Publications by authors named "Didier Wion"

55 Publications

3D two-photon polymerization of smart cell gelatin - collagen matrixes with incorporated ruthenium complexes for the monitoring of local oxygen tensions.

Acta Biomater 2021 08 12;130:172-182. Epub 2021 Jun 12.

MoVe, Laboratoire interdisciplinaire de physique, CNRS UMR 5588, Université Grenoble Alpes, St-Martin d'Hères, France. Electronic address:

The extra cellular matrix plays a major role in the biomechanical properties of tissues that impact cell behavior and fate. It is therefore crucial to mimic these complex cell-matrix interactions in 3D cell cultures. Here, two-photon polymerization is applied to produce gelatin methacryloyl (GelMA) - collagen matrixes that further enable local pO measurement, when ruthenium complexes are used as photo-activators. The fluorescence intensity of these complexes has a direct and inverse relationship with the local pO. The 3D structures reached their maximum size in cell culture conditions after 3H with a swelling factor of ~1.5. Their shape and the ruthenium fluorescence intensity of the alveoli walls stayed constant for at least 2 weeks in the absence of cells. They were used in time series to monitor the local pO adjacent to cancer cells during their division, migration and the formation of a tumor tissue mass. At the presence of these cell activities that consume O, a significant ~3-fold increase of the ruthenium fluorescence intensity in the alveoli walls was observed. This study demonstrates that online monitoring of the local pO is possible. The ruthenium complexes provide the bio-optical sensors that are useful for further analysis of cancer and healthy cell energy metabolism in a 3D matrix that better mimics in vivo conditions and migration paths. Unraveling the cancer cell metabolic adaptations in a changing micro-environment will help the development of new therapeutic opportunities. STATEMENT OF SIGNIFICANCE: In 3D cell cultures, monitoring pericellular pO is as critical as controlling pH. This facility is currently missing. Here, we take advantage of the direct and inverse relationship between pO and the fluorescence intensity of ruthenium complexes to generate stable gelatin-collagen matrixes able to continuously monitoring the pO at the pericellular level. The ruthenium complexes, which are photo-activators in the two-photon polymerization of these matrixes, became covalently bind to the collagen fibers. Indeed, local O consumption by cancer cells during migration, mitosis and tumor mass formation caused a 3-fold increase of the ruthenium fluorescence. In the future, incorporating ruthenium complexes with other bio-optical sensors will create new drug screening platforms that monitor cell culture parameters at the pericellular level.
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http://dx.doi.org/10.1016/j.actbio.2021.06.021DOI Listing
August 2021

Randomized clinical trials of oral vitamin D supplementation in need of a paradigm change: The vitamin D autacoid paradigm.

Med Hypotheses 2020 Jan 1;134:109417. Epub 2019 Oct 1.

INSERM UMR1205, Université Grenoble Alpes, Faculté de Médecine Pharmacie, 38700 La Tronche, France. Electronic address:

Epidemiological studies highlight the negative correlation between vitamin D levels and the incidence of many non-skeletal diseases including inflammatory diseases, cancer, and metabolic and neurological disorders. However, most randomized controlled trials (RCTs) with oral vitamin D supplementation give mixed results or are inconclusive. It has been said that "discovery commences with the awareness of anomaly". The "anomaly" between our preclinical and clinical data provides the opportunity to propose an alternative paradigm to the vitamin D endocrine system: the vitamin D autacoid paradigm. In the vitamin D autacoid paradigm, the extra-skeletal effects of vitamin D depend on the tissue reserves of vitamin D metabolites. These vitamin D autacoid systems are inducible oscillatory ecosystems in which 1,25D is produced, acts and is inactivated locally. In the vitamin D autacoid paradigm, attaining adequacy of vitamin D in the systemic circulation is necessary but not sufficient; we must also ensure the repletion of the tissue stores. The co-existence of two different vitamin D systems, endocrine and autacoid, with different functions and regulations leads to "significant shifts in the criteria determining the legitimacy both of problems and of proposed solutions". With respect to our clinical trials of vitamin D supplementation for unconventional effects, the proposed solution is administering and quantifying vitamin D metabolites directly to the target tissue.
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http://dx.doi.org/10.1016/j.mehy.2019.109417DOI Listing
January 2020

Early Prophylactic Hypothermia for Patients With Severe Traumatic Injury: Premature to Close the Case.

Front Neurol 2019 9;10:344. Epub 2019 Apr 9.

INSERM UMR1205, Faculté Médecine Pharmacie, Université Grenoble Alpes, La Tronche, France.

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http://dx.doi.org/10.3389/fneur.2019.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465559PMC
April 2019

Letter to the Editor: "Decreased Serum 25-Hydroxyvitamin D in Aging Male Mice Is Associated With Reduced Hepatic Cyp2r1 Abundance".

Authors:
Didier Wion

Endocrinology 2018 10;159(10):3563-3564

INSERM UMR1205, Faculté Médecine Pharmacie, Université Grenoble Alpes, La Tronche, France.

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http://dx.doi.org/10.1210/en.2018-00692DOI Listing
October 2018

The Temporal Relationship Between Alzheimer's Disease and Depressive Symptoms: Variable Matters.

Authors:
Didier Wion

Am J Psychiatry 2018 08;175(8):793

From INSERM UMR1205, Brain Tech Lab, Université Grenoble Alpes, La Tronche, France.

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http://dx.doi.org/10.1176/appi.ajp.2018.18020164DOI Listing
August 2018

Inflammation and Inflammatory Diseases: How Our Language Influences Our Therapeutic Paradigms.

Bioessays 2018 09 10;40(9):e1800103. Epub 2018 Jul 10.

INSERM UMR1205, BrainTech Lab, Université Grenoble Alpes, La Tronche, 38706, France.

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http://dx.doi.org/10.1002/bies.201800103DOI Listing
September 2018

Biomarkers of aging associated with past treatments in breast cancer survivors: when therapy-induced pathways turn out to be potential therapeutic targets.

NPJ Breast Cancer 2018 6;4. Epub 2018 Mar 6.

2INSERM U1205, BrainTech Lab, Université Grenoble Alpes, Domaine de la Merci, 38700 La Tronche, France.

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http://dx.doi.org/10.1038/s41523-018-0058-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840380PMC
March 2018

Locoregional Confinement and Major Clinical Benefit of Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma.

Theranostics 2017 12;7(18):4517-4536. Epub 2017 Oct 12.

CRCINA, INSERM, Université de Nantes, Université d'Angers, 49933 Angers, France.

Purpose: Gold standard beam radiation for glioblastoma (GBM) treatment is challenged by resistance phenomena occurring in cellular populations well prepared to survive or to repair damage caused by radiation. Among signals that have been linked with radio-resistance, the SDF1/CXCR4 axis, associated with cancer stem-like cell, may be an opportune target. To avoid the problem of systemic toxicity and blood-brain barrier crossing, the relevance and efficacy of an original system of local brain internal radiation therapy combining a radiopharmaceutical with an immuno-nanoparticle was investigated.

Experiment Design: The nanocarrier combined lipophilic thiobenzoate complexes of rhenium-188 loaded in the core of a lipid nanocapsule (LNCRe) with a function-blocking antibody, 12G5 directed at the CXCR4, on its surface. The efficiency of 12G5-LNCRe was investigated in an orthotopic and xenogenic GBM model of CXCR4-positive U87MG cells implanted in the striatum of Scid mice.

Results: We demonstrated that 12G5-LNCRe single infusion treatment by convection-enhanced delivery resulted in a major clinical improvement in median survival that was accompanied by locoregional effects on tumor development including hypovascularization and stimulation of the recruitment of bone marrow derived CD11b- or CD68-positive cells as confirmed by immunohistochemistry analysis. Interestingly, thorough analysis by spectral imaging in a chimeric U87MG GBM model containing CXCR4-positive/red fluorescent protein (RFP)-positive- and CXCR4-negative/RFP-negative-GBM cells revealed greater confinement of DiD-labeled 12G5-LNCs than control IgG2a-LNCs in RFP compartments. Main conclusion: These findings on locoregional impact and targeting of disseminated cancer cells in tumor margins suggest that intracerebral active targeting of nanocarriers loaded with radiopharmaceuticals may have considerable benefits in clinical applications.
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http://dx.doi.org/10.7150/thno.19403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695146PMC
March 2018

Therapeutic dormancy to delay postsurgical glioma recurrence: the past, present and promise of focal hypothermia.

Authors:
Didier Wion

J Neurooncol 2017 Jul 17;133(3):447-454. Epub 2017 May 17.

BrainTech Lab, INSERM U1205, CEA, Grenoble, France.

Surgery precedes both radiotherapy and chemotherapy as the first-line therapy for glioma. However, despite multimodal treatment, most glioma patients die from local recurrence in the resection margin. Glioma surgery is inherently lesional, and the response of brain tissue to surgery includes hemostasis, angiogenesis, reactive gliosis and inflammation. Unfortunately, these processes are also associated with tumorigenic side-effects. An increasing amount of evidence indicates that the response to a surgery-related brain injury is hijacked by residual glioma cells and participates in the local regeneration of tumor tissues at the resection margin. Inducing therapeutic hypothermia in the brain has long been used to treat the secondary damage, such as neuroinflammation and edema, that are caused by accidental traumatic brain injuries. There is compelling evidence to suggest that inducing therapeutic hypothermia at the resection margin would delay the local recurrence of glioma by (i) limiting cell proliferation, (ii) disrupting the pathological connection between inflammation and glioma recurrence, and (iii) limiting the consequences of the functional heterogeneity and complexity inherent to the tumor ecosystem. While the global whole-body cooling methods that are currently used to treat stroke in clinical practice may not adequately treat the resection margin, the future lies in implantable focal microcooling devices similar to those under development for the treatment of epilepsy. Preclinical and clinical strategies to evaluate focal hypothermia must be implemented to prevent glioma recurrence in the resection margin. Placing the resection margin in a state of hibernation may potentially provide such a long-awaited therapeutic breakthrough.
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http://dx.doi.org/10.1007/s11060-017-2471-3DOI Listing
July 2017

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin.

Tumour Biol 2017 May;39(5):1010428317699797

6 Department of Neurosurgery, University of Ulm, Ulm, Germany.

Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration- and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.
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http://dx.doi.org/10.1177/1010428317699797DOI Listing
May 2017

Glioma resection and tumor recurrence: back to Semmelweis.

Neuro Oncol 2016 12 7;18(12):1688-1689. Epub 2016 Oct 7.

Clinatec, Centre de recherche biomédicale Edmond J. Safra, CEA-LETI 17 rue des Martyrs, 38054 Grenoble cedex, France (D.R.); INSERM U1205, bâtiment modulaire 40-23, CEA 17 rue des Martyrs, 38054 Grenoble cedex, France (B.v.d.S., D.W.).

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http://dx.doi.org/10.1093/neuonc/now201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744249PMC
December 2016

Extent of Resection and Survival in Glioblastoma Multiforme.

JAMA Oncol 2016 11;2(11):1509

INSERM U1205, BrainTech Lab, CEA Grenoble, France.

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http://dx.doi.org/10.1001/jamaoncol.2016.3809DOI Listing
November 2016

Design of Hyaluronic Acid Hydrogels to Promote Neurite Outgrowth in Three Dimensions.

ACS Appl Mater Interfaces 2016 Sep 16;8(38):25051-9. Epub 2016 Sep 16.

Grenoble Alpes University , Centre de Recherches sur les Macromolécules Végétales (CERMAV-CNRS), 601, rue de la Chimie, BP 53, Grenoble 38041 Cedex 9, France.

A hyaluronic acid (HA)-based extracellular matrix (ECM) platform with independently tunable stiffness and density of cell-adhesive peptide (RGD, arginine-glycine-aspartic acid) that mimics key biochemical and mechanical features of brain matrix has been designed. We demonstrated here its utility in elucidating ECM regulation of neural progenitor cell behavior and neurite outgrowth. The analysis of neurite outgrowth in 3-D by two-photon microscopy showed several important results in the development of these hydrogels. First, the ability of neurites to extend deeply into these soft HA-based matrices even in the absence of cell-adhesive ligand further confirms the potential of HA hydrogels for central nervous system (CNS) regeneration. Second, the behavior of hippocampal neural progenitor cells differed markedly between the hydrogels with a storage modulus of 400 Pa and those with a modulus of 800 Pa. We observed an increased outgrowth and density of neurites in the softest hydrogels (G' = 400 Pa). Interestingly, cells seeded on the surface of the hydrogels functionalized with the RGD ligand experienced an optimum in neurite outgrowth as a function of ligand density. Surprinsingly, neurites preferentially progressed inside the gels in a vertical direction, suggesting that outgrowth is directed by the hydrogel structure. This work may provide design principles for the development of hydrogels to facilitate neuronal regeneration in the adult brain.
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http://dx.doi.org/10.1021/acsami.6b06446DOI Listing
September 2016

Glioma Recurrence following Surgery: Peritumoral or Perilesional?

Front Neurol 2016 31;7:52. Epub 2016 Mar 31.

INSERM UA01, Clinatec, Institut E.J. Safra, CEA , Grenoble , France.

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http://dx.doi.org/10.3389/fneur.2016.00052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814895PMC
April 2016

The brain tissue response to surgical injury and its possible contribution to glioma recurrence.

J Neurooncol 2016 05 9;128(1):1-8. Epub 2016 Mar 9.

INSERM UA 01, Clinatec, Centre de recherche biomédicale Edmond J. Safra, CEA 17 rue des Martyrs, 38054, Grenoble cedex, France.

Surgery is the first line therapy for glioma. However, glioma recurs in 90 % of the patients in the resection margin. The impact of surgical brain injury (SBI) on glioma recurrence is largely overlooked. Herein, we review some of the mechanisms involved in tissue repair that may impact glioma recurrence at the resection margin. Many processes or molecules involved in tissue repair after brain injury are also critical for glioma growth. They include a wide array of secreted growth factors, cytokines and transcription factors including NFКB and STAT3 which in turn activate proliferative and anti-apoptotic genes and processes such as angiogenesis and inflammation. Because some residual glioma cells always remain in the tumor resection margin, there are now compelling arguments to suggest that some aspects of the brain tissue response to SBI can also participate to glioma recurrence at the resection margin. Brain tissue response to SBI recruits angiogenesis and inflammation that precede and then follow tumor recurrence at the resection margin. The healing response to SBI is double edged, as inflammation is involved in regeneration and healing, and has both pro- and anti-tumorigenic functions. A promising therapeutic approach is to normalize and re-educate the molecular and cellular responses at the resection margin to promote anti-tumorigenic processes involved in healing while inhibiting pro-tumorigenic activities. Manipulation of the inflammatory response to SBI to prevent local recurrence could also enhance the efficacy of other therapies such as immunotherapy. However, our current knowledge is far from sufficient to achieve this goal. Acknowledging, understanding and manipulating the double-edged role played by SBI in glioma recurrence is surely challenging, but it cannot be longer delayed.
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http://dx.doi.org/10.1007/s11060-016-2096-yDOI Listing
May 2016

RE: Circulating Adipokines and Inflammatory Markers and Postmenopausal Breast Cancer Risk.

J Natl Cancer Inst 2016 Jan 7;108(1). Epub 2015 Nov 7.

Clinique Universitaire d'Endocrinologie-Diabétologie-Maladies de la Nutrition, Centre Hospitalier Universitaire, Grenoble, France (NWB); INSERM UA01, Clinatec, Centre de Recherche Biomédicale Edmond J Safra, CEA, Grenoble, France (DW).

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http://dx.doi.org/10.1093/jnci/djv320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517620PMC
January 2016

Cancer research in need of a scientific revolution: Using 'paradigm shift' as a method of investigation.

J Biosci 2015 Sep;40(3):657-66

INSERM UA 01, Clinatec, Centre de Recherche Biomedicale Edmond J. Safra, CHU Michallon, Universite Joseph Fourier, CEA 17 rue des Martyrs, 38054, Grenoble Cedex, France,

Despite important human and financial resources and considerable accumulation of scientific publications, patents, and clinical trials, cancer research has been slow in achieving a therapeutic revolution similar to the one that occurred in the last century for infectious diseases. It has been proposed that science proceeds not only by accumulating data but also through paradigm shifts. Here, we propose to use the concept of 'paradigm shift' as a method of investigation when dominant paradigms fail to achieve their promises. The first step in using the 'paradigm shift' method in cancer research requires identifying its founding paradigms. In this review, two of these founding paradigms will be discussed: (i) the reification of cancer as a tumour mass and (ii) the translation of the concepts issued from infectious disease in cancer research. We show how these founding paradigms can generate biases that lead to over-diagnosis and over-treatment and also hamper the development of curative cancer therapies. We apply the 'paradigm shift' method to produce perspective reversals consistent with current experimental evidence. The 'paradigm shift' method enlightens the existence of a tumour physiologic-prophylactic-pathologic continuum. It integrates the target/antitarget concept and that cancer is also an extracellular disease. The 'paradigm shift' method has immediate implications for cancer prevention and therapy. It could be a general method of investigation for other diseases awaiting therapy.
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http://dx.doi.org/10.1007/s12038-015-9543-3DOI Listing
September 2015

Investigating the relationship between vitamin D and cancer requires dosing the bioavailable nonhydroxylated vitamin D storage in cancer tissues.

Cancer 2015 Sep 19;121(18):3362-3. Epub 2015 May 19.

INSERM UA01, Clinatec, Edmond J. Safra Biomedical Research Center CEA, Grenoble, France.

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http://dx.doi.org/10.1002/cncr.29451DOI Listing
September 2015

Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model.

Neuroreport 2015 Mar;26(5):245-8

INSERM UA 01, Clinatec, Edmond J. Safra Biomedical Research Center, CEA, Grenoble CHU, Grenoble Alpes University, Grenoble, France.

1,25 Dihydroxyvitamin D3 (1,25D) is a hormone produced from vitamin D through two hydroxylating steps catalyzed successively in the liver by the vitamin D 25-hydroxylase Cyp2R1 and in the kidney by the 25-hydroxyvitamin D3 1α-hydroxylase Cyp27B1. 1,25D behaves like a steroid hormone. It regulates gene transcription by interacting with a nuclear receptor named vitamin D receptor (VDR) for the vitamin D receptor. Although the role of vitamin D is historically related to rickets, its physiological function largely encompasses bone tissues. Accumulating evidence has indicated that 1,25D can also be considered a neurosteroid. For example, both VDR and CYP27B1 are expressed in brain cells. Similarly, the neuroprotective and anti-inflammatory potential of 1,25D in nervous tissue has been shown experimentally. The regulation of Cyp27B1, which catalyzes the last step of 1,25D synthesis, by the inflammatory cytokines tumor necrosis factor-α and interferon-γ has been reported recently. However, the fate of Cyp2R1 that catalyzes the first enzymatic reaction of the vitamin D metabolism has not received attention. Using human brain pericytes, we studied the expression of CYP2R1 and VDR genes when these cells were challenged to an inflammatory stimulus. We found a significant upregulation of these two genes in human brain pericytes challenged with tumor necrosis factor-α and interferon-γ. These results suggest the existence of an autocrine/paracrine vitamin D system in the neurovascular unit. The function of this novel signaling system might be critical in the control of neuroinflammation and in brain pathologies.
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http://dx.doi.org/10.1097/WNR.0000000000000328DOI Listing
March 2015

Additional clues for a protective role of vitamin D in neurodegenerative diseases: 1,25-dihydroxyvitamin D3 triggers an anti-inflammatory response in brain pericytes.

J Alzheimers Dis 2014 ;42(3):789-99

INSERM U1167, CLINATEC, Centre de Recherche Edmond J Safra, MINATEC Campus CEA, Grenoble, France INSERM U836, Grenoble Institut des Neurosciences, Team Nanomedicine and Brain, Grenoble, France.

Epidemiological and experimental studies suggest that 1,25-dihydroxyvitamin D3 (1,25D) plays a neuroprotective role in neurodegenerative diseases including Alzheimer's disease. Most of the experimental data regarding the genes regulated by this hormone in brain cells have been obtained with neuron and glial cells. Pericytes play a critical role in brain function that encompasses their classical function in blood-brain barrier control and maintenance. However, the gene response of brain pericyte to 1,25D remains to be investigated. Analyses of the transcriptomic response of human brain pericytes to 1,25D demonstrate that human brain pericytes in culture respond to 1,25D by regulating genes involved in the control of neuroinflammation. In addition, pericytes respond to the pro-inflammatory cytokines tumor necrosis factor-α and Interferon-γ by inducing the expression of the CYP27B1 gene which is involved in 1,25D synthesis. Taken together, these results suggest that neuroinflammation could trigger the synthesis of 1,25D by brain pericytes, which in turn respond to the hormone by a global anti-inflammatory response. These findings identify brain pericytes as a novel 1,25D-responsive cell type and provide additional evidence for the potential value of vitamin D in the prevention or therapy of Alzheimer's disease and other neurodegenerative/neuropsychiatric diseases associated with an inflammatory component.
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http://dx.doi.org/10.3233/JAD-140411DOI Listing
August 2015

Generation of brain cancer stem cells: the dark side of brain pericytes?

Neurosci Res 2014 Aug 27;85:69. Epub 2014 May 27.

INSERM U1167, CLINATEC, Centre de recherche Edmond J Safra, MINATEC Campus CEA, Université Joseph Fourier, 38054 Grenoble, France. Electronic address:

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http://dx.doi.org/10.1016/j.neures.2014.05.004DOI Listing
August 2014

Brain mesenchymal stem cells: The other stem cells of the brain?

World J Stem Cells 2014 Apr;6(2):134-43

Florence Appaix, Marie-France Nissou, Jean-Paul Issartel, Didier Wion, INSERM U836, Grenoble Institut des Neurosciences, Bâtiment Edmond J Safra, Université Joseph Fourier, CHU Michallon, 38042 Grenoble, France.

Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.
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http://dx.doi.org/10.4252/wjsc.v6.i2.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999771PMC
April 2014

Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal.

J Neurosci Methods 2014 Jan 11;221:159-65. Epub 2013 Oct 11.

Clinique de neurochirurgie, CHU Grenoble, B.P. 217, 38043 Grenoble Cedex 09, France; Equipe 7 nanomedecine et cerveau, Inserm U836, Grenoble institut des Neurosciences, Chemin Fortuné Ferrini, Université Joseph Fourier - Site Santé, Bâtiment: Edmond J. Safra, 38706 La Tronche Cedex, France. Electronic address:

The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood-brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use.
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http://dx.doi.org/10.1016/j.jneumeth.2013.10.002DOI Listing
January 2014

Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice.

J Synchrotron Radiat 2013 Sep 3;20(Pt 5):777-84. Epub 2013 Jul 3.

INSERM U836, Grenoble Institut des Neurosciences, Grenoble, France.

Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.
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http://dx.doi.org/10.1107/S0909049513016567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943558PMC
September 2013

Translation of the ecological trap concept to glioma therapy: the cancer cell trap concept.

Future Oncol 2013 Jun;9(6):817-24

INSERM U836, Grenoble Institut des Neurosciences, Université Joseph Fourier, CHU Michallon, Grenoble, France.

Viewing tumors as ecosystems offers the opportunity to consider how ecological concepts can be translated to novel therapeutic perspectives. The ecological trap concept emerged approximately half a century ago when it was observed that animals can prefer an environment of low quality for survival over other available environments of higher quality. The presence of such a trap can drive a local population to extinction. The cancer cell trap concept is the translation of the ecological trap into glioma therapy. It exploits and diverts the invasive potential of glioma cells by guiding their migration towards specific locations where a local therapy can be delivered efficiently. This illustrates how an ecological concept can change therapeutic obstacles into therapeutic tools.
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http://dx.doi.org/10.2217/fon.13.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788699PMC
June 2013

Hypoxia-induced expression of VE-cadherin and filamin B in glioma cell cultures and pseudopalisade structures.

J Neurooncol 2013 Jun 31;113(2):239-49. Epub 2013 Mar 31.

INSERM U836, Grenoble Institut des Neurosciences, Université Joseph Fourier, CHU Grenoble, Bâtiment E.J. Safra, 38042, Grenoble, France.

Most of our knowledge regarding glioma cell biology comes from cell culture experiments. For many years the standards for glioma cell culture were the use of cell lines cultured in the presence of serum and 20 % O2. However, in vivo, normoxia in many brain areas is in close to 3 % O2. Hence, in cell culture, the experimental value referred as the norm is hyperoxic compared to any brain physiological value. Likewise, cells in vivo are not usually exposed to serum, and low-passaged glioma neurosphere cultures maintained in serum-free medium is emerging as a new standard. A consequence of changing the experimental normoxic standard from 20 % O2 to the more brain physiological value of 3 % O2, is that a 3 % O2 normoxic reference point enabled a more rigorous characterization of the level of regulation of genes by hypoxia. Among the glioma hypoxia-regulated genes characterized using this approach we found VE-cadherin that is required for blood vessel formation, and filamin B a gene involved in endothelial cell motility. Both VE-cadherin and filamin B were found expressed in pseudopalisades, a glioblastoma pathognomonic structure made of hypoxic migrating cancer cells. These results provide additional clues on the role played by hypoxia in the acquisition of endothelial traits by glioma cells and on the functional links existing between pseudopalisades, hypoxia, and tumor progression.
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http://dx.doi.org/10.1007/s11060-013-1124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850216PMC
June 2013

The transcriptomic response of mixed neuron-glial cell cultures to 1,25-dihydroxyvitamin d3 includes genes limiting the progression of neurodegenerative diseases.

J Alzheimers Dis 2013 ;35(3):553-64

INSERM U836, Bâtiment Edmond J. Safra, Université Joseph Fourier, CHU Michallon, Grenoble, France.

Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer's disease. These data provide support for a role of 1,25-dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered.
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http://dx.doi.org/10.3233/JAD-122005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962683PMC
October 2013

Angiogenesis and the tumor space-time continuum.

Proc Natl Acad Sci U S A 2012 Apr 26;109(16):E914; author reply E915. Epub 2012 Mar 26.

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http://dx.doi.org/10.1073/pnas.1203154109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341059PMC
April 2012

Cortical dysplasia: a possible substrate for brain tumors.

Future Oncol 2012 Mar;8(3):251-8

Epilepsy Center of the Neurosurgery Department, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, People's Republic of China.

The similarities between brain tumor stem cells and neural stem cells suggest a possible stem cell origin of tumorigenesis. Recently, cells with features of stem cells have been observed in lesions of adult and pediatric cortical dysplasia (CD). Given the evidence for a close relationship between CD and certain brain tumors, together with the finding that CD neural stem cells/progenitors are abnormally developed, we propose that CD is a possible substrate for brain tumors. The neural stem cells/progenitors in CD have accumulating abnormalities, and these abnormal stem/progenitor cells may be the initiating, transformed cells of brain tumors, when subsequently exposed to a carcinogen.
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http://dx.doi.org/10.2217/fon.12.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788700PMC
March 2012

Biodiversity as a barrier to glioma cell invasion.

Med Hypotheses 2012 Apr 1;78(4):459-61. Epub 2012 Feb 1.

Department of Neurosurgery, University Hospital Centre, 38042 Grenoble, France.

Gliomas are extremely aggressive and lethal forms of brain cancer. Unlike many other cancer types, glioma cells rarely metastasize. They spread throughout the brain and invasiveness of glioma cells is a major cause of therapeutic failure. In plant ecosystem, biodiversity acts locally as a barrier to ecological invasion. By analogy, we hypothesize that the low cell diversity of differentiated tissues, a counterpart of their functional specificity, opens the way to local cancer cell invasion. Seeding the brain tumor microenvironment with heterogeneous cell populations could be a mean to limit cancer cell invasion by enhancing cell biodiversity.
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http://dx.doi.org/10.1016/j.mehy.2012.01.005DOI Listing
April 2012
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