27 results on '"Luiz Gustavo Dubois"'
Search Results
2. CdTe quantum dots as fluorescent nanotools for in vivo glioblastoma imaging
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Maria Aparecida Barreto Lopes Seabra, Luiz Gustavo Dubois, Eraldo Fonseca dos Santos-Júnior, Renata Virgínia Cavalcanti Santos, Antônio Gomes de Castro Neto, Alinny Rosendo Isaac, Adriana Fontes, Gunther Hochhaus, Belmira Lara da Silveira Andrade da Costa, Vivaldo Moura Neto, and Beate Saegesser Santos
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U87 cell line ,Xenograft mouse model ,Fluorescence microscopy ,Applied optics. Photonics ,TA1501-1820 ,Optics. Light ,QC350-467 - Abstract
Glioblastoma (GBM) is the most aggressive and infiltrating primary tumor of the central nervous system (CNS), showing a variety of mutations and a high degree of vascularity, cell polymorphism, and nuclear atypia. GBM treatment often recurs to surgical resection, but such protocol lacks efficacy since complete tumor removal is not entirely successful due to invasive cells that cannot be detected at the moment of the surgery. Here, we describe a new in vivo targeting and imaging method for GBM detection in an orthotropic mouse model using fluorescent CdTe quantum dots (CdTe QDs) conjugated to anti-glial fibrillary acidic protein (anti-GFAP). We conjugated and optimized red-emitting CdTe QDs to anti-GFAP to label GBM (U87 cell line) in vivo. The in vivo tumor growth was visualized by the hematoxylin and eosin staining and showed the successful delivery of GBM cells into the mouse brain parenchyma. CdTe/anti-GFAP QDs were injected into the tumor region, and their uptake by tumor cells was visualized by fluorescence microscopy, showing a specific dual labeling with vimentin-immunoreactive GBM. The results reported here provide new perspectives for using CdTe QDs in GBM detection, suggesting their potential application in imaging-guided surgery and a potential fluorescent tool to be applied in the monitoring of 3D tumor glial cultures.
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- 2024
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- View/download PDF
3. Case report: Regression of Glioblastoma after flavivirus infection
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Patricia P. Garcez, André Guasti, Nina Ventura, Luiza Mendonça Higa, Felipe Andreiuolo, Gabriella Pinheiro A. de Freitas, Liane de Jesus Ribeiro, Richard Araújo Maia, Sheila Maria Barbosa de Lima, Adriana de Souza Azevedo, Waleska Dias Schwarcz, Elena Cristina Caride, Leila Chimelli, Luiz Gustavo Dubois, Orlando da Costa Ferreira Júnior, Amilcar Tanuri, Vivaldo Moura-Neto, and Paulo Niemeyer
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glioblastoma ,flavivirus ,oncolytic virus ,ZIKV ,DENV ,immunovirotherapy ,Medicine (General) ,R5-920 - Abstract
Glioblastoma is the most frequent and aggressive primary brain cancer. In preclinical studies, Zika virus, a flavivirus that triggers the death of glioblastoma stem-like cells. However, the flavivirus oncolytic activity has not been demonstrated in human patients. Here we report a glioblastoma patient who received the standard of care therapy, including surgical resection, radiotherapy and temozolomide. However, shortly after the tumor mass resection, the patient was clinically diagnosed with a typical arbovirus-like infection, during a Zika virus outbreak in Brazil. Following the infection resolution, the glioblastoma regressed, and no recurrence was observed. This clinical response continues 6 years after the glioblastoma initial diagnosis.
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- 2023
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4. The Expression of Connexins and SOX2 Reflects the Plasticity of Glioma Stem-Like Cells
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Joana Balça-Silva, Diana Matias, Luiz Gustavo Dubois, Brenno Carneiro, Anália do Carmo, Henrique Girão, Fernanda Ferreira, Valeria Pereira Ferrer, Leila Chimelli, Paulo Niemeyer Filho, Hermínio Tão, Olinda Rebelo, Marcos Barbosa, Ana Bela Sarmento-Ribeiro, Maria Celeste Lopes, and Vivaldo Moura-Neto
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor, with an average survival rate of 15 months. GBM is highly refractory to therapy, and such unresponsiveness is due, primarily, but not exclusively, to the glioma stem-like cells (GSCs). This subpopulation express stem-like cell markers and is responsible for the heterogeneity of GBM, generating multiple differentiated cell phenotypes. However, how GBMs maintain the balance between stem and non-stem populations is still poorly understood. We investigated the GBM ability to interconvert between stem and non-stem states through the evaluation of the expression of specific stem cell markers as well as cell communication proteins. We evaluated the molecular and phenotypic characteristics of GSCs derived from differentiated GBM cell lines by comparing their stem-like cell properties and expression of connexins. We showed that non-GSCs as well as GSCs can undergo successive cycles of gain and loss of stem properties, demonstrating a bidirectional cellular plasticity model that is accompanied by changes on connexins expression. Our findings indicate that the interconversion between non-GSCs and GSCs can be modulated by extracellular factors culminating on differential expression of stem-like cell markers and cell-cell communication proteins. Ultimately, we observed that stem markers are mostly expressed on GBMs rather than on low-grade astrocytomas, suggesting that the presence of GSCs is a feature of high-grade gliomas. Together, our data demonstrate the utmost importance of the understanding of stem cell plasticity properties in a way to a step closer to new strategic approaches to potentially eliminate GSCs and, hopefully, prevent tumor recurrence.
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- 2017
- Full Text
- View/download PDF
5. The anti‐hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ‐dependent inhibition of the AKT pathway
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Suzana Assad Kahn, Silvia Lima Costa, Sharareh Gholamin, Ryan T Nitta, Luiz Gustavo Dubois, Marie Fève, Maria Zeniou, Paulo Lucas Cerqueira Coelho, Elias El‐Habr, Josette Cadusseau, Pascale Varlet, Siddhartha S Mitra, Bertrand Devaux, Marie‐Claude Kilhoffer, Samuel H Cheshier, Vivaldo Moura‐Neto, Jacques Haiech, Marie‐Pierre Junier, and Hervé Chneiweiss
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glioma ,GL261 ,rottlerin ,sh PKCδ ,δV1.1 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor‐initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1‐ and α2B‐adrenergic receptor antagonist, as the most potent inducer of patient‐derived glioblastoma‐initiating cell death. Prazosin triggered apoptosis of glioblastoma‐initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient‐derived glioblastoma‐initiating cells, and increased survival of glioblastoma‐bearing mice. We found that prazosin acted in glioblastoma‐initiating cells independently from adrenergic receptors. Its off‐target activity occurred via a PKCδ‐dependent inhibition of the AKT pathway, which resulted in caspase‐3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin‐treated glioblastoma‐initiating cells, as well as prazosin‐induced apoptosis. Based on these data, we conclude that prazosin, an FDA‐approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ‐dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.
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- 2016
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6. Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro.
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Fabio A Mendes, Juliana M Coelho Aguiar, Suzana A Kahn, Alice H Reis, Luiz Gustavo Dubois, Luciana Ferreira Romão, Lais S S Ferreira, Hervé Chneiweiss, Vivaldo Moura Neto, and José G Abreu
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Medicine ,Science - Abstract
Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFβ, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments.
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- 2015
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7. Glioblastoma heterogeneity and resistance: A glance in biology and therapeutic approach
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Vanessa Coelho-Santos, Diana Matias, Luiz Gustavo Dubois, Veronica Aran, Vivaldo Moura-Neto, and Joana Balça-Silva
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- 2023
8. Contributors
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Samira Aghajani, Mazaher Ahmadi, Nobuyoshi Akimitsu, Iban Aldecoa, José Luís Alves, Veronica Aran, Ivan Archilla, Oscar Arrieta, Geetanjali Arora, C.S. Bal, Carmen Balaña, Joana Balça-Silva, Marcos Barbosa, João Basso, Amir Barzegar Behrooz, Mattia Bramini, Francesco Bruno, Célia Cabral, Andrés F. Cardona, Cristina Carrato, Simona Casalino, Rita Cascão, Valentina Castagnola, Sara Castañer Llanes, Miguel Castelo-Branco, Courtney Clark, Vanessa Coelho-Santos, Alexander B. Cook, Bárbara Costa, Bruno M. Costa, Gustavo Costa, Gabriella Costabile, Tânia F.G.G. Cova, Seyed Mohammad Hossein Dabiri, Ahmad Daher, Jéssica Delgado, Ana María Díaz-Lanza, Marta Domenech, Eva María Domínguez-Martín, Luiz Gustavo Dubois, Jason T. Duskey, Thomas Efferth, Claudia C. Faria, Ana Fortuna, Juan Esteban Garcia-Robledo, Saeid Ghavami, Alfredo Gimeno, Célia M.F. Gomes, Joana F. Guerreiro, Ankit Halder, Ainhoa Hernandez, Electra Eduina Hernández Santana, Santosh Kesari, Antonio Lopez-Rueda, Tayyebeh Madrakian, Mariana Magalhães, Bruno Manadas, Cláudia Martins, Diana Matias, Filipa Mendes, Maria Mendes, Donald W. Miller, Teresa Moran, Ana Moreira, Montse Moreno, Matteo Moschetta, Andrés Mosquera, Vivaldo Moura-Neto, Arani Mukherjee, Sandra C.C. Nunes, Laura Oleaga, Camila Ordoñez, Catarina Pacheco, Alberto A.C.C. Pais, António Paulo, Alessia Pellerino, Mariana Pereira, Estela Pineda, Catarina I.G. Pinto, Prasoon Prakash, Edoardo Pronello, Josep Puig, Teresa Ribalta, Patrícia Rijo, Katerina Rojas, Roberta Rudà, Luca Saba, Bruno Sarmento, Michele Schlich, Shreoshi Sengupta, Fernando Silva, Francisco Silva, Kumaravel Somasundaram, João Sousa, Sanjeeva Srivastava, Giovanni Tosi, Martina Trevisani, Nuno Vale, Carla Varela, Ayushi Verma, Maria Vieito, Carla Vitorino, Rui Vitorino, Tavia Walsh, and Vinith Yathindranath
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- 2023
9. Obstacles to Glioblastoma Treatment Two Decades after Temozolomide
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João Victor Roza Cruz, Carolina Batista, Bernardo de Holanda Afonso, Magna Suzana Alexandre-Moreira, Luiz Gustavo Dubois, Bruno Pontes, Vivaldo Moura Neto, and Fabio de Almeida Mendes
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Cancer Research ,Oncology - Abstract
Glioblastomas are considered the most common and aggressive primary brain tumor in adults, with an average of 15 months’ survival rate. The treatment is surgery resection, followed by chemotherapy with temozolomide, and/or radiotherapy. Glioblastoma must have wild-type IDH gene and some characteristics, such as TERT promoter mutation, EGFR gene amplification, microvascular proliferation, among others. Glioblastomas have great heterogeneity at cellular and molecular levels, presenting distinct phenotypes and diversified molecular signatures in each tumor mass, making it difficult to define a specific therapeutic target. It is believed that the main responsibility for the emerge of these distinct patterns lies in subcellular populations of tumor stem cells, capable of tumor initiation and asymmetric division. Studies are now focused on understanding molecular mechanisms of chemoresistance, the tumor microenvironment, due to hypoxic and necrotic areas, cytoskeleton and extracellular matrix remodeling, and in controlling blood brain barrier permeabilization to improve drug delivery. Another promising therapeutic approach is the use of oncolytic viruses that are able to destroy specifically glioblastoma cells, preserving the neural tissue around the tumor. In this review, we summarize the main biological characteristics of glioblastoma and the cutting-edge therapeutic targets that are currently under study for promising new clinical trials.
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- 2022
10. GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/β-Catenin Signaling
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Leila Chimelli, Luciana Romão, Luciane Rosário, Anna Carolina Carvalho da Fonseca, Joana Balça-Silva, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Bruno Pontes, Paulo Niemeyer Filho, Tania Cristina Leite de Sampaio e Spohr, Diana Matias, Maria do Carmo Lopes, José G. Abreu, Lucy Wanjiku Macharia, Valéria Pereira Ferrer, and Flavia Regina Souza Lima
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0301 basic medicine ,Neuroscience (miscellaneous) ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Wnt3A Protein ,Gene expression ,medicine ,Humans ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,Microglia ,Chemistry ,Wnt signaling pathway ,Phenotype ,nervous system diseases ,Crosstalk (biology) ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Tumor progression ,Cancer research ,Glioblastoma ,030217 neurology & neurosurgery ,WNT3A - Abstract
Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/β-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial β-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1β gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/β-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.
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- 2018
11. p53 expression and subcellular survivin localization improve the diagnosis and prognosis of patients with diffuse astrocytic tumors
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Luiz Gustavo Dubois, Paula Sabbo Bernardo, Roberta Soares Faccion, Priscila Valverde Fernandes, Giselle Pinto Faria de Lopes, Leonardo Soares Bastos, Cristina Lordello Teixeira, Raquel Ciuvalschi Maia, José Antonio de Oliveira, and Leila Chimelli
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Male ,Cancer Research ,Survivin ,medicine.medical_treatment ,Central nervous system ,Astrocytoma ,Inhibitor of Apoptosis Proteins ,03 medical and health sciences ,0302 clinical medicine ,Diffuse Astrocytoma ,medicine ,Humans ,Astrocytic Tumor ,business.industry ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Subcellular localization ,Carmustine ,Radiation therapy ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Immunohistochemistry ,Female ,Tumor Suppressor Protein p53 ,business ,030217 neurology & neurosurgery ,Anaplastic astrocytoma - Abstract
Diffuse astrocytic tumors are the most frequently occurring primary central nervous system (CNS) tumors. Their histological sub-classification into diffuse astrocytoma (DA), anaplastic astrocytoma (AA) and glioblastoma (GB) is challenging and the available prognostic factors are limited to age and tumor subtype. Biomarkers that may improve the histological sub-classification and/or serve as prognostic factors are, therefore, urgently needed. The relationship between survivin and p53 in diffuse astrocytic tumor progression and survival is currently unclear. Here, we aimed to assess the relevance of these proteins in the accuracy of the histological sub-classification of these tumors and their respective treatment responses. One hundred and thirty-three formalin-fixed paraffin-embedded diffuse astrocytic tumor samples were included. The tumor samples were histologically reviewed and subsequently assessed for p53 and survivin expression and the presence of the IDH R132H mutation by immunohistochemistry. p53 expression levels and survivin subcellular localization patterns were correlated with histological classification and clinical outcome. We found that age and histological subtype were the only features with a prognostic impact. In addition, we found that high p53 expression levels and a nuclear survivin localization correlated with the AA subtype, whereas cytoplasmic survivin localization correlated with the GB subtype. We also found that patients carrying tumors with a high cytoplasmic survivin expression, a high nuclear survivin expression or a high p53 expression, and who did not receive radiotherapy, exhibited poorer short-term and long-term overall survival rates. Our data suggest that subcellular survivin localization and p53 expression may be employed as valuable tools to improve the accuracy of the histological sub-classification of diffuse astrocytic tumors. Patients whose tumors overexpress these proteins may benefit from radiotherapy, irrespective age and/or histological classification.
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- 2018
12. The Expression of Connexins and SOX2 Reflects the Plasticity of Glioma Stem-Like Cells
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Fernanda Meireles Ferreira, Joana Balça-Silva, Paulo Niemeyer Filho, Leila Chimelli, Henrique Girão, Valéria Pereira Ferrer, Maria do Carmo Lopes, Anália do Carmo, Diana Matias, Marcos Barbosa, Olinda Rebelo, Hermínio Tão, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Brenno Carneiro, and Ana Bela Sarmento-Ribeiro
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0301 basic medicine ,Original article ,endocrine system ,Cancer Research ,Cell signaling ,Cellular differentiation ,fungi ,Cell ,Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Stem cell marker ,medicine.disease ,lcsh:RC254-282 ,nervous system diseases ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,SOX2 ,Cell culture ,Glioma ,medicine ,Stem cell - Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor, with an average survival rate of 15 months. GBM is highly refractory to therapy, and such unresponsiveness is due, primarily, but not exclusively, to the glioma stem-like cells (GSCs). This subpopulation express stem-like cell markers and is responsible for the heterogeneity of GBM, generating multiple differentiated cell phenotypes. However, how GBMs maintain the balance between stem and non-stem populations is still poorly understood. We investigated the GBM ability to interconvert between stem and non-stem states through the evaluation of the expression of specific stem cell markers as well as cell communication proteins. We evaluated the molecular and phenotypic characteristics of GSCs derived from differentiated GBM cell lines by comparing their stem-like cell properties and expression of connexins. We showed that non-GSCs as well as GSCs can undergo successive cycles of gain and loss of stem properties, demonstrating a bidirectional cellular plasticity model that is accompanied by changes on connexins expression. Our findings indicate that the interconversion between non-GSCs and GSCs can be modulated by extracellular factors culminating on differential expression of stem-like cell markers and cell-cell communication proteins. Ultimately, we observed that stem markers are mostly expressed on GBMs rather than on low-grade astrocytomas, suggesting that the presence of GSCs is a feature of high-grade gliomas. Together, our data demonstrate the utmost importance of the understanding of stem cell plasticity properties in a way to a step closer to new strategic approaches to potentially eliminate GSCs and, hopefully, prevent tumor recurrence.
- Published
- 2017
13. Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition
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Luciane Rosário, Joana Balça-Silva, Bruno Pontes, Diana Matias, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Juliana Echevarria-Lima, Maria do Carmo Lopes, Ana Bela Sarmento-Ribeiro, Valéria Pereira Ferrer, and Anália do Carmo
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0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Motility ,Pharmacology ,Matrix metalloproteinase ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Temozolomide ,medicine ,Humans ,Cytotoxic T cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Brain Neoplasms ,Chemistry ,Mesenchymal stem cell ,General Medicine ,Dacarbazine ,Blot ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Glioblastoma ,Naphthoquinones ,medicine.drug - Abstract
Glioblastomas (GBM) comprise 17% of all primary brain tumors. These tumors are extremely aggressive due to their infiltrative capacity and chemoresistance, with glial-to-mesenchymal transition (GMT) proteins playing a prominent role in tumor invasion. One compound that has recently been used to reduce the expression of these proteins is shikonin (SHK), a naphthoquinone with anti-tumor properties. Temozolomide (TMZ), the most commonly used chemotherapeutic agent in GBM treatment, has so far not been studied in combination with SHK. Here, we investigated the combined effects of these two drugs on the proliferation and motility of GBM-derived cells. The cytotoxic and proliferative effects of SHK and TMZ on human GBM-derived cells were tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), Ki67 staining and BrdU incorporation assays. The migration capacities of these cells were evaluated using a scratch wound assay. The expression levels of β3 integrin, metalloproteinases (MMPs) and GMT-associated proteins were determined by Western blotting and immunocytochemistry. We found that GBM-derived cells treated with a combination of SHK and TMZ showed decreases in their proliferation and migration capacities. These decreases were followed by the suppression of GMT through a reduction of β3 integrin, MMP-2, MMP-9, Slug and vimentin expression via inactivation of PI3K/AKT signaling. From our results we conclude that dual treatment with SHK and TMZ may constitute a powerful new tool for GBM treatment by reducing therapy resistance and tumor recurrence.
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- 2017
14. Glioblastoma entities express subtle differences in molecular composition and response to treatment
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Anália do Carmo, Joana Balça-Silva, Ana Cristina Gonçalves, Henrique Girão, Jorge Marcondes de Souza, Ana Helena Pereira Correia, Nathalie Henriques Silva Canedo, Maria do Carmo Lopes, Ana Bela Sarmento-Ribeiro, Luiz Gustavo Dubois, Vivaldo Moura-Neto, and Diana Matias
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cell cycle checkpoint ,Cell ,Apoptosis ,glioma cancer stem-like cells ,Astrocytoma ,cell motility ,Biology ,Stem cell marker ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,cellular heterogeneity ,Temozolomide ,medicine ,Humans ,chemotherapeutic resistance ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,U87 ,Protein Kinase C ,Cell Proliferation ,Cell growth ,glioblastoma ,Cell Cycle Checkpoints ,Articles ,General Medicine ,Cell cycle ,Molecular medicine ,nervous system diseases ,3. Good health ,Dacarbazine ,Gene Expression Regulation, Neoplastic ,Tamoxifen ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Neoplasm Grading ,Signal Transduction ,medicine.drug - Abstract
Glioblastoma (GBM) is a grade IV astrocytoma. GBM patients show resistance to chemotherapy such as temozolomide (TMZ), the gold standard treatment. In order to simulate the molecular mechanisms behind the different chemotherapeutic responses in GBM patients we compared the cellular heterogeneity and chemotherapeutic resistance mechanisms in different GBM cell lines. We isolated and characterized a human GBM cell line obtained from a GBM patient, named GBM11. We studied the GBM11 behaviour when treated with Tamoxifen (TMX) that, among other functions, is a protein kinase C (PKC) inhibitor, alone and in combination with TMZ in comparison with the responses of U87 and U118 human GBM cell lines. We evaluated the cell death, cell cycle arrest and cell proliferation, mainly through PKC expression, by flow cytometry and western blot analysis and, ultimately, cell migration capability and F-actin filament disorganization by fluorescence microscopy. We demonstrated that the constitutive activation of p-PKC seems to be one of the main metabolic implicated on GBM malignancy. Despite of its higher resistance, possibly due to the overexpression of P-glycoprotein and stem-like cell markers, GBM11 cells presented a subtle different chemotherapeutic response compared to U87 and U118 cells. The GBM11, U87, U118 cell lines show subtle molecular differences, which clearly indicate the characterization of GBM heterogeneity, one of the main reasons for tumor resistance. The adding of cellular heterogeneity in molecular behaviour constitutes a step closer in the understanding of resistant molecular mechanisms in GBM, and can circumvents the eventual impaired therapy.
- Published
- 2017
15. Glioblastoma Therapy in the Age of Molecular Medicine
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Diana Matias, Caroline Muriithi Wanjiru, Izabella Grimaldi, José Marcos Janeiro, Rackele Ferreira do Amaral, Tania Cristina Leite de Sampaio e Spohr, Barbara Gomes da Rosa, Luiz Henrique Medeiros Geraldo, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Lucy Wanjiku Macharia, Flavia Regina Souza Lima, Catarina Freitas, Celina Garcia, Cláudia Pereira, Felipe Sceanu Leser, Anna Carolina Carvalho da Fonseca, Eduardo Sabino de Camargo Magalhães, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
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0301 basic medicine ,Cancer Research ,Bevacizumab ,Angiogenesis ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Angiogenesis Inhibitors ,Immunotherapy, Adoptive ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Tumor microenvironment ,Microglia ,Brain Neoplasms ,business.industry ,Genetic Therapy ,Immunotherapy ,Molecular medicine ,Chimeric antigen receptor ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Drug development ,030220 oncology & carcinogenesis ,Cancer research ,Energy Metabolism ,Glioblastoma ,business ,medicine.drug - Abstract
Glioblastoma (GBM) is the most common and fatal primary malignant brain tumor. Despite advances in the understanding of the biology of gliomas, little has changed in the treatment of these tumors in the past decade. Phase III clinical trials showed no benefit for the use of bevacizumab in newly diagnosed patients, leading to a renewed search for new antiangiogenic drugs, as well as immunotherapeutic approaches, including checkpoint inhibitors, chimeric antigen receptor T cells, and intracerebral CpG-oligodeoxynucleotides. The emerging role of infiltrating microglia and macrophages, and of metabolic alterations, is also being taken into account in preclinical research and drug development. In this review, we discuss progress in the search for new therapeutic strategies, particularly approaches focusing on the tumor microenvironment.
- Published
- 2019
16. Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling
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Elias A. El-Habr, Catherine Leclerc, Jacques Haiech, Luiz Gustavo Dubois, Marc Moreau, Isabelle Néant, Nassera Tounsi, Suzana Assad Kahn, Francisco J. Aulestia, Samuel H. Cheshier, Jihu Dong, Marie-Pierre Junier, Marie-Claude Kilhoffer, Hervé Chneiweiss, Maria Zeniou, François Daubeuf, Nelly Frossard, Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Bisacodyl ,Cellular differentiation ,Pharmacology ,Biology ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,medicine ,Humans ,Inositol 1,4,5-Trisphosphate Receptors ,Cytotoxic T cell ,Calcium Signaling ,Cytotoxicity ,Receptor ,Molecular Biology ,Macro-tumorospheres ,Brain Neoplasms ,InsP3R ,Cancer ,Cell Biology ,Cancer stem-like cells ,medicine.disease ,In vitro ,3. Good health ,030104 developmental biology ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,Calcium ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Glioblastoma - Abstract
International audience; Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca(2+) release from the InsP3 receptors.
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- 2017
17. Sirtuin-2 Activity is Required for Glioma Stem Cell Proliferation Arrest but not Necrosis Induced by Resveratrol
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Elias A. El-Habr, Luiz Gustavo Dubois, Joanna Lipecka, Cécile Thirant, Hervé Chneiweiss, Alexandra Bogeas, Marie-Pierre Junier, Salwa Sayd, Nadia Tahiri-Jouti, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ARC, Region Ile de France-Canceropole, CAPES/COFECUB, Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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endocrine system ,Cancer Research ,endocrine system diseases ,SIRT3 ,Cell Survival ,Resveratrol ,SIRT2 ,Structure-Activity Relationship ,Necrosis ,chemistry.chemical_compound ,Sirtuin 2 ,Cancer stem cell ,Stilbenes ,Tumor Cells, Cultured ,Humans ,Sirtuin ,RNA, Small Interfering ,Cell Proliferation ,Dose-Response Relationship, Drug ,biology ,Cell growth ,fungi ,food and beverages ,Cell Biology ,Neural stem cell ,chemistry ,Biochemistry ,Neoplastic Stem Cells ,alpha-tubulin ,biology.protein ,Cancer research ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Stem cell ,Glioblastoma - Abstract
International audience; Glioblastomas, the most common form of primary brain tumors, are the fourth cause of death by cancer in adults. Increasing evidences suggest that glioblastoma resistance to existing radio- and chemotherapies rely on glioblastoma stem cells (GSCs). GSCs are endowed with a unique combination of stem-like properties alike to normal neural stem cells (NSCs), and of tumor initiating properties. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Here, we used resveratrol to explore the molecular mechanisms differing between GSCs and NSCs. We observed a dual action of resveratrol on GSCs: resveratrol blocked GSC proliferation up to 150 mu M and induced their necrosis at higher doses. On the opposite, resveratrol had no effect on NSC behavior. To determine the mechanisms underlying resveratrol effects, we focused our attention on the family of NAD-dependent deacetylases sirtuins (SIRT). A member of this family, SIRT1, has been repetitively shown to constitute a preferential resveratrol target, at least in normal cells. Western blot analysis showed that SIRT1 and SIRT3 were expressed by both GSCs and NSCs whereas SIRT2 expression was restricted to GSCs. Pharmacological blockade of SIRT2 activity or down-regulation of SIRT2 expression with siRNAs counteracted the inhibitory effect of resveratrol on cell proliferation. On the contrary, inhibition of SIRT2 activity or expression did not counteract GSC necrosis observed in presence of high doses of resveratrol. Our results highlight SIRT2 as a novel target for altering GSC properties.
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- 2013
18. The availability of the embryonic TGF-β protein Nodal is dynamically regulated during glioblastoma multiforme tumorigenesis
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Luiz Gustavo Dubois, Vivaldo Moura-Neto, Ana Luiza de Oliveira Barbeitas, Loraine Campanati, Tania Cristina Leite de Sampaio e Spohr, William Querido, Katia Carneiro, Grasiella Maria Ventura Matioszek, José Marques de Brito Neto, Suzana Assad Kahn, Maria Cecilia Oliveira-Nunes, and Flavia Regina Souza Lima
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0301 basic medicine ,Cancer Research ,Cellular differentiation ,Endocytic cycle ,Nodal signaling ,Nodal ,Biology ,Nestin ,Embryonic stem cell ,Endocytosis ,Cell biology ,Cancer stem-cell ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Cancer stem cell ,030220 oncology & carcinogenesis ,Immunology ,Tumorigenesis ,Genetics ,Stem cell ,NODAL ,Primary Research ,Glioblastoma - Abstract
Background Glioblastoma (GBM) is the most common primary brain tumor presenting self-renewing cancer stem cells. The role of these cells on the development of the tumors has been proposed to recapitulate programs from embryogenesis. Recently, the embryonic transforming growth factor-β (TGF-β) protein Nodal has been shown to be reactivated upon tumor development; however, its availability in GBM cells has not been addressed so far. In this study, we investigated by an original approach the mechanisms that dynamically control both intra and extracellular Nodal availability during GBM tumorigenesis. Methods We characterized the dynamics of Nodal availability in both stem and more differentiated GBM cells through morphological analysis, immunofluorescence of Nodal protein and of early (EEA1 and Rab5) and late (Rab7 and Rab11) endocytic markers and Western Blot. Tukey’s test was used to analyze the prevalent correlation of Nodal with different endocytic markers inside specific differentiation states, and Sidak’s multiple comparisons test was used to compare the prevalence of Nodal/endocytic markers co-localization between two differentiation states of GBM cells. Paired t test was used to analyze the abundance of Nodal protein, in extra and intracellular media. Results The cytoplasmic distribution of Nodal was dynamically regulated and strongly correlated with the differentiation status of GBM cells. While Nodal-positive vesicle-like particles were symmetrically distributed in GBM stem cells (GBMsc), they presented asymmetric perinuclear localization in more differentiated GBM cells (mdGBM). Strikingly, when subjected to dedifferentiation, the distribution of Nodal in mdGBM shifted to a symmetric pattern. Moreover, the availability of both intracellular and secreted Nodal were downregulated upon GBMsc differentiation, with cells becoming elongated, negative for Nodal and positive for Nestin. Interestingly, the co-localization of Nodal with endosomal vesicles also depended on the differentiation status of the cells, with Nodal seen more packed in EEA1/Rab5 + vesicles in GBMsc and more in Rab7/11 + vesicles in mdGBM. Conclusions Our results show for the first time that Nodal availability relates to GBM cell differentiation status and that it is dynamically regulated by an endocytic pathway during GBM tumorigenesis, shedding new light on molecular pathways that might emerge as putative targets for Nodal signaling in GBM therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12935-016-0324-3) contains supplementary material, which is available to authorized users.
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- 2016
19. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKC-dependent inhibition of the AKT pathway
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Jacques Haiech, Samuel H. Cheshier, Silvia Lima Costa, Suzana Assad Kahn, Marie Fève, Elias A. El-Habr, Paulo Lucas Cerqueira Coelho, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Bertrand Devaux, Pascale Varlet, Ryan T. Nitta, Sharareh Gholamin, Marie-Pierre Junier, Josette Cadusseau, Siddhartha S. Mitra, Hervé Chneiweiss, Marie-Claude Kilhoffer, Maria Zeniou, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer, CAPES/COFECUB [Me 757/12], French government [LABEX ANR-10-LABX-0034_Medalis], CAPES, CNPq, PEW Latin American Fellowship, Price Family Charitable Fund, Center for Children's Brain Tumors, St Baldrick's Foundation, American Brain Tumor Foundation, French Ministere de l'enseignement superieur et de la recherche, Lucile Packard Children's Hospital, Universidade Federal da Bahia (UFBA), Instituto Estadual do cerebro Paulo Niemeyer, Laboratoire d'Innovation Thérapeutique (LIT), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Inserm, UMR-955, F-94000 Créteil, France, Service de Neuropathologie [Sainte-Anne], Hôpital Sainte-Anne, Université Paris Descartes - Paris 5 (UPD5), APHP Ste Anne, département de neurochirurgie, HAL UPMC, Gestionnaire, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal da Bahia - UFBA (BRAZIL), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine ( NPS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Universidade Federal da Bahia ( UFBA ), Laboratoire d'Innovation Thérapeutique ( LIT ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), and Université Paris Descartes - Paris 5 ( UPD5 )
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0301 basic medicine ,Apoptosis ,Pharmacology ,rottlerin ,Mice ,chemistry.chemical_compound ,glioma ,sh PKC omega ,Receptor ,Research Articles ,Cancer ,omega V1.1 ,δV1.1 ,Receptor antagonist ,3. Good health ,Oncogene Protein v-akt ,Protein Kinase C-delta ,Heterografts ,Molecular Medicine ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Signal transduction ,Research Article ,Signal Transduction ,medicine.drug ,Cell Survival ,medicine.drug_class ,GL261 ,Antineoplastic Agents ,sh PKCδ ,03 medical and health sciences ,Glioma ,Prazosin ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,neoplasms ,Antihypertensive Agents ,PI3K/AKT/mTOR pathway ,V1 ,business.industry ,Drug Repositioning ,medicine.disease ,Survival Analysis ,nervous system diseases ,Disease Models, Animal ,030104 developmental biology ,chemistry ,sh PKC ,Glioblastoma ,business ,Rottlerin ,Neuroscience - Abstract
Published online; International audience; A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an a1-and a2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. We found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCd-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCd activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis. Based on these data, we conclude that prazosin, an FDA-approved drug for the control of hyperten-sion, inhibits glioblastoma growth through a PKCd-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients.
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- 2016
20. Glioblastoma cells: A heterogeneous and fatal tumor interacting with the parenchyma
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Vivaldo Moura Neto, Flavia Regina Souza Lima, Suzana Assad Kahn, Luiz Gustavo Dubois, Helena L. Borges, Rossana C. Soletti, Denise S. Lobo, and Tercia Alves
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Pathology ,medicine.medical_specialty ,Angiogenesis ,Nervous System Neoplasms ,Context (language use) ,Matrix metalloproteinase ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Extracellular matrix ,Pharmacology, Toxicology and Pharmaceutics(all) ,Immune system ,Neoplasm invasion ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,General Pharmacology, Toxicology and Pharmaceutics ,Pathologic angiogenesis ,Neovascularization, Pathologic ,Microglia ,Biochemistry, Genetics and Molecular Biology(all) ,Neoplastic stem cells ,Cancer ,General Medicine ,Pore forming cytotoxic proteins ,medicine.disease ,nervous system diseases ,medicine.anatomical_structure ,Metalloproteases ,Stem cell ,Glioblastoma - Abstract
Glioblastomas (GBMs) are considered to be one of the deadliest human cancers, characterized by a high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy, as well as a short patient survival period. Moreover, GBMs are among the most vascularized and invasive cancers in humans. Angiogenesis in GBMs is correlated with the grade of malignancy and is inversely correlated with patient survival. One of the first steps in tumor invasions is migration. GBM cells have the ability to infiltrate and disrupt physical barriers such as basement membranes, extracellular matrix and cell junctions. The invasion process includes the overexpression of several members of a super-family of zinc-based proteinases, the Metzincin, in particular a sub-group, metalloproteinases. Another interesting aspect is that, inside the GBM tissue, there are up to 30% of microglia or macrophages. However, little is known about the immune performance and interactions of the microglia with GBMs. These singular properties of GBMs will be described here. A sub-population of cells with stem-like properties may be the source of tumors since, apparently, GBM stem cells (GSCs) are highly resistant to current cancer treatments. These cancer therapies, while killing the majority of tumor cells, ultimately fail in GBM treatment because they do not eliminate GSCs, which survive to regenerate new tumors. Finally, GBM patient prognostic has shown little improvement in decades. In this context, we will discuss how the membrane-acting toxins called cytolysins can be a potential new tool for GBM treatment.
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- 2011
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21. Abstract B66: P53 expression and survivin subcellular localization contribute to the diagnosis and prognosis of patients with astrocytomas
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Paula Sabbo Bernardo, Leonardo Soares Bastos, Raquel Ciuvalschi Maia, Leila Maria Chimelli, Cristina Lordello Teixeira, Giselle Pinto de Faria Lopes, Luiz Gustavo Dubois, José Antonio de Oliveira, Roberta Soares Faccion, and Priscila Valverde Fernades
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Astrocytoma ,medicine.disease ,Subcellular localization ,Radiation therapy ,Diffuse Astrocytoma ,Internal medicine ,Survivin ,medicine ,Immunohistochemistry ,business ,neoplasms ,Grading (tumors) ,Anaplastic astrocytoma - Abstract
Astrocytomas are the most frequent subtype of primary central nervous system (CNS) tumors. Diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma (GB–grade IV) are diffuse infiltrating astrocytomas derived from glial cells or precursors. Despite continuous efforts from the scientific community, these tumors still have a poor prognosis. Histologic grading is still challenging, and prognostic factors are still limited to age and tumor grade. Biomarkers that could improve histologic grading, especially that could help differentiate grade III from the other subtypes, and/or serve as prognostic factors are much needed. Furthermore, the relationship between survivin and p53 in astrocytoma progression and survival is still controversial. The present study aims to investigate the role of these proteins in the accuracy of histologic grading of diffuse astrocytic tumors and treatment response. One hundred thirty-five formalin-fixed, paraffin-embedded astrocytoma samples were obtained from patients. Tumor samples were reviewed and stained for survivin and p53 by immunohistochemistry, and the staining levels and survivin subcellular localization were correlated with histologic grading and patient outcomes. Age and histologic grade were the only clinical features that had a prognostic impact. High nuclear survivin and p53 correlated with grade III astrocytomas. High cytoplasmic survivin correlated with GB. Furthermore, patients whose tumors expressed high cytoplasmic survivin, high nuclear surviving, or high p53 and did not receive radiotherapy had worse short-term and long-term survival. Our results suggest that survivin subcellular localization and p53 expression improve the accuracy of histologic grading. Patients whose tumors overexpress these proteins benefit from radiotherapy regardless of age and histologic grade. Furthermore, patients whose tumors overexpress survivin may benefit from novel targeted antisurvivin treatment. Citation Format: Roberta Soares Faccion*, Paula Sabbo Bernardo*, Giselle Pinto de Faria Lopes*, Leonardo Soares Bastos, Cristina Lordello Teixeira, José Antonio de Oliveira, Priscila Valverde Fernades, Luiz Gustavo Dubois, Leila Maria Chimelli, Raquel Ciuvalschi Maia. P53 expression and survivin subcellular localization contribute to the diagnosis and prognosis of patients with astrocytomas [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B66.
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- 2018
22. Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro
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Vivaldo Moura Neto, Alice H. Reis, Luiz Gustavo Dubois, Laís S. S. Ferreira, Hervé Chneiweiss, Luciana Romão, Juliana M. Coelho Aguiar, Fabio A. Mendes, José G. Abreu, Suzana Assad Kahn, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Programa de Nucleos de Excelencia (PRONEX), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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MAP Kinase Signaling System ,Cellular differentiation ,medicine.medical_treatment ,lcsh:Medicine ,Xenopus Proteins ,Nestin ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Humans ,Phosphorylation ,lcsh:Science ,Cells, Cultured ,030304 developmental biology ,Gliogenesis ,Cerebral Cortex ,0303 health sciences ,Multidisciplinary ,Mitogen-Activated Protein Kinase 3 ,biology ,integumentary system ,Growth factor ,SOXB1 Transcription Factors ,lcsh:R ,Wnt signaling pathway ,Connective Tissue Growth Factor ,Cell Differentiation ,Recombinant Proteins ,Cell biology ,Fibronectins ,Neoplasm Proteins ,Fibronectin ,CTGF ,Gene Expression Regulation ,CYR61 ,Astrocytes ,biology.protein ,lcsh:Q ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Stem cell ,Glioblastoma ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Cell Division ,Research Article - Abstract
Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFβ, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments.
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- 2015
23. Gliomas and the vascular fragility of the blood brain barrier
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Adriana Ximenes-da-Silva, Isabel Porto-Carreiro, Marcela de Almeida Rabello Oliveira, Isabella D’Andrea-Meira, Marcos F. DosSantos, Maria do Carmo Lopes, Joana Balça-Silva, Cassia Righy, Suzana Assad Kahn, Loraine Campanati, Tania Cristina Leite de Sampaio e Spohr, Cláudia Pereira, Luiz Gustavo Dubois, Vivaldo Moura-Neto, Emerson Leandro Gasparetto, and Eduardo C. Faveret
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Pathology ,medicine.medical_specialty ,Cell ,Population ,Context (language use) ,Review Article ,exosomes ,brain tumor related edema ,Blood–brain barrier ,lcsh:RC321-571 ,Cellular and Molecular Neuroscience ,Glioma ,medicine ,education ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,miRNA ,neural stem cells ,education.field_of_study ,Microglia ,business.industry ,glioblastoma ,blood-brain barrier ,medicine.disease ,Neural stem cell ,Microvesicles ,medicine.anatomical_structure ,business ,tumor-related epileptic seizures ,Neuroscience - Abstract
Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.
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- 2014
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24. The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model
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Luciana Romão, Celina Garcia, Jorge Marcondes de Souza, Ana Helena Pereira Correia, Anna L.R. Xavier, Fernanda Tovar-Moll, Nathalie Henriques Silva Canedo, Flavia Regina Souza Lima, Grasiella M. Ventura, Anna Carolina Carvalho da Fonseca, Fernanda Meirelles, João R. L. Menezes, Luiz Henrique Medeiros Geraldo, Luiz Gustavo Dubois, and Vivaldo Moura-Neto
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Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Transplantation, Heterologous ,Brain tumor ,Glial tumor ,Mice ,Necrosis ,Parenchyma ,Genetics ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Gliosis ,Tumor microenvironment ,Microglia ,Neovascularization, Pathologic ,business.industry ,Brain Neoplasms ,Brain ,Macrophage Activation ,medicine.disease ,Magnetic Resonance Imaging ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Technical Advance ,Stem cell ,medicine.symptom ,business ,Glioblastoma ,Immunocompetence ,Reactive gliosis - Abstract
Background Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. Methods Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. Results Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood–brain barrier disruption. Conclusions This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-923) contains supplementary material, which is available to authorized users.
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- 2014
25. Differential Proteomic Analysis of Human Glioblastoma and Neural Stem Cells Reveals HDGF as a Novel Angiogenic Secreted Factor
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Fabrice Soncin, Julie Gavard, Luiz Gustavo Dubois, Cécile Thirant, Cédric Broussard, Sébastien Pinte, Bertrand Devaux, Pascale Varlet, Hervé Chneiweiss, Philippe Chafey, Eva María Galán-Moya, Marie-Pierre Junier, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ARC, Region Ile de France-Canceropole, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)
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Male ,Proteomics ,medicine.medical_treatment ,Tumor initiation ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Cell Movement ,Tumor Cells, Cultured ,Secreted factor ,Neoangiogenesis ,0303 health sciences ,Neovascularization, Pathologic ,Cancer stem cells ,Tumor progression ,Neural stem cell ,3. Good health ,030220 oncology & carcinogenesis ,Intercellular Signaling Peptides and Proteins ,Molecular Medicine ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Adult ,endocrine system ,Transplantation, Heterologous ,Adult glioma ,Biology ,03 medical and health sciences ,Cancer stem cell ,Glioma ,medicine ,Animals ,Humans ,030304 developmental biology ,Growth factor ,fungi ,Endothelial Cells ,Cell Biology ,Two-dimensional differential gel electrophoresis ,medicine.disease ,Molecular biology ,Transplantation ,Culture Media, Conditioned ,Cancer cell ,Cancer research ,Angiogenesis Inducing Agents ,Glioblastoma ,Neoplasm Transplantation ,Developmental Biology - Abstract
International audience; Presence in glioblastomas of cancer cells with normal neural stem cell (NSC) properties, tumor initiating capacity, and resistance to current therapies suggests that glioblastoma stem-like cells (GSCs) play central roles in glioblastoma development. We cultured human GSCs endowed with all features of tumor stem cells, including tumor initiation after xenograft and radio-chemoresistance. We established proteomes from four GSC cultures and their corresponding whole tumor tissues (TTs) and from human NSCs. Two-dimensional difference gel electrophoresis and tandem mass spectrometry revealed a twofold increase of hepatoma-derived growth factor (HDGF) in GSCs as compared to TTs and NSCs. Western blot analysis confirmed HDGF overexpression in GSCs as well as its presence in GSC-conditioned medium, while, in contrast, no HDGF was detected in NSC secretome. At the functional level, GSC-conditioned medium induced migration of human cerebral endothelial cells that can be blocked by anti-HDGF antibodies. In vivo, GSC-conditioned medium induced neoangiogenesis, whereas HDGF-targeting siRNAs abrogated this effect. Altogether, our results identify a novel candidate, by which GSCs can support neoangiogenesis, a high-grade glioma hallmark. Our strategy illustrates the usefulness of comparative proteomic analysis to decipher molecular pathways, which underlie GSC properties. STEM CELLS 2012;30:845853
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- 2012
26. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells
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Sara S. Nunes, Jane Cristina de Oliveira Faria, Suzana Assad Kahn, Chantal Legrand, Nathan B. Viana, Aline Oliveira da Silva, Jorge Marcondes, Verônica Morandi, Anna Carolina Carvalho da Fonseca, Luiz Gustavo Dubois, Vivaldo Moura-Neto, and Tercia Alves
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Endothelium ,Angiogenesis ,Tenascin C ,Matricellular protein ,Endothelial Cells ,Tenascin ,Cell Biology ,Glioma ,Biology ,Cell biology ,Extracellular Matrix ,Rats ,Fibronectin ,Extracellular matrix ,medicine.anatomical_structure ,medicine ,biology.protein ,Cell Adhesion ,Animals ,Humans ,Anoikis ,Endothelium, Vascular ,Rats, Wistar ,Fibroblast ,Cell Proliferation - Abstract
The extracellular matrix (ECM) contains important cues for tissue homeostasis and morphogenesis. The matricellular protein tenascin-C (TN-C) is overexpressed in remodeling tissues and cancer. In the present work, we studied the effect of different ECM-which exhibited a significant diversity in their TN-C content-in endothelial survival, proliferation and tubulogenic differentiation: autologous (endothelial) ECM devoid of TN-C, but bearing large amounts of FN; fibroblast ECM, bearing both high TN-C and FN contents; and finally, glioma-derived matrices, usually poor in FN, but very rich in TN-C. HUVECs initially adhered to the immobilized matrix produced by U373 MG glioma cells, but significantly detached and died by anoikis (50 to 80%) after 24h, as compared with cells incubated with endothelial and fibroblast matrices. Surviving endothelial cells (20 to 50%) became up to 6-fold more proliferative and formed 74-97% less tube-like structures in vitro than cells grown on non-tumoral matrices. An antibody against the EGF-like repeats of tenascin-C (TN-C) partially rescued cells from the tubulogenic defect, indicating that this molecule is responsible for the selection of highly proliferative and tubulogenic defective endothelial cells. Interestingly, by using defined substrata, in conditions that mimic glioma and normal cell ECM composition, we observed that fibronectin (FN) modulates the TN-C-induced selection of endothelial cells. Our data show that TN-C is able to modulate endothelial branching morphogenesis in vitro and, since it is prevalent in matrices of injured and tumor tissues, also suggest a role for this protein in vascular morphogenesis, in these physiological contexts.
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- 2010
27. The Origin of Microglia and the Development of the Brain
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Jane Cristina de Oliveira Faria, Vivaldo Moura Neto, Luiz Gustavo Dubois, Giselle Pinto de Faria, Flavia Regina Souza Lima, Tercia Alves, and Anna Carolina Carvalho da Fonseca
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Mesoderm ,medicine.anatomical_structure ,Microglia ,Neuroectoderm ,Growth factor ,medicine.medical_treatment ,Parenchyma ,Neurogenesis ,medicine ,Context (language use) ,Biology ,Neuroscience ,Neural development - Abstract
We discuss the origin and development of microglial cells and their influence on neural development. Unlike astrocytes, oligodendrocytes, and neurons, which are derived from neuroectoderm, microglial cells originate from mesoderm. Microglial hematopoietic precursors enter the developing CNS from the bloodstream, ventricles, and meninges. In the brain, these cells migrate and proliferate, as ameboid microglia, and become distributed throughout the nervous parenchyma. Ameboid microglial cells differentiate into ramified microglia when they reach their definitive location. The factors that control the invasion of the nervous parenchyma, migration, proliferation, and differentiation of microglial cells are not completely known. These important events may depend on environmental factors such as soluble or cell-surface-bound molecules and components of the extracellular matrix. In the developing CNS, microglial cells are involved in clearing cell debris and withdrawing transitory or misdirected axons, and presumably support neurogenesis, cell survival, and neurite growth. In the adult brain, activated microglia occur mostly in response to neuronal injuries, when, they destroy invading microorganisms, remove harmful debris, and promote tissue repair, as well as partaking in the immune response by secreting cytokines, facilitating the return to homeostasis. Microglial activation is an important event in the defense of the nervous parenchyma against infectious, neurodegenerative, and inflammatory diseases. The majority of data in the literature describes microglial cells in a neuropathological context. Little is known of the development of these cells in the nervous parenchyma and their effective role in neurogenesis.
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- 2009
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