Publications by authors named "François-Xavier Maquart"

78 Publications

Jacques-Paul Borel.

Biol Aujourdhui 2019;213(1-2):73-74. Epub 2019 Jul 5.

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http://dx.doi.org/10.1051/jbio/2019017DOI Listing
January 2020

Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA.

Br J Cancer 2019 02 11;120(4):453-465. Epub 2019 Feb 11.

Université de Reims Champagne Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.

Background: Carcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release. This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. We previously demonstrate that EDPs exert protumoural activities through Hsp90 secretion to stabilised extracellular proteinases.

Methods: EDP influence on cancer cell blebbing and extracellular vesicle shedding were examined with a videomicroscope coupled with confocal Yokogawa spinning disk, by transmission electron microscopy, scanning electron microscopy and confocal microscopy. The ribosomal protein SA (RPSA) elastin receptor was identified after affinity chromatography by western blotting and cell immunolocalisation. mRNA expression was studied using real-time PCR. SiRNA were used to confirm the essential role of RPSA.

Results: We demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp90 and proteinases in the extracellular space. EDPs influence intracellular calcium influx and cytoskeleton reorganisation. Among matrikines, VGVAPG and AGVPGLGVG peptides reproduced EDP effects through RPSA binding.

Conclusions: Our data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites.
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http://dx.doi.org/10.1038/s41416-019-0382-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461924PMC
February 2019

Medical biology in the face of the evolution of health care needs.

Ann Biol Clin (Paris) 2018 Oct;76(5):485-491

Membre de l'Académie nationale de pharmacie, Paris, France.

Since the publication of the ordinance of January 13th 2010, ratified by the law of May 30th 2013, medical biology in France has undergone a massive restructuration with the emergence of groups of several hundred laboratories. This evolution, which leads to a considerable reduction in the number of structures, causes numerous problems related to increased industrialization and financialization, difficulties of accreditation and disappearance of the proximity link between the biologist and the prescriber or the patient. It also leads to a clear disaffection of students, especially medical students, for this specialty whose medical character has been clearly affirmed by the law. This report takes stock of the current situation of medical biology and makes recommendations to strengthen the role of the medical biologist in the health system and patients' care.
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http://dx.doi.org/10.1684/abc.2018.1370DOI Listing
October 2018

Conformation-dependent binding of a Tetrastatin peptide to αβ integrin decreases melanoma progression through FAK/PIK/Akt pathway inhibition.

Sci Rep 2018 06 29;8(1):9837. Epub 2018 Jun 29.

UMR CNRS/URCA 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), Reims, F-51100, France.

Tetrastatin, a 230 amino acid sequence from collagen IV, was previously demonstrated to inhibit melanoma progression. In the present paper, we identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin in vivo and in vitro on melanoma cell proliferation, migration and invasion. We demonstrated that QS-13 binds to SK-MEL-28 melanoma cells through the αβ integrin using blocking antibody and β3 integrin subunit siRNAs strategies. Relevant QS-13 conformations were extracted from molecular dynamics simulations and their interactions with αβ integrin were analyzed by docking experiments to determine the binding areas and the QS-13 amino acids crucial for the binding. The in silico results were confirmed by in vitro experiments. Indeed, QS-13 binding to SK-MEL-28 was dependent on the presence of a disulfide-bound as shown by mass spectroscopy and the binding site on αβ was located in close vicinity to the RGD binding site. QS-13 binding inhibits the FAK/PIK/Akt pathway, a transduction pathway that is largely involved in tumor cell proliferation and migration. Taken together, our results demonstrate that the QS-13 peptide binds αβ integrin in a conformation-dependent manner and is a potent antitumor agent that could target cancer cells through αβ.
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http://dx.doi.org/10.1038/s41598-018-28003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026150PMC
June 2018

Lumican as a multivalent effector in wound healing.

Adv Drug Deliv Rev 2018 04 1;129:344-351. Epub 2018 Mar 1.

Université de Reims Champagne-Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France. Electronic address:

Wound healing, a complex physiological process, is responsible for tissue repair after exposure to destructive stimuli, without resulting in complete functional regeneration. Injuries can be stromal or epithelial, and most cases of wound repair have been studied in the skin and cornea. Lumican, a small leucine-rich proteoglycan, is expressed in the extracellular matrices of several tissues, such as the cornea, cartilage, and skin. This molecule has been shown to regulate collagen fibrillogenesis, keratinocyte phenotypes, and corneal transparency modulation. Lumican is also involved in the extravasation of inflammatory cells and angiogenesis, which are both critical in stromal wound healing. Lumican is the only member of the small leucine-rich proteoglycan family expressed by the epithelia during wound healing. This review summarizes the importance of lumican in wound healing and potential methods of lumican drug delivery to target wound repair are discussed. The involvement of lumican in corneal wound healing is described based on in vitro and in vivo models, with critical emphasis on its underlying mechanisms of action. Similarly, the expression and role of lumican in the healing of other tissues are presented, with emphasis on skin wound healing. Overall, lumican promotes normal wound repair and broadens new therapeutic perspectives for impaired wound healing.
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http://dx.doi.org/10.1016/j.addr.2018.02.011DOI Listing
April 2018

Unexpected M-protein in an Anticoagulated Patient.

Clin Chem 2018 03;64(3):614-615

CHU de Reims, Laboratoire de Biochimie - Pharmacologie - Toxicologie, Hôpital Robert Debré, Reims, France;

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http://dx.doi.org/10.1373/clinchem.2017.278184DOI Listing
March 2018

Small leucine-rich proteoglycans and matrix metalloproteinase-14: Key partners?

Matrix Biol 2019 01 15;75-76:271-285. Epub 2017 Dec 15.

CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France; Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France. Electronic address:

Small leucine-rich proteoglycans (SLRPs) are important regulators of extracellular matrix assembly and cell signaling. They are a family of proteoglycans that are present in extracellular matrix and that share in common multiple repeats of a leucine-rich structural motif. SLRPs have been identified as inhibitors of cancer progression by affecting MMPs, especially MMP-14 activity. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess anti-tumor activity. Interestingly, it was demonstrated recently that lumican interacts directly with the catalytic domain of MMP-14 and inhibits its activity. The aim of this review was to summarize the interactions between SLRPs and MMPs with a special interest to lumican.
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http://dx.doi.org/10.1016/j.matbio.2017.12.006DOI Listing
January 2019

Tau protein as a possible marker of cerebrospinal fluid leakage in cerebrospinal fluid rhinorrhoea: A pilot study.

Biochem Med (Zagreb) 2017 Oct 28;27(3):030703. Epub 2017 Aug 28.

CHU de Reims, Laboratoire Central de Biochimie, Reims, France.

Introduction: The management of posttraumatic cerebrospinal fluid (CSF) rhinorrhoea remains a clinical challenge. Cerebrospinal fistula is a dural defect responsible for possible CSF leakage into the contiguous air-filled cavities located at the skull base. The risk of central nervous system infection in these conditions is severe and can be life threatening. Consequently, a specific CSF biomarker might be used in case of difficult diagnosis of CSF rhinorrhoea. CSF Tau protein is a neuronal protein, commonly assessed for diagnosis of Alzheimer Disease (AD). The aim of this study was to determine whether the Tau protein could be a relevant marker of CSF leakage.

Materials And Methods: Tau protein measurement was performed by enzyme-linked immunosorbent assay in 13 patients with CSF leakage (CSF rhinorrhoea group), and 8 patients with spontaneous aqueous rhinorrhoea (non-CSF leakage group). The serum concentration of Tau protein was measured by ELISA in both CSF rhinorrhoea group and non-CSF leakage group.

Results: In patients with CSF leakage, CSF Tau protein median concentration was 479 ng/L (197 - 2325 ng/L). On the other hand, the Tau protein concentration was below the lower limit of quantification (LLoQ) (< 87 ng/L) in non-CSF leakage group. Serum Tau protein concentration by ELISA was also below LLoQ (< 87 ng/L) for all subjects.

Conclusion: ELISA measurement of Tau protein in rhinorrhoea fluid may be a reliable and relevant marker for detecting the presence of CSF in the nasal discharge and sign the existence of a CSF leakage.
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http://dx.doi.org/10.11613/BM.2017.030703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575651PMC
October 2017

Confusing Hyperkalemia.

Clin Chem 2017 07;63(7):1305-1306

CHU de Reims, Laboratoire Central de Biochimie, Hôpital Robert Debré, Reims, France;

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http://dx.doi.org/10.1373/clinchem.2016.270306DOI Listing
July 2017

Lumican effectively regulates the estrogen receptors-associated functional properties of breast cancer cells, expression of matrix effectors and epithelial-to-mesenchymal transition.

Sci Rep 2017 03 23;7:45138. Epub 2017 Mar 23.

Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.

Lumican is a small leucine-rich proteoglycan that has been shown to contribute in several physiological processes, but also to exert anticancer activity. On the other hand, it has been recently shown that knockdown of the estrogen receptor α (ERα) in low invasive MCF-7 (ERα+) breast cancer cells and the suppression of ERβ in highly aggressive MDA-MB-231 (ERβ+) cells significantly alter the functional properties of breast cancer cells and the gene expression profile of matrix macromolecules related to cancer progression and cell morphology. In this report, we evaluated the effects of lumican in respect to the ERs-associated breast cancer cell behaviour, before and after suppression of ERs, using scanning electron and confocal microscopies, qPCR and functional assays. Our data pinpointed that lumican significantly attenuated cell functional properties, including proliferation, migration and invasion. Furthermore, it modified cell morphology, inducing cell-cell junctions, evoked EMT/MET reprogramming and suppressed the expression of major matrix effectors (matrix metalloproteinases and EGFR) implicated in breast cancer progression. The effects of lumican were found to be related to the type of breast cancer cells and the ERα/β type. These data support the anticancer activity of lumican and open a new area for the pharmacological targeting of the invasive breast cancer.
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http://dx.doi.org/10.1038/srep45138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362815PMC
March 2017

Consistent, but Totally Misleading, Thyroid Function Test Results.

Clin Chem 2017 03;63(3):788-789

CHU de Reims, Service Endocrinologie, Diabète-Nutrition, Reims, France.

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http://dx.doi.org/10.1373/clinchem.2016.265959DOI Listing
March 2017

The influence of oral copper-methionine on matrix metalloproteinase-2 gene expression and activation in right-sided heart failure induced by cold temperature: A broiler chicken perspective.

J Trace Elem Med Biol 2017 Jan 7;39:71-75. Epub 2016 Jul 7.

Unité de Recherche "Matrice Extracellulaire et Dynamique Cellulaire" (MEDyC), UMR CNRS/URCA N° 7369, Faculté de Médecine de Reims, 51095 Reims cedex, France; CHU de Reims, Laboratoire Central de Biochimie, 51092 Reims cedex, France.

This study was designed to investigate the expression, activation and activity of matrix metalloproteinase-2 (MMP-2) in the heart of broiler chickens reared in cold conditions and fed with copper-methionine supplement at different levels. The chickens (n=480) were randomly allotted to six treatments and four replicates. Treatments included two rearing temperatures (i.e. normal and cold temperatures) each combined with three levels of supplemental copper-methionine (i.e. 0, 100 and 200mg/kg). On d 38 and 45 of age, four broilers from each treatment were sacrificed and their hearts were stored at -80°C. Right-sided heart failure, as evident from abdominal and pericardial fluid accumulation, was observed in broilers under cold stress and not receiving supplemental copper. This clinical observation was confirmed at molecular level through increased MMP-2 expression, activation and activity in this group. Birds reared under normal temperature, however, were not involved in right-sided heart failure nor benefitted from copper-methionine supplementation. In contrast, gelatin zymography and real-time PCR demonstrated that dietary supplementation with copper-methionine decreased pro-MMP-2 and MMP-2 in the heart of chickens reared in cold conditions. However, gelatin reverse zymography did not show any difference between treatments in tissue inhibitor of metalloproteinase-2. Level of supplementation showed similar effects on parameters determined. It is concluded that dietary supplementation with copper-methionine reduced right-sided heart failure at clinical and molecular levels in cold-stressed chickens.
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http://dx.doi.org/10.1016/j.jtemb.2016.07.003DOI Listing
January 2017

Unexpected Creatinine Values.

Clin Chem 2016 12;62(12):1675-1676

CHU de Reims, Laboratoire Central de Biochimie, Hôpital Robert Debré, Reims, France.

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http://dx.doi.org/10.1373/clinchem.2016.263038DOI Listing
December 2016

Evaluation of Lumipulse® G1200 for the measurement of six tumor markers: Comparison with AIA® 2000.

Clin Biochem 2016 Nov 10;49(16-17):1302-1306. Epub 2016 Aug 10.

CHU de Reims, Laboratoire Central de Biochimie, 51092 Reims, France; Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), 51095 Reims, France. Electronic address:

Tumor marker assays are daily practiced, for screening and follow up of cancers. Interassay precision is an important parameter for the interpretation of the kinetics of the markers, in order to conclude to the efficiency or failure of treatment. The aim of this study was to compare two automated Immunoassay analyzers, Lumipulse® G1200 and AIA® 2000. Both analyzers used an immunoassay system but with different antibodies. Six tumor markers commonly used were studied: AFP, PSA, CA 19-9, CA 15-3, CA 125 and CEA. 253 samples have been collected over a period of one month and analyzed by both analyzers. Regression of Passing-Badblock and Bland-Altman diagram were used to analyze the results for AFP (n=36), PSA (n=39), CA-125 (n=40), CA 15-3 (n=40), CA 19-9 (n=46) and CEA (n=52) were performed. Analytical performances of Lumipulse® G1200 highlighted the good inter-run and intra-run precision of the analyzer. We obtained a good correlation coefficient between Lumipulse G1200® and AIA 2000®, >0.96 for most markers except CA 19-9 which provided a correlation coefficient significantly lower than that obtained with other markers. The concordance for all markers was >94% except for CA 19-9 (83.7%). This study showed a good correlation between the two analyzers and, therefore, a transfer from one analyzer to the other is possible for the different markers studied. However, we found here the classical difficulty to transfer this type of analysis, due to the absence of method standardization. This difficulty was particularly illustrated by CA19-9.
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http://dx.doi.org/10.1016/j.clinbiochem.2016.08.003DOI Listing
November 2016

Type XIX collagen: A new partner in the interactions between tumor cells and their microenvironment.

Matrix Biol 2017 01 1;57-58:169-177. Epub 2016 Aug 1.

Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), 51095 Reims, France; CHU de Reims, Laboratoire Central de Biochimie, 51092 Reims, France. Electronic address:

Type XIX collagen is a minor collagen that is associated with the basement membrane zone that belongs to the FACIT family (Fibril-Associated Collagens with Interrupted Triple helices). The FACIT family is composed of type IX, XII, XIV, XVI, XX, XXI, XXII and XIX collagens, which share many highly conserved structural motifs: a short NC1 domain, a thrombospondin-like N-terminal domain (TSPN), and numerous cysteine residues. The main role of FACITs is to ensure the integrity and stability of the extracellular matrix and its fibrillar collagen network by regulating the formation and size of the collagen fibrils. Type XIX collagen was discovered in a human rhabdomyosarcoma cell line. The collagen α1(XIX) chain is composed of 5 triple-helical domains (COL) interrupted by 6 non-triple-helical (NC) domains with a short, C-terminal, 19 amino acid non-collagenous domain (NC1). This collagen is involved in the differentiation of muscle cells, central nervous system development, and formation of the esophagus. Type XIX collagen is associated with the basement membrane zone, like type XVIII and XV collagens. Its short NC1(XIX) C-terminal domain inhibits the migration and invasion of melanoma cells. It also exerts a strong anti-angiogenic effect by inhibiting MMP-14 and VEGF expression. NC1(XIX) binding to αvβ3 integrin decreases the phosphorylation of proteins involved in the FAK (Focal Adhesion Kinase)/PI3K (PhosphoInositide 3-Kinase)/Akt (protein kinase B)/mTOR (Mammalian Target Of Rapamycin) pathway. On the other hand, NC1(XIX) induces an increase in GSK3β activity by decreasing its level of phosphorylation. The inhibition of this pathway could explain the anti-tumor properties of the NC1(XIX) domain.
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http://dx.doi.org/10.1016/j.matbio.2016.07.010DOI Listing
January 2017

Unexpected Case of Bright Pink-Colored Plasma.

Clin Chem 2016 08;62(8):1162-3

Laboratoire Central de Biochimie, Hôpital Robert Debré, CHU de Reims, Reims, France; Laboratoire de Biochimie Médicale et de Biochimie Moléculaire, UMR CNRS/URCA 7369, Faculté de Médecine de Reims, Reims, France.

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http://dx.doi.org/10.1373/clinchem.2015.252619DOI Listing
August 2016

Aging decreases collagen IV expression in vivo in the dermo-epidermal junction and in vitro in dermal fibroblasts: possible involvement of TGF-β1.

Eur J Dermatol 2016 Aug;26(4):350-60

Laboratoire de Biochimie Médicale et de Biologie Moléculaire, CNRS UMR 7369: Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Médecine, Université de Reims Champagne-Ardenne, 51 rue Cognacq Jay, CS 30018, 51095.

Collagen IV is a major component of the dermo-epidermal junction (DEJ). To study expression of collagen IV upon aging in the DEJ and dermal fibroblasts isolated from the same patients. A model of senescent fibroblasts was developed in order to identify biological compounds that might restore the level of collagen IV. Skin fragments of women (30 to 70 years old) were collected. Localisation of collagen IV expression in the DEJ was studied by immunofluorescence. Fibroblast collagen IV expression was studied by real-time PCR, ELISA, and western blotting. Premature senescence was simulated by exposing fibroblasts to subcytotoxic H2O2 concentrations. Collagen IV decreased in the DEJ and fibroblasts relative to age. TGF-β1 treatment significantly increased collagen IV gene and protein expression in fibroblasts and restored expression in the model of senescence. Addition of TGF-β1-neutralizing antibody to fibroblast cultures decreased collagen IV expression. Taken together, the results suggest that the decrease in collagen IV in the DEJ, relative to age, could be due to a decrease in collagen IV expression by senescent dermal fibroblasts and may involve TGF-β1 signalling.
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http://dx.doi.org/10.1684/ejd.2016.2782DOI Listing
August 2016

Lumican Inhibits SNAIL-Induced Melanoma Cell Migration Specifically by Blocking MMP-14 Activity.

PLoS One 2016 1;11(3):e0150226. Epub 2016 Mar 1.

CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et de Biologie Moléculaire, Reims, France.

Lumican, a small leucine rich proteoglycan, inhibits MMP-14 activity and melanoma cell migration in vitro and in vivo. Snail triggers epithelial-mesenchymal transitions endowing epithelial cells with migratory and invasive properties during tumor progression. The aim of this work was to investigate lumican effects on MMP-14 activity and migration of Snail overexpressing B16F1 (Snail-B16F1) melanoma cells and HT-29 colon adenocarcinoma cells. Lumican inhibits the Snail induced MMP-14 activity in B16F1 but not in HT-29 cells. In Snail-B16F1 cells, lumican inhibits migration, growth, and melanoma primary tumor development. A lumican-based strategy targeting Snail-induced MMP-14 activity might be useful for melanoma treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773148PMC
July 2016

Effects of Dietary Copper-Methionine on Matrix Metalloproteinase-2 in the Lungs of Cold-Stressed Broilers as an Animal Model for Pulmonary Hypertension.

Biol Trace Elem Res 2016 Aug 9;172(2):504-510. Epub 2016 Jan 9.

Unité de Recherche "Matrice Extracellulaire et Dynamique Cellulaire" (MEDyC), UMR CNRS/URCA NO 7369, Faculté de Médecine de Reims, 51095, Reims Cedex, France.

The objective of the present study was to investigate the effects of different levels of copper (as supplemental copper-methionine) on ascites incidence and matrix metalloproteinase-2 (MMP-2) changes in the lungs of cold-stressed broilers. For this purpose, 480 1-day-old Ross 308 broiler chickens were randomly assigned to six treatments. Treatments consisted of two ambient temperatures (thermoneutral and cold stress) each combined with 0, 100, and 200 mg supplemental copper/kg as copper-methionine in a 2 × 3 factorial arrangement in a completely randomized design with four replicates. Ascites was diagnosed based on abdominal and pericardial fluid accumulation at 45 days of age. Fourty-eight broilers were killed at 38 and 45 days of age, and their lungs were collected for biological analysis. Results showed that MMP-2 increased in the lungs of ascitic broilers and that copper-methionine supplementation significantly reduced MMP-2 in cold-stressed broiler chickens. Treatments did not affect tissue inhibitor of metalloproteinase-2 (TIMP-2) at 38 and 45 days of age, and no difference was observed between 100 and 200 mg/kg copper-methionine treatments. In conclusion, copper-methionine at higher than conventional levels of supplementation decreased ascites incidence in low temperature through reduced MMP-2 concentration. Further research is warranted to investigate the effect of copper on MMP-2 concentrations in other tissues with high oxygen demand.
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http://dx.doi.org/10.1007/s12011-015-0612-0DOI Listing
August 2016

The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction.

Oncotarget 2016 Jan;7(2):1516-28

Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France.

Type XIX collagen is a minor collagen associated with basement membranes. It was isolated for the first time in a human cDNA library from rhabdomyosarcoma and belongs to the FACITs family (Fibril Associated Collagens with Interrupted Triple Helices). Previously, we demonstrated that the NC1 domain of collagen XIX (NC1(XIX)) exerts anti-tumor properties on melanoma cells by inhibiting their migration and invasion. In the present work, we identified for the first time the integrin αvβ3 as a receptor of NC1(XIX). Moreover, we demonstrated that NC1(XIX) inhibits the FAK/PI3K/Akt/mTOR pathway, by decreasing the phosphorylation and activity of the major proteins involved in this pathway. On the other hand, NC1(XIX) induced an increase of GSK3β activity by decreasing its degree of phosphorylation. Treatments targeting this central signaling pathway in the development of melanoma are promising and new molecules should be developed. NC1(XIX) seems to have the potential for the design of new anti-cancer drugs.
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http://dx.doi.org/10.18632/oncotarget.6399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811477PMC
January 2016

[An acute monoclonal gammopathy?].

Ann Biol Clin (Paris) 2015 Mar-Apr;73(2):185-9

Laboratoire central de biochimie, Hôpital Robert Debré, CHU de Reims, Reims, France, Laboratoire de biochimie médicale et de biologie moléculaire, UMR CNRS 7369, Faculté de médecine de Reims, Reims, France.

Serum protein electrophoresis is commonly used in case of acute or chronic renal failure. It can lead to the etiologic diagnosis by detecting monoclonal gammopathies which are frequently complicated by renal failure, such as cast nephropathy, Randall's disease or amyloidosis, or to explore an associated inflammatory syndrome. We report the occurrence of two monoclonal components in a patient without any monoclonal component 10 days earlier. The sudden appearance of these two monoclonal components associated to the context of sepsis of urinary origin suggested the diagnosis of transient monoclonal gammopathy. This hypothesis was confirmed by monitoring serum protein electrophoresis that showed a gradual decrease of these two monoclonal components few weeks after the resolution of the infectious disease. The main etiological factors of transient monoclonal gammopathies are infectious or autoimmune diseases. In this context, it is important to delay the achievement of serum protein electrophoresis after the acute episode, in order to avoid to falsely conclude to hematologic malignancy diagnosis. This can prevent costly biological examinations of these transient monoclonal gammopathies and invasive procedures like bone marrow examination.
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http://dx.doi.org/10.1684/abc.2015.1034DOI Listing
April 2016

Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX.

Oncotarget 2015 Feb;6(6):3656-68

Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France.

During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I β-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414144PMC
http://dx.doi.org/10.18632/oncotarget.2849DOI Listing
February 2015

Endostatin level in cerebrospinal fluid of patients with Alzheimer's disease.

J Alzheimers Dis 2015 ;44(4):1253-61

Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086 CNRS, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.

The aim of this study was to measure the level of endostatin, a fragment of collagen XVIII that accumulates in the brain of patients with Alzheimer's disease (AD), in the cerebrospinal fluids (CSF) of patients with neurodegenerative diseases. The concentrations of total protein, endostatin, amyloid-β1-42 peptide, tau, and hyperphosphorylated tau proteins were measured by enzyme-linked immunosorbent assay in CSF of patients with AD (n = 57), behavioral frontotemporal dementia (bvFTD, n = 22), non AD and non FTD dementia (nAD/nFTD, n = 84), and 45 subjects without neurodegenerative diseases. The statistical significance of the results was assessed by Mann-Whitney and Kruskal and Wallis tests, and by ROC analysis. The concentration of endostatin in CSF was higher than the levels of the three markers of AD both in control subjects and in patients with neurodegenerative diseases. The endostatin/amyloid-β1-42 ratio was significantly increased in patients with AD (257%, p < 0.0001) and nAD/nFTD (140%, p < 0.0001) compared to controls. The endostatin/tau protein ratio was significantly decreased in patients with AD (-49%, p < 0.0001) but was increased in bvFTD patients (89%, p < 0.0001) compared to controls. In the same way, the endostatin/hyperphosphorylated tau protein ratio was decreased in patients with AD (-21%, p = 0.0002) but increased in patients with bvFTD (81%, p = 0.0026), compared to controls. The measurement of endostatin in CSF and the calculation of its ratio relative to well-established AD markers improve the diagnosis of bvFTD patients and the discrimination of patients with AD from those with bvFTD and nAD/nFTD.
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http://dx.doi.org/10.3233/JAD-142544DOI Listing
November 2015

Lumican: a new inhibitor of matrix metalloproteinase-14 activity.

FEBS Lett 2014 Nov 7;588(23):4319-24. Epub 2014 Oct 7.

CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France; Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et de Biologie Moléculaire, Reims, France. Electronic address:

We previously showed that lumican regulates MMP-14 expression. The aim of this study was to compare the effect of lumican and decorin on MMP-14 activity. In contrast to decorin, the glycosylated form of lumican was able to significantly decrease MMP-14 activity in B16F1 melanoma cells. Our results suggest that a direct interaction occurs between lumican and MMP-14. Lumican behaves as a competitive inhibitor which leads to a complete blocking of the activity of MMP-14. It binds to the catalytic domain of MMP-14 with moderate affinity (KD∼275 nM). Lumican may protect collagen against MMP-14 proteolysis, thus influencing cell-matrix interaction in tumor progression.
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http://dx.doi.org/10.1016/j.febslet.2014.09.040DOI Listing
November 2014

Glycosaminoglycan profiling in different cell types using infrared spectroscopy and imaging.

Anal Bioanal Chem 2014 Sep 15;406(24):5795-803. Epub 2014 Jul 15.

Laboratoire de Biochimie médicale et de Biologie Moléculaire, UFR de Médecine, Université de Reims Champagne-Ardenne, 51 rue Cognacq-Jay, 51095, Reims Cedex, France.

We recently identified vibrational spectroscopic markers characteristic of standard glycosaminoglycan (GAG) molecules. The aims of the present work were to further this investigation to more complex biological systems and to characterize, via their spectral profiles, cell types with different capacities for GAG synthesis. After recording spectral information from individual GAG standards (hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate) and GAG-GAG mixtures, GAG-defective mutant Chinese hamster ovary (CHO)-745 cells, wild-type CHO cells, and chondrocytes were analyzed as suspensions by high-throughput infrared spectroscopy and as single isolated cells by infrared imaging. Spectral data were processed and interpreted by exploratory unsupervised chemometric methods based on hierarchical cluster analysis and principal component analysis. Our results showed that the spectral information obtained was discriminant enough to clearly delineate between the different cell types both at the cell suspension and single-cell levels. The abilities of the technique are to perform spectral profiling and to identify single cells with different potentials to synthesize GAGs. Infrared microspectroscopy/imaging could therefore be developed for cell screening purposes and further for identifying GAG molecules in normal tissues during physiological conditions (aging, healing process) and numerous pathological states (arthritis, cancer).
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http://dx.doi.org/10.1007/s00216-014-7994-2DOI Listing
September 2014

[Urinary investigations in the diagnosis and monitoring of monoclonal gammopathies in daily practice].

Ann Biol Clin (Paris) 2014 Mar-Apr;72(2):147-52

Laboratoire central de biochimie, Hôpital Robert Debré, CHU de Reims, Reims, France, Laboratoire de biochimie médicale et de biologie moléculaire, UMR 7369 CNRS, Faculté de médecine de Reims, Reims, France.

The management of monoclonal gammopathies remains a public health issue with an incidence greater than 3% of the population over 50 years. Laboratory investigations, including urinary investigations play a key role in the diagnosis and monitoring of the patients. Urinary investigations are not recommended when screening monoclonal gammopathies. However, the initial laboratory evaluation of the monoclonal gammopathies systematically relies on renal function and proteinuria assessment. Urinary proteins electrophoresis combined with urinary proteins immunofixation are also recommended in the initial evaluation, with the exception of the Waldenström's disease. In some cases, serum investigations remain negative whereas urinary investigations confirm the presence of a monoclonal component. National and international recommendations have also been published about the monitoring of monoclonal gammopathies. The biological monitoring of monoclonal gammopathy of undetermined significance is mostly done by serum tests. Urinary investigations are commonly included in the response criteria in case of multiple myeloma or AL amyloidosis. Laboratory investigations like serum free light chain assay tend to decrease the need of urinary investigations in the monoclonal gammopathies. However, these urinary investigations currently maintain a leading role in the diagnosis and monitoring of monoclonal gammopathies.
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http://dx.doi.org/10.1684/abc.2014.0937DOI Listing
January 2015

Matrikines from basement membrane collagens: a new anti-cancer strategy.

Biochim Biophys Acta 2014 Aug 6;1840(8):2589-98. Epub 2014 Jan 6.

FRE CNRS/URCA 7369, Université de Reims Champagne Ardenne, UFR Médecine, 51 Rue Cognacq Jay, 51095 Reims Cedex, France; Laboratoire Central de Biochimie, CHU de Reims, France. Electronic address:

Background: Tumor microenvironment is a complex system composed of a largely altered extracellular matrix with different cell types that determine angiogenic responses and tumor progression. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. In addition to stromal ECM breakdown, proteases exert various pro- or anti-tumorigenic functions and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to act as endogenous angiogenesis inhibitors and to limit tumor progression.

Scope Of Review: We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV.

Major Conclusions: The putative targets of the matrikine control are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. Collagen-derived matrikines such as canstatin, tumstatin or tetrastatin for example, decrease tumor growth in various cancer models. Their anti-cancer activities comprise anti-proliferative effects on tumor or endothelial cells by induction of apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. They were used in various preclinical therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences, iii) used in combined therapies with conventional chemotherapy or radiotherapy.

General Significance: Collagen-derived matrikines strongly inhibited tumor growth in many preclinical cancer models in mouse. They constitute a new family of anti-cancer agents able to limit cancer progression. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
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http://dx.doi.org/10.1016/j.bbagen.2013.12.029DOI Listing
August 2014

Lumican - derived peptides inhibit melanoma cell growth and migration.

PLoS One 2013 2;8(10):e76232. Epub 2013 Oct 2.

Laboratoire de Biochimie Médicale et de Biologie Moléculaire, CNRS FRE 3481, Université de Reims-Champagne-Ardenne, Reims, France.

Lumican, a small leucine-rich proteoglycan of the extracellular matrix, presents potent anti-tumor properties. Previous works from our group showed that lumican inhibited melanoma cell migration and tumor growth in vitro and in vivo. Melanoma cells adhered to lumican, resulting in a remodeling of their actin cytoskeleton and preventing their migration. In addition, we identified a sequence of 17 amino acids within the lumican core protein, named lumcorin, which was able to inhibit cell chemotaxis and reproduce anti-migratory effect of lumican in vitro. The aim of the present study was to characterize the anti-tumor mechanism of action of lumcorin. Lumcorin significantly decreased the growth in monolayer and in soft agar of two melanoma cell lines - mice B16F1 and human SK-MEL-28 cells - in comparison to controls. Addition of lumcorin to serum free medium significantly inhibited spontaneous motility of these two melanoma cell lines. To characterize the mechanisms involved in the inhibition of cell migration by lumcorin, the status of the phosphorylation/dephosphorylation of proteins was examined. Inhibition of focal adhesion kinase phosphorylation was observed in presence of lumcorin. Since cancer cells have been shown to migrate and to invade by mechanisms that involve matrix metalloproteinases (MMPs), the expression and activity of MMPs were analyzed. Lumcorin induced an accumulation of an intermediate form of MMP-14 (~59kDa), and inhibited MMP-14 activity. Additionally, we identified a short, 10 amino acids peptide within lumcorin sequence, which was able to reproduce its anti-tumor effect on melanoma cells. This peptide may have potential pharmacological applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076232PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788744PMC
July 2014

A new anti-tumor strategy based on in vivo tumstatin overexpression after plasmid electrotransfer in muscle.

Biochem Biophys Res Commun 2013 Mar 27;432(4):549-52. Epub 2013 Feb 27.

FRE CNRS/URCA 3481, University of Reims Champagne-Ardenne, 51 rue Cognacq Jay, F-51095 Reims, France.

The NC1 domains from the different α(IV) collagen chains were found to exert anti-tumorigenic and/or anti-angiogenic activities. A limitation to the therapeutic use of these matrikines is the large amount of purified recombinant proteins, in the milligram range in mice that should be administered daily throughout the experimental procedures. In the current study, we developed a new therapeutic approach based on tumstatin (NC1α3(IV)) overexpression in vivo in a mouse melanoma model. Gene electrotransfer of naked plasmid DNA (pDNA) is particularly attractive because of its simplicity, its lack of immune responsiveness and its safety. The pDNA electrotransfer in muscle mediates a substantial gene expression that lasts several months. A pVAX1© vector containing the tumstatin cDNA was injected into the legs of C57BL/6 mice and submitted to electrotranfer. Sera were collected at different times and tumstatin was quantified by ELISA. Tumstatin secretion reached a plateau at day 21 with an expression level of 12 μg/mL. For testing the effects of tumstatin expression on tumor growth in vivo, B16F1 melanoma cells were subcutaneously injected in mice 7 days after empty pVAX1© (Mock) or pVAX1©-tumstatin electrotransfer. Tumstatin expression triggered a large decrease in tumor growth and an increase in mouse survival. This new therapeutic approach seems promising to inhibit tumor progression in vivo.
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http://dx.doi.org/10.1016/j.bbrc.2013.02.074DOI Listing
March 2013