CAFs that exploits PDGFRbeta/JNK signalling axis to promote tumor invasiveness in BC. [less ▲]

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See detailMethod for increasing the bioavailability of inhaled compounds
Vanbever, Rita; Koussoroplis, Salome; Cataldo, Didier ULiege et al

Patent (2019)

The present invention relates to a compound comprising one or more PEG moieties , wherein said compound is a therapeutic agent active for treating a respiratory disease . The present invention also ... [more ▼]

The present invention relates to a compound comprising one or more PEG moieties , wherein said compound is a therapeutic agent active for treating a respiratory disease . The present invention also relates to a method for preventing and / or treating a respiratory disease in a subject in need thereof comprising the administration of a PEGylated therapeutic agent. Another object of the invention is a method for enhancing the bioavailability of a therapeutic agent , for enhancing the pulmonary residency of a therapeutic agent and / or for reducing the pulmonary clearance of a therapeutic agent , wherein said methods comprise the PEGylation of the therapeutic agent . [less ▲]

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See detailOzone-primed neutrophils promote early steps of tumor cell metastasis to lungs by enhancing their NET production
Rocks, Natacha ULiege; Vanwinge, Céline ULiege; Radermecker, Coraline ULiege et al

in Thorax (2019), 0

Air pollution, including particulates and gazes such as ozone (O3), is detrimental for patient’s health and has repeatedly been correlated to increased morbidity and mortality in industrialized countries ... [more ▼]

Air pollution, including particulates and gazes such as ozone (O3), is detrimental for patient’s health and has repeatedly been correlated to increased morbidity and mortality in industrialized countries. Although studies have described a link between ambient particulate matter and increased lung cancer morbidity, no direct relation has yet been established between O3 exposure and metastatic dissemination to lungs. [less ▲]

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See detailADAM10 mediates malignant pleural mesothelioma invasiveness
Sepult, Christelle ULiege; Bellefroid, Marine ULiege; Rocks, Natacha ULiege et al

in Oncogene (2019)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and ... [more ▼]

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and mesothelioma development is very long, the local invasion of mesothelioma is very rapid leading to a mean survival of one year after diagnosis. ADAM10 (A Disintegrin And Metalloprotease) sheddase targets membrane-bound substrates and its overexpression is associated with progression in several cancers. However, nothing is known about ADAM10 implication in MPM. In this study, we demonstrated higher ADAM10 expression levels in human MPM as compared to control pleural samples and in human MPM cell line. This ADAM10 overexpression was also observed in murine MPM samples. Two mouse mesothelioma cell lines were used in this study including one primary cell line obtained by repeated asbestos fibre injections. We show, in vitro, that ADAM10 targeting through shRNA and pharmacological (GI254023X) approaches reduced drastically mesothelioma cell migration and invasion, as well as for human mesothelioma cells treated with siRNA targeting ADAM10. Moreover, ADAM10 downregulation in murine mesothelioma cells significantly impairs MPM progression in vivo after intrapleural cell injection. We also demonstrate that ADAM10 sheddase downregulation decreases the production of a soluble N-cadherin fragment through membrane N-cadherin, which stimulated mesothelioma cell migration. Taken together, we demonstrate that ADAM10 is overexpressed in MPM and takes part to MPM progression through the generation of N-cadherin fragment that stimulates mesothelioma cell migration. ADAM10 inhibition is worth considering as a therapeutic perspective in mesothelioma context. [less ▲]

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See detailLocally instructed CXCR4(hi) neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps.
Radermecker, Coraline ULiege; Sabatel, Catherine ULiege; Vanwinge, Céline ULiege et al

in Nature Immunology (2019)

Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to ... [more ▼]

Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS-induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b(+)Ly-6C(+) dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4(hi) neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma. [less ▲]

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See detailLymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling
Dubois, Charline; Rocks, Natacha ULiege; Blacher, Silvia ULiege et al

in Endocrine-Related Cancer (2019), 26(2), 201-216

Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based ... [more ▼]

Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based treatments and identify patients who could potentially benefit from anti-oestrogen treatments. In this study, we highlight the contribution of lymphatic and blood endothelia in the sex-dependent modulation of lung cancer. The orthotopic graft of syngeneic lung cancer cells into immunocompetent mice showed that lung tumours grow faster in female mice than in males. Moreover, oestradiol (E2) promoted tumour development, increased lymph/angiogenesis and VEGFA and bFGF levels in lung tumours of females through an oestrogen receptor (ER) alpha-dependent pathway. Furthermore, while treatment with ERb antagonist was inefficient, ERa antagonist (MPP) and tamoxifen decreased lung tumour volumes, altered blood and lymphatic vasculature and reduced VEGFA and bFGF levels in females, but not in males. Finally, the quantification of lymphatic and blood vasculature of lung adenocarcinoma biopsies from patients aged between 35 and 55 years revealed more extensive lymphangiogenesis and angiogenesis in tumour samples issued from women than from men. In conclusion, our findings highlight an E2/ERa-dependent modulation of lymphatic and blood vascular components of lung tumour microenvironment. Our study has potential clinical implication in a personalised medicine perspective by pointing to the importance of oestrogen status or supplementation on lung cancer development that should be considered to adapt therapeutic strategies. [less ▲]

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See detailRelationship between peak expiratory flow and incidence of frailty, deaths and falls among nursing home residents: Results of the SENIOR cohort
Charles, Alexia ULiege; Buckinx, Fanny ULiege; Cataldo, Didier ULiege et al

in Archives of Gerontology and Geriatrics (2019), 85

Objective: To correlate peak expiratory flow (PEF) with the incidence of frailty, deaths and falls among nursing home residents. Methods: This is a 1-year longitudinal analysis performed on the clinical ... [more ▼]

Objective: To correlate peak expiratory flow (PEF) with the incidence of frailty, deaths and falls among nursing home residents. Methods: This is a 1-year longitudinal analysis performed on the clinical data of the SENIOR cohort. PEF, measured by peak flow meter, was considered as “low” when the observed value was ≤80% of the theoretical value. Physical capacity was evaluated using Short Physical Performance Battery, balance and gait using Tinetti test and muscle strength using a dynamometer. The incidence of frailty was defined as the transition from a “robust” or “prefrail” status to a “frail” status following Fried's criteria. Deaths and falls were also collected. Results: Among 646 subjects included at baseline (83.2 ± 9 years and 72.1% women), 297 (45.7%) displayed a low PEF. In this subgroup, physical capacity (p-values from 0.01 to <0.001), muscle strength (p < 0.001), balance and gait score (p < 0.001) were significantly lower compared to subjects displaying normal PEF. Subjects who became frail after one year displayed a lower % of the theoretical PEF value compared to those that did not (88.52 ± 45.06 vs 102.78 ± 50.29, respectively, p = 0.03). After adjustment for potential confounding variables (calf circumference, Tinetti test, SPPB test and handgrip strength), PEF was no longer associated with the occurrence of frailty. There was no association between PEF and mortality and falls. Conclusion: In a nursing home setting, PEF is not an independent factor associated with the incidence of frailty, deaths and falls. © 2019 Elsevier B.V. [less ▲]

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See detailADAM28 deletion in mice impacts lung metastasis formation
Hubeau, Céline ULiege; Gerard, Catherine; Carnet, Oriane ULiege et al

Conference (2018, September 19)

ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. In addition, ADAM28 is thought to be an important regulator of ... [more ▼]

ADAM28 expression is upregulated in non-small cell lung carcinoma and correlated with cell proliferation and metastatic dissemination. In addition, ADAM28 is thought to be an important regulator of inflammatory signaling pathways as this protease shed the pro-inflammatory cytokine, pro-TNF-alpha. ADAM28 also interacts with integrins and a P-selectin ligand (PSGL-1) involved in inflammatory cell migration. All these findings suggest that ADAM28 contributes to cancer development and progression. This project aims to characterize the effects of host-derived ADAM28 on lung metastasis formation using an ADAM28-/- mouse model. Lewis Lung Carcinoma cells and B16K1 melanoma cells were intravenously injected in ADAM28-/- and wild-type (WT) mice. An unexpected increased tumor development was found in lungs of ADAM28-/- mice. As ADAM28 is associated with lymphocyte transendothelial migration, lymphocyte subtypes implicated in tumor cytotoxicity or in regulation of immune response were studied by flow cytometry. Results showed that less CD8+ T and NK cells were infiltrated within lungs of ADAM28-/- tumor-bearing mice as compared to WT mice. Moreover, less CD8+ T cells were counted within the spleen of naïve ADAM28-/- mice. These data were confirmed in a mouse model where 4T1 breast carcinoma cells were intravenously injected in ADAM28-/- BALB/c mice. Intrinsic properties of CD8+ T cells from ADAM28-/- mice were not affected by ADAM28 depletion as they were able to proliferate, to be activated and to migrate. Further investigations are required to explain the CD8+ T cell phenotype in ADAM28-deficient mice. Our results suggest a protective effect of ADAM28 derived from the host microenvironment by indirectly regulate the immune response. [less ▲]

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See detailNEUTROPHIL EXTRACELLULAR TRAPS AS MAJOR DETERMINANTS OF ASTHMA
Radermecker, Coraline ULiege; Sabatel, Catherine ULiege; Vanwinge, Céline ULiege et al

Conference (2018, September)

Detailed reference viewed: 31 (2 ULiège)
See detailAnti-metastatic effect of ADAM28 derived from the microenvironment
Gérard, Catherine ULiege; Rocks, Natacha ULiege; Carnet, Oriane ULiege et al

Poster (2018, July 01)

Detailed reference viewed: 33 (12 ULiège)
See detailCyclodextrin and Budesonide derivative compositions and methods
Cataldo, Didier ULiege; Evrard, Brigitte ULiege; Dufour, Gilles et al

Patent (2018)

The present invention relates to novel and useful pharmaceutical compositions formulated with a cyclodextrin compound and a budesonide derivative for the treatment and/or prevention of pulmonary ... [more ▼]

The present invention relates to novel and useful pharmaceutical compositions formulated with a cyclodextrin compound and a budesonide derivative for the treatment and/or prevention of pulmonary inflammatory disease. The present invention also relates to a novel and useful analytical technique for the detection and the quantification of ΗΡ-β-CD in solution. More specifically, the present invention relates to the use of a validated 1H NMR analysis for the detection and quantification of cyclodextrins directly in pharmaceutical formulations without any extraction or separation steps for liquid formulations. [less ▲]

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See detailEffect of ADAM28 depletion on angiogenesis and lymphangiogenesis processes
Hubeau, Céline ULiege; Gerard, Catherine; Carnet, Oriane ULiege et al

Conference (2018, May 30)

Introduction ADAM28, a protease of the adamalysin family, is overexpressed by carcinoma cells in various cancers including non-small cell lung carcinoma (NSCLC) and breast cancer. In vivo studies reported ... [more ▼]

Introduction ADAM28, a protease of the adamalysin family, is overexpressed by carcinoma cells in various cancers including non-small cell lung carcinoma (NSCLC) and breast cancer. In vivo studies reported that knockdown of ADAM28 reduced primary tumor growth and lung metastatic formation suggesting a potential pro-tumoral role of ADAM28. Although cellular mechanism remain poorly described, ADAM28 is thought to stimulate angiogenesis and thus, promoting tumor progression. Indeed, ADAM28 can cleave CTGF from the CTGF/VEGF165 complex leading to the release of VEGF165. Another known substrate of ADAM28 is von Willebrand factor (vWF) which deficiency is associated with an increased angiogenesis and vasculature density. Therefore, we could hypothesize that ADAM28 induces angiogenesis through the cleavage of vWF. All these findings suggest that ADAM28 contributes to cancer development and progression by stimulating angiogenesis. Aim This project aims to investigate ADAM28 functions in the lung tumor microenvironment especially in the angiogenesis using an ADAM28 conditional knockout mouse model. Results Angiogenesis and lymphangiogenesis were assessed in lung metastasis of both ADAM28 KO and WT mice after intravenous injection of LLC cells. Immunofluorescence staining indicated that blood vessel density was increased within lung metastasis of WT mice as compared to ADAM28 KO mice. In contrast, lymphatic vessel density was similar between both groups. In addition, endothelial cell migration was evaluated in tumor-free mice using the ex vivo aortic ring assay. Result indicated that endothelial cells from ADAM28 KO mice migrated more than endothelial cells from WT mice. We also showed that blood vessel permeability was similar in WT and ADAM28 KO mice suggesting that ADAM28 depletion don’t affect blood vessel structure. Moreover, we assessed the expression of adhesion markers (ICAM-1, VCAM-1) and found no difference between both groups. Perspectives All these data need to be confirmed before drawing further conclusions. Indeed, we will confirm the increased blood vessel density in lung metastasis of WT mice using other tumor mouse models. It could also be interesting to evaluate angiogenesis in primary tumor of WT and ADAM28 KO mice. We will repeat the aortic ring experiment and perform immunostaining of pericytes and endothelial cells to study in more details the structure of the newly formed blood vessels. Angiogenesis and lymphangiogenesis will be investigated using different in vivo models such as the ear sponge assay and the corneal neovascularization model which are well-established in the laboratory. Furthermore, we would like to isolate endothelial cells from the lung of WT and ADAM28 KO mice to determine ADAM28 expression level in these cells and then, perform different in vitro assays (proliferation, migration, activation). [less ▲]

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See detailImplication of ADAM10 protease in malignant pleural mesothelioma
Bellefroid, Marine ULiege; Sepult, Christelle ULiege; Rocks, Natacha ULiege et al

Conference (2018, May 03)

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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