References of "Rocks, Natacha"
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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 detailMesoporous silica impregnation using supercritical carbon dioxide: is the solubility in the supercritical fluid a critical parameter?
Koch, Nathan ULiege; Jennotte, Olivier ULiege; Rocks, Natacha ULiege et al

Conference (2019, May 20)

Recently, mesoporous silica (MS) has been used as a material able to maintain amorphous state of active pharmaceutical ingredients (APIs) due to appropriate pore size and pore morphologies. Among the ... [more ▼]

Recently, mesoporous silica (MS) has been used as a material able to maintain amorphous state of active pharmaceutical ingredients (APIs) due to appropriate pore size and pore morphologies. Among the impregnation methods of MS, techniques using supercritical carbon dioxide (sc-CO2) are promising tools since they provide many advantages, such as the ability to produce a final medicine without any residual toxic material. Solubility of the API in sc-CO2 is reported as one of the most critical parameters, which usually limits its use in drug formulation. Most of APIs have a poor solubility in sc-CO2 and the use of organic solvents is often required1,2. The goal of this study is to evaluate the feasibility of using sc-CO2 techniques for the impregnation of MS by APIs insoluble in sc-CO2. To do so, fenofibrate (FF) is used as model drug since by changing pressure and temperature conditions of the equipment, FF can be either soluble in sc-CO2 or not soluble but molten in the supercritical phase3. FF-MS complexes were produced by four different methods. Physical mixture (PM) composed of FF (70%, 50%, 43% and 41%) and MS were produced using a mixer during 15 minutes. Fusion at atmospheric pressure inclusion was performed in a water bath by keeping PM at a temperature above the fenofibrate melting point during 1h. Supercritical method with dissolved FF was performed by placing PM in a high pressure reactor for 1 hour under supercritical conditions (40°C and minimum 140 bars) leading to the dissolution of FF in sc-CO2 while supercritical method with melted FF was perfomed under supercritical conditions (60°C and 90 bars) leading to the melting but not to the dissolution of FF in sc-CO2. FF-MS complexes were characterized in terms of drug loading by high performance liquid chromatography, in terms of crystallinity by differential scanning calorimetry and in terms of dissolution profile by an appropriate in vitro dissolution test. We have shown that the use of sc-CO2 as fusion medium allows to work with lower temperature and an increased drug loading and homogeneity in comparison with classical melting inclusion methods. FF-MS formulations produced with sc-CO2 as fusion medium give similar crystallinity and dissolution results compare to those produced with supercritical fluids as solvent. Through this study, we show new possibilities of using sc-CO2 for APIs insoluble in this fluid. [less ▲]

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See detailDevelopment of new manufacturing processes for amorphous solid dispersions
Jennotte, Olivier ULiege; Koch, Nathan ULiege; Rocks, Natacha ULiege et al

Conference (2019, May 20)

Use of the hot-melt extrusion form amorphous solid dispersions of atorvastatin calcium trihydrate with a selection of three polymers in order to enhance its aqueous solubility

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See detailUpdate of the progresses and development prospects of the FEDER project Phare
Emonts, Paul ULiege; Penoy, Noémie ULiege; Rocks, Natacha ULiege et al

Scientific conference (2019, January 19)

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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 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 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 detailAnti-metastatic effect of ADAM28 derived from the microenvironment
Gérard, Catherine ULiege; Rocks, Natacha ULiege; Carnet, Oriane ULiege et al

Poster (2018, July 01)

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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 detailMicroenvironment-derived ADAM28 prevents cancer dissemination
Gérard, Catherine ULiege; Hubeau, Céline ULiege; Carnet, Oriane ULiege et al

in Oncotarget (2018), 9(98), 37185-37199

Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes ... [more ▼]

Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes remains unclear. Genetically engineered-mice fully deficient for ADAM28 unexpectedly display increased lung colonization by pulmonary, melanoma or breast tumor cells. In experimental tumor cell dissemination models, host ADAM28 deficiency is further associated with a decreased lung infiltration by CD8+ T lymphocytes. Notably, naive ADAM28-deficient mice already display a drastic reduction of CD8+ T cells in spleen which is further observed in lungs. Interestingly, ex vivo CD8+ T cell characterization revealed that ADAM28-deficiency does not impact proliferation, migration nor activation of CD8+ T cells. Our data highlight a functional role of ADAM28 in T cell mobilization and point to an unexpected protective role for host ADAM28 against metastasis. [less ▲]

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See detailInflammation-Generated Extracellular Matrix Fragments Drive Lung Metastasis
BEKAERT, Sandrine ULiege; Fillet, Marianne ULiege; Detry, Benoit et al

in Cancer Growth and Metastasis (2017), 10

Mechanisms explaining the propensity of a primary tumor to metastasize to a specific site still need to be unveiled, and clinical studies support a link between chronic inflammation and cancer ... [more ▼]

Mechanisms explaining the propensity of a primary tumor to metastasize to a specific site still need to be unveiled, and clinical studies support a link between chronic inflammation and cancer dissemination to specific tissues. Using different mouse models, we demonstrate the role of inflammation-generated extracellular matrix fragments ac-PGP (N-acetyl-proline-glycine-proline) on tumor cells dissemination to lung parenchyma. In mice exposed to cigarette smoke or lipopolysaccharide, lung neutrophilic inflammation produces increased levels of MMP-9 (matrix metalloproteinase 9) that contributes to collagen breakdown and allows the release of ac-PGP tripeptides. By silencing CXCR2 gene expression in tumor cells, we show that these generated ac-PGP tripeptides exert a chemotactic activity on tumor cells in vivo by binding CXCR2. [less ▲]

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See detailDusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner
Vandereyken, Maud; Jacques, Sophie ULiege; Van Overmeire, Eva et al

in PLoS ONE (2017)

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion ... [more ▼]

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel out- growth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice devel- oped larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour- promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the pres- ence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demon- strates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs. [less ▲]

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See detailImpact of ADAM28 depletion in metastasis dissemination and lung cancer progression.
Hubeau, Céline ULiege; Gerard, Catherine; Carnet, Oriane ULiege et al

Conference (2017, May 10)

ADAM28 is highly overexpressed in non-small-cell lung cancer samples. Notably through a global proteomic approach, we recently identified an upregulation of ADAM28 after induction of lung inflammation in ... [more ▼]

ADAM28 is highly overexpressed in non-small-cell lung cancer samples. Notably through a global proteomic approach, we recently identified an upregulation of ADAM28 after induction of lung inflammation in a mouse model of asthma. In addition to data published in the literature and to our findings about ADAM28 expression in various pathological tissues, intrinsic characteristics of this proteinase argue for considering it as a potential regulator of cellular signalling pathways leading to an inflammatory pulmonary microenvironment and to carcinogenesis. Indeed, ADAM28 possesses an active catalytic domain and interacts in a non-proteolytic manner with some integrins (α4β1) and some P-selectin ligands involved in inflammatory cell migration. Recently, ADAM28 was shown to shed pro-TNF-alpha suggesting an important role in tumour control. This project aims to characterize molecular mechanisms involving host-derived ADAM28 in tumour development and metastatic dissemination to lung tissues. We intend to determine the effects of ADAM28 depletion on physiological and pathological processes in ADAM28 conditional knockout mice, which have been developed in our laboratory (in collaboration with the Max Planck Institute, Munich). This unique mouse strain provides a precious tool to investigate ADAM28 implication in disease models including tumour growth and dissemination. There is no spontaneous phenotype for ADAM28 full knockout animals, which are fertile and do not display any significant abnormality or defect. To understand the implication of ADAM28 in lung tumour cell dissemination, ADAM28 KO mice were intravenously injected with Lewis Lung Carcinoma cells and B16K1 melanoma cells. Our results show an increased tumour development in lungs of KO mice. To explain these surprising data, the vessel structure and permeability will be observed in our KO and WT littermates. Moreover, ADAM28 is described to be associated with lymphocyte transendothelial migration and is known to be expressed by lymphocytes. Consequently, we analysed the presence of lymphocyte subtypes implicated in tumour cytotoxicity or in the regulation of immune response. We observed that CD8 positive T-cells are less expressed in the spleen of naive KO mice and in the early stages after tumour cells injection. We also observed less CD8 T-cells in the lung of KO mice at a later stage in our model of tumour dissemination. These preliminary data suggest a role of ADAM28 in maturation and function of T cells. Hence, we will investigate the antigen presentation to immune cells and the link between tumour cells, cytokines production and B and T-cells stimulation. The role of ADAM28 derived from tumour cell as a pro-tumour factor is widely described in the literature. However, our results demonstrate an anti-tumour function of ADAM28 expressed in tumour microenvironment suggesting a dual role of ADAM28, depending on the origin of the protease. More investigations are required to explain this contradictory effect before drawing further conclusions. [less ▲]

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See detailNeutrophil-Derived Interleukin 16 in Premetastatic Lungs Promotes Breast Tumor Cell Seeding
Donati, Kim ULiege; Sepult, Christelle ULiege; Rocks, Natacha ULiege et al

in Cancer Growth and Metastasis (2017)

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See detailNeutrophil-Derived Interleukin 16 in Premetastatic Lungs Promotes Breast Tumor Cell Seeding.
Donati, Kim; Sepult, Christelle ULiege; Rocks, Natacha ULiege et al

in Cancer Growth and Metastasis (2017), 10

The premetastatic niche in distant organs prior to metastatic cell arrival emerged as an important step in the metastatic cascade. However, molecular mechanisms underlying this process are still poorly ... [more ▼]

The premetastatic niche in distant organs prior to metastatic cell arrival emerged as an important step in the metastatic cascade. However, molecular mechanisms underlying this process are still poorly understood. In particular, whether neutrophil recruitment at a premetastatic stage promotes or inhibits metastatic cell seeding has to be clarified. We aimed at unraveling how neutrophil infiltration in lung parenchyma induced by the distant primary tumor influences the establishment of lung metastasis. Elevated neutrophil counts and IL-16 levels were found in premetastatic lungs in a syngenic mouse model using 4T1 tumor cells. 4T1 cell-derived soluble factors stimulated IL-16 secretion by neutrophils. The functional contribution of IL-16 is supported by metastasis burden reduction in lungs observed on instillation of an IL-16 neutralizing antibody. Moreover, IL-16 promotes in vitro 4T1 cell adhesiveness, invasiveness, and migration. In conclusion, at a premetastatic stage, neutrophil-derived IL-16 favors tumor cell engraftment in lung parenchyma. [less ▲]

Detailed reference viewed: 46 (14 ULiège)