61 results on '"Guerrero-Cazares H"'
Search Results
2. Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition
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Ying, M, Wang, S, Sang, Y, Sun, P, Lal, B, Goodwin, C R, Guerrero-Cazares, H, Quinones-Hinojosa, A, Laterra, J, and Xia, S
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- 2011
- Full Text
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3. From the Operating Room to the Laboratory: Role of the Neuroscience Tissue Biorepository in the Clinical, Translational, and Basic Science Research Pipeline.
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Quiñones-Hinojosa A, Basil A, Moniz-Garcia D, Suarez-Meade P, Ramos A, Jentoft M, Middlebrooks E, Grewal S, Abode-Iyamah K, Bydon M, Sarkaria J, Dickson D, Swanson K, Rosenfeld S, Schiapparelli P, Guerrero-Cazares H, Chaichana K, and Meyer F
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- Humans, Operating Rooms, Biological Specimen Banks
- Abstract
Objective: To establish a neurologic disorder-driven biospecimen repository to bridge the operating room with the basic science laboratory and to generate a feedback cycle of increased institutional and national collaborations, federal funding, and human clinical trials., Methods: Patients were prospectively enrolled from April 2017 to July 2022. Tissue, blood, cerebrospinal fluid, bone marrow aspirate, and adipose tissue were collected whenever surgically safe. Detailed clinical, imaging, and surgical information was collected. Neoplastic and nonneoplastic samples were categorized and diagnosed in accordance with current World Health Organization classifications and current standard practices for surgical pathology at the time of surgery., Results: A total of 11,700 different specimens from 813 unique patients have been collected, with 14.2% and 8.5% of patients representing ethnic and racial minorities, respectively. These include samples from a total of 463 unique patients with a primary central nervous system tumor, 88 with metastasis to the central nervous system, and 262 with nonneoplastic diagnoses. Cerebrospinal fluid and adipose tissue dedicated banks with samples from 130 and 16 unique patients, respectively, have also been established. Translational efforts have led to 42 new active basic research projects; 4 completed and 6 active National Institutes of Health-funded projects; and 2 investigational new drug and 5 potential Food and Drug Administration-approved phase 0/1 human clinical trials, including 2 investigator initiated and 3 industry sponsored., Conclusion: We established a comprehensive biobank with detailed notation with broad potential that has helped us to transform our practice of research and patient care and allowed us to grow in research and clinical trials in addition to providing a source of tissue for new discoveries., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)
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- 2024
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4. A mutant methionyl-tRNA synthetase-based toolkit to assess induced-mesenchymal stromal cell secretome in mixed-culture disease models.
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Burgess JD, Amerna D, Norton ES, Parsons TM, Perkerson RB 3rd, Faroqi AH, Wszolek ZK, Guerrero Cazares H, Kanekiyo T, Delenclos M, and McLean PJ
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- Lipopolysaccharides, Secretome, Amino Acids, Methionine-tRNA Ligase genetics, Methionine-tRNA Ligase metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Background: Mesenchymal stromal cells (MSCs) have a dynamic secretome that plays a critical role in tissue repair and regeneration. However, studying the MSC secretome in mixed-culture disease models remains challenging. This study aimed to develop a mutant methionyl-tRNA synthetase-based toolkit (MetRS
L274G ) to selectively profile secreted proteins from MSCs in mixed-culture systems and demonstrate its potential for investigating MSC responses to pathological stimulation., Methods: We used CRISPR/Cas9 homology-directed repair to stably integrate MetRSL274G into cells, enabling the incorporation of the non-canonical amino acid, azidonorleucine (ANL), and facilitating selective protein isolation using click chemistry. MetRSL274G was integrated into both in H4 cells and induced pluripotent stem cells (iPSCs) for a series of proof-of-concept studies. Following iPSC differentiation into induced-MSCs, we validated their identity and co-cultured MetRSL274G -expressing iMSCs with naïve or lipopolysaccharide (LPS)-treated THP-1 cells. We then profiled the iMSC secretome using antibody arrays., Results: Our results showed successful integration of MetRSL274G into targeted cells, allowing specific isolation of proteins from mixed-culture environments. We also demonstrated that the secretome of MetRSL274G -expressing iMSCs can be differentiated from that of THP-1 cells in co-culture and is altered when co-cultured with LPS-treated THP-1 cells compared to naïve THP-1 cells., Conclusions: The MetRSL274G -based toolkit we have generated enables selective profiling of the MSC secretome in mixed-culture disease models. This approach has broad applications for examining not only MSC responses to models of pathological conditions, but any other cell type that can be differentiated from iPSCs. This can potentially reveal novel MSC-mediated repair mechanisms and advancing our understanding of tissue regeneration processes., (© 2023. BioMed Central Ltd., part of Springer Nature.)- Published
- 2023
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5. Perivascular invasion of primary human glioblastoma cells in organotypic human brain slices: human cells migrating in human brain.
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Ravin R, Suarez-Meade P, Busse B, Blank PS, Vivas-Buitrago T, Norton ES, Graepel S, Chaichana KL, Bezrukov L, Guerrero-Cazares H, Zimmerberg J, and Quiñones-Hinojosa A
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- Humans, Brain pathology, Tumor Cells, Cultured, Cell Movement physiology, Cell Line, Tumor, Tumor Microenvironment, Glioblastoma pathology, Brain Neoplasms pathology
- Abstract
Introduction: Glioblastoma (GBM) is an aggressive primary brain cancer. Lack of effective therapy is related to its highly invasive nature. GBM invasion has been studied with reductionist systems that do not fully recapitulate the cytoarchitecture of the brain. We describe a human-derived brain organotypic model to study the migratory properties of GBM IDH-wild type ex vivo., Methods: Non-tumor brain samples were obtained from patients undergoing surgery (n = 7). Organotypic brain slices were prepared, and green fluorescent protein (GFP)-labeled primary human GBM IDH-wild type cells (GBM276, GBM612, GBM965) were placed on the organotypic slice. Migration was evaluated via microscopy and immunohistochemistry., Results: After placement, cells migrated towards blood vessels; initially migrating with limited directionality, sending processes in different directions, and increasing their speed upon contact with the vessel. Once merged, migration speed decreased and continued to decrease with time (p < 0.001). After perivascular localization, migration is limited along the blood vessels in both directions. The percentage of cells that contact blood vessels and then continue to migrate along the vessel was 92.5% (- 3.9/ + 2.9)% while the percentage of cells that migrate along the blood vessel and leave was 7.5% (- 2.9/ + 3.9) (95% CI, Clopper-Pearson (exact); n = 256 cells from six organotypic cultures); these percentages are significantly different from the random (50%) null hypothesis (z = 13.6; p < 10
-7 ). Further, cells increase their speed in response to a decrease in oxygen tension from atmospheric normoxia (20% O2 ) to anoxia (1% O2 ) (p = 0.033)., Conclusion: Human organotypic models can accurately study cell migration ex vivo. GBM IDH-wild type cells migrate toward the perivascular space in blood vessels and their migratory parameters change once they contact vascular structures and under hypoxic conditions. This model allows the evaluation of GBM invasion, considering the human brain microenvironment when cells are removed from their native niche after surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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6. Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.
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Ruiz-Garcia H, Zarco N, Watanabe F, De Araujo Farias V, Suarez-Meade P, Guerrero-Cazares H, Imitola J, Quinones-Hinojosa A, and Trifiletti D
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- Animals, Cell Line, Tumor, Humans, Neoplastic Stem Cells pathology, Organoids pathology, Tumor Microenvironment, Brain Neoplasms pathology, Glioblastoma pathology, Neoplasms, Experimental pathology
- Abstract
Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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7. Platelet-derived exosomes induce cell proliferation and wound healing in human endometrial cells.
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Miller CM, L Enninga EA, Rizzo SA, Phillipps J, Guerrero-Cazares H, Destephano CC, Peterson TE, Stalboerger PG, Behfar A, and Khan Z
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- Cell Proliferation, Endometrium, Female, Humans, Stromal Cells metabolism, Wound Healing, Exosomes
- Abstract
Aim: To investigate the regenerative effects of a platelet-derived purified exosome product (PEP) on human endometrial cells. Materials & methods: Endometrial adenocarcinoma cells (HEC-1A), endometrial stromal cells (T HESC) and menstrual blood-derived stem cells (MenSC) were assessed for exosome absorption and subsequent changes in cell proliferation and wound healing properties over 48 h. Results: Cell proliferation increased in PEP treated T HESC (p < 0.0001) and MenSC (p < 0.001) after 6 h and in HEC-1A (p < 0.01) after 12 h. PEP improved wound healing after 6 h in HEC-1A (p < 0.01) and MenSC (p < 0.0001) and in T HESC between 24 and 36 h (p < 0.05). Conclusion: PEP was absorbed by three different endometrial cell types. PEP treatment increased cell proliferation and wound healing capacity.
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- 2022
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8. Transcriptional landscape of human microglia implicates age, sex, and APOE-related immunometabolic pathway perturbations.
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Patel T, Carnwath TP, Wang X, Allen M, Lincoln SJ, Lewis-Tuffin LJ, Quicksall ZS, Lin S, Tutor-New FQ, Ho CCG, Min Y, Malphrus KG, Nguyen TT, Martin E, Garcia CA, Alkharboosh RM, Grewal S, Chaichana K, Wharen R, Guerrero-Cazares H, Quinones-Hinojosa A, and Ertekin-Taner N
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- Apolipoproteins E genetics, Apolipoproteins E metabolism, Humans, Microglia metabolism, Transcriptome genetics, Alzheimer Disease metabolism, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism
- Abstract
Microglia have fundamental roles in health and disease; however, effects of age, sex, and genetic factors on human microglia have not been fully explored. We applied bulk and single-cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex, and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single-cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex, and APOE-ε4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single-cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2, and BIN1. Meta-analyses with published bulk and single-cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource and highlight age, sex, and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
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- 2022
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9. Functional Characterization of Brain Tumor-Initiating Cells and Establishment of GBM Preclinical Models that Incorporate Heterogeneity, Therapy, and Sex Differences.
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Garcia CA, Bhargav AG, Brooks M, Suárez-Meade P, Mondal SK, Zarco N, ReFaey K, Jentoft M, Middlebrooks EH, Snuderl M, Carrano A, Guerrero-Cazares H, Schiapparelli P, Sarabia-Estrada R, and Quiñones-Hinojosa A
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- Aged, Animals, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Line, Tumor, Cell Proliferation, Female, Glioblastoma mortality, Glioblastoma pathology, Humans, Male, Mice, Middle Aged, Sex Characteristics, Survival Analysis, Neoplastic Stem Cells metabolism
- Abstract
Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rh TNFSF10 (rhTRAIL), and rh BMP4 All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies., (©2021 American Association for Cancer Research.)
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- 2021
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10. SERPINA3 in glioblastoma and Alzheimer's disease.
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Norton ES, Da Mesquita S, and Guerrero-Cazares H
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- Aging, Humans, Alzheimer Disease, Glioblastoma, Serpins
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- 2021
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11. Editorial: Neural Stem Cells of the Subventricular Zone: From Neurogenesis to Glioblastoma Origin.
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Matarredona ER, Zarco N, Castro C, and Guerrero-Cazares H
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2021
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12. NIH funding trends for neurosurgeon-scientists from 1993-2017: Biomedical workforce implications for neurooncology.
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ReFaey K, Freeman WD, Tripathi S, Guerrero-Cazares H, Eatz TA, Meschia JF, Carter RE, Petrucelli L, Meyer FB, and Quinones-Hinojosa A
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- Health Workforce, Humans, Medical Oncology, Neurology, United States, Biomedical Research economics, National Institutes of Health (U.S.), Neurosurgeons economics, Research Support as Topic trends
- Abstract
Introduction: Neurosurgeons represent 0.5% of all physicians and currently face a high burden of disease. Physician-scientists are essential to advance the mission of National Academies of Science (NAS) and National Institutes of Health (NIH) through discovery and bench to bedside translation. We investigated trends in NIH neurosurgeon-scientist funding over time as an indicator of physician-scientist workforce training., Methods: We used NIH Research Portfolio Online Reporting Tools (RePORTER) to extract grants to neurosurgery departments and neurosurgeons from 1993 to 2017. Manual extraction of each individual grant awardee was conducted., Results: After adjusting for U.S. inflation (base year: 1993), NIH funding to neurosurgery departments increased yearly (P < 0.00001). However, neurosurgeon-scientists received significantly less NIH funding compared to scientists (including basic scientists and research only neurosurgeons) (P = 0.09). The ratio of neurosurgeon-scientists to scientists receiving grants was significantly reduced (P = 0.002). Interestingly, the percentage of oncology-related neurosurgery grants significantly increased throughout the study period (P = 0.002). The average number of grants per neurosurgeon-scientists showed an upward trend (P < 0.001); however, the average number of grants for early-career neurosurgeon-scientists, showed a significant downward trend (P = 0.05)., Conclusion: Over the past 23 years, despite the overall increasing trends in the number of NIH grants awarded to neurosurgery departments overall, the proportion of neurosurgeon-scientists that were awarded NIH grants compared to scientists demonstrates a declining trend. This observed shift is disproportionate in the number of NIH grants awarded to senior level compared to early-career neurosurgeon-scientists, with more funding allocated towards neurosurgical-oncology-related grants., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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13. Sex-Specific Differences in Glioblastoma.
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Carrano A, Juarez JJ, Incontri D, Ibarra A, and Guerrero Cazares H
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- Brain Neoplasms genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Phenotype, Brain Neoplasms metabolism, Glioblastoma metabolism, Sex Characteristics, Tumor Microenvironment physiology
- Abstract
Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.
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- 2021
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14. Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma.
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Lara-Velazquez M, Zarco N, Carrano A, Phillipps J, Norton ES, Schiapparelli P, Al-Kharboosh R, Rincon-Torroella J, Jeanneret S, Corona T, Segovia J, Jentoft ME, Chaichana KL, Asmann YW, Quiñones-Hinojosa A, and Guerrero-Cazares H
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- Adult, Animals, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Mice, Serpins, Brain Neoplasms genetics, Glioblastoma genetics, Neoplastic Stem Cells, alpha 1-Antichymotrypsin
- Abstract
Background: Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo., Methods: We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections., Results: GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model., Conclusions: SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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15. Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential.
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Alvarado-Estrada K, Marenco-Hillembrand L, Maharjan S, Mainardi VL, Zhang YS, Zarco N, Schiapparelli P, Guerrero-Cazares H, Sarabia-Estrada R, Quinones-Hinojosa A, and Chaichana KL
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- A549 Cells, Adenocarcinoma of Lung blood supply, Animals, Cell Movement, Cell Survival, Computer Simulation, Epithelial-Mesenchymal Transition, Female, Humans, Lung blood supply, Lung pathology, Lung Neoplasms blood supply, Microfluidic Analytical Techniques, Rats, Stress, Mechanical, Tumor Microenvironment, Xenograft Model Antitumor Assays, Adenocarcinoma of Lung secondary, Hemorheology, Lung Neoplasms pathology, Neoplastic Stem Cells pathology, Side-Population Cells pathology
- Abstract
Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival.
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- 2021
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16. Chitosan-Based Non-viral Gene and Drug Delivery Systems for Brain Cancer.
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Lara-Velazquez M, Alkharboosh R, Norton ES, Ramirez-Loera C, Freeman WD, Guerrero-Cazares H, Forte AJ, Quiñones-Hinojosa A, and Sarabia-Estrada R
- Abstract
Central nervous system (CNS) tumors are a leading source of morbidity and mortality worldwide. Today, different strategies have been developed to allow targeted and controlled drug delivery into the brain. Gene therapy is a system based on the modification of patient's cells through the introduction of genetic material to exert a specific action. Administration of the foreign genetic material can be done through viral-mediated delivery or non-viral delivery via physical or mechanical systems. For brain cancer specifically, gene therapy can overcome the actual challenge of blood brain barrier penetration, the main reason for therapeutic failure. Chitosan (CS), a natural based biodegradable polymer obtained from the exoskeleton of crustaceans such as crab, shrimp, and lobster, has been used as a delivery vehicle in several non-viral modification strategies. This cationic polysaccharide is highly suitable for gene delivery mainly due to its chemical properties, its non-toxic nature, its capacity to protect nucleic acids through the formation of complexes with the genetic material, and its ease of degradation in organic environments. Recent evidence supports the use of CS as an alternative gene delivery system for cancer treatment. This review will describe multiple studies highlighting the advantages and challenges of CS-based delivery structures for the treatment of brain tumors. Furthermore, this review will provide insight on the translational potential of various CS based-strategies in current clinical cancer studies. Specifically, CS-based nanostructures including nanocapsules, nanospheres, solid-gel formulations, and nanoemulsions, also microshperes and micelles will be evaluated., (Copyright © 2020 Lara-Velazquez, Alkharboosh, Norton, Ramirez-Loera, Freeman, Guerrero-Cazares, Forte, Quiñones-Hinojosa and Sarabia-Estrada.)
- Published
- 2020
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17. A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks.
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Lopez-Bertoni H, Kotchetkov IS, Mihelson N, Lal B, Rui Y, Ames H, Lugo-Fagundo M, Guerrero-Cazares H, Quiñones-Hinojosa A, Green JJ, and Laterra J
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- Animals, Bcl-2-Like Protein 11 metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms radiotherapy, Cell Death, Cell Dedifferentiation genetics, Cell Line, Tumor, Cellular Reprogramming physiology, Epigenetic Repression, Female, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma radiotherapy, Heterografts, Humans, Mice, Mice, Nude, MicroRNAs administration & dosage, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Nanoparticles administration & dosage, Neoplasm Proteins genetics, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Neoplastic Stem Cells radiation effects, Neural Stem Cells, Octamer Transcription Factor-3 metabolism, Radiation Tolerance, Random Allocation, SOXB1 Transcription Factors genetics, SOXB1 Transcription Factors metabolism, Transfection methods, Tumor Burden, Tumor Stem Cell Assay methods, Up-Regulation, Brain Neoplasms pathology, Cell Survival, Forkhead Box Protein O1 genetics, Genes, Tumor Suppressor, Glioblastoma pathology, MicroRNAs metabolism, Neoplasm Proteins physiology, PTEN Phosphohydrolase genetics, SOXB1 Transcription Factors physiology
- Abstract
Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways. SIGNIFICANCE: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p-dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival., (©2020 American Association for Cancer Research.)
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- 2020
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18. Self-assembling and self-formulating prodrug hydrogelator extends survival in a glioblastoma resection and recurrence model.
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Schiapparelli P, Zhang P, Lara-Velazquez M, Guerrero-Cazares H, Lin R, Su H, Chakroun RW, Tusa M, Quiñones-Hinojosa A, and Cui H
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- Animals, Camptothecin, Cell Line, Tumor, Humans, Mice, Brain Neoplasms drug therapy, Glioblastoma drug therapy, Prodrugs
- Abstract
Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain cancer. Despite surgery and chemo/radiation therapy, recurrence often takes place and leads to patient death. We report here on the development of a camptothecin (CPT)-based self-assembling prodrug (SAPD) hydrogel that can be used as an adjunct therapy for local treatment of GBM following maximal tumor resection. When dispersed in aqueous solution, the designed CPT prodrug spontaneously assembles into supramolecular filaments with a 100% CPT loading. In both in vitro and ex vivo assays, we show that the designed CPT prodrug can be steadily released from its supramolecular filament hydrogel, effectively killing primary GBM cells derived from patients. We also found that the solution containing self-assembling CPT filaments can be directly applied to the tumor cavity after surgical removal, and forms a gel immediately upon contact with the brain tissue. Our in vivo studies with a resection and recurrence mouse model suggest that this prodrug hydrogel can release cancer therapeutics into brain parenchyma over a long period of time, suppressing tumor recurrence and leading to prolonged survival. We believe that the simplicity in prodrug design and the high efficacy in suppressing GBM growth enable the unique potential of this SAPD hydrogels for clinical translation as an adjunct therapy for GBM treatment., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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19. Engineered nanoparticles for systemic siRNA delivery to malignant brain tumours.
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Karlsson J, Rui Y, Kozielski KL, Placone AL, Choi O, Tzeng SY, Kim J, Keyes JJ, Bogorad MI, Gabrielson K, Guerrero-Cazares H, Quiñones-Hinojosa A, Searson PC, and Green JJ
- Subjects
- Animals, Humans, Male, Mice, Mice, Nude, Xenograft Model Antitumor Assays, Blood-Brain Barrier metabolism, Blood-Brain Barrier pathology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Drug Delivery Systems, Gene Silencing, Glioblastoma drug therapy, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma pathology, Nanoparticles chemistry, Nanoparticles therapeutic use, RNA, Small Interfering chemistry, RNA, Small Interfering pharmacokinetics, RNA, Small Interfering pharmacology
- Abstract
Improved delivery materials are needed to enable siRNA transport across biological barriers, including the blood-brain barrier (BBB), to treat diseases like brain cancer. We engineered bioreducible nanoparticles for systemic siRNA delivery to patient-derived glioblastoma cells in an orthotopic mouse tumor model. We first utilized a newly developed biomimetic in vitro model to evaluate and optimize the performance of the engineered bioreducible nanoparticles at crossing the brain microvascular endothelium. We performed transmission electron microscopy imaging which indicated that the engineered nanoparticles are able to cross the BBB endothelium via a vesicular mechanism. The nanoparticle formulation engineered to best cross the BBB model in vitro led to safe delivery across the BBB to the brain in vivo. The nanoparticles were internalized by human brain cancer cells, released siRNA to the cytosol via environmentally-triggered degradation, and gene silencing was obtained both in vitro and in vivo. This study opens new frontiers for the in vitro evaluation and engineering of nanomedicines for delivery to the brain, and reports a systemically administered biodegradable nanocarrier for oligonucleotide delivery to treat glioma.
- Published
- 2019
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20. Response to Blast-like Shear Stresses Associated with Mild Blast-Induced Brain Injury.
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Ravin R, Morgan NY, Blank PS, Ravin N, Guerrero-Cazares H, Quinones-Hinojosa A, and Zimmerberg J
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- Explosions, Humans, Pressure, Blast Injuries, Brain Injuries, Lab-On-A-Chip Devices, Shear Strength, Stress, Mechanical
- Abstract
Toward the goal of understanding the pathophysiology of mild blast-induced traumatic brain injury and identifying the physical forces associated with the primary injury phase, we developed a system that couples a pneumatic blast to a microfluidic channel to precisely and reproducibly deliver shear transients to dissociated human central nervous system (CNS) cells, on a timescale comparable to an explosive blast but with minimal pressure transients. Using fluorescent beads, we have characterized the shear transients experienced by the cells and demonstrate that the system is capable of accurately and reproducibly delivering uniform shear transients with minimal pressure across the cell culture volume. This system is compatible with high-resolution, time-lapse optical microscopy. Using this system, we demonstrate that blast-like shear transients produced with minimal pressure transients and submillisecond rise times activate calcium responses in dissociated human CNS cultures. Cells respond with increased cytosolic free calcium to a threshold shear stress between 8 and 21 Pa; the propagation of this calcium response is a result of purinergic signaling. We propose that this system models, in vitro, the fundamental injury wave produced by shear forces consequent to blast shock waves passing through density inhomogeneity in human CNS cells., (Copyright © 2019. Published by Elsevier Inc.)
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- 2019
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21. Osteosarcoma of the Upper Extremities: A National Analysis of the US Population.
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Huayllani MT, Restrepo DJ, Boczar D, Sisti A, Spaulding AC, Parker AS, Sarabia-Estrada R, Guerrero-Cazares H, Moran SL, and Forte AJ
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- Adult, Female, Humans, Male, Middle Aged, Osteoblasts pathology, Prognosis, Retrospective Studies, Survival Rate, Young Adult, Osteosarcoma pathology, Upper Extremity pathology
- Abstract
Background/aim: Osteosarcoma of the upper extremities is rare, and characteristics in this location have not been described before. We aimed to analyze the characteristics and survival rate of osteosarcoma of the upper extremities., Materials and Methods: A retrospective cohort study was performed by querying the National Cancer Database. Statistical analysis was performed using a multivariate logistic regression model and Kaplan-Meier log-rank tests for survival., Results: A total of 991 patients were diagnosed with osteosarcoma of the upper extremities. Most tumors were osteogenic and osteoblastic (66.8%), larger than 8 cm (47.9%), high grade (64.3%), lymph node-negative (7.9%), and without metastasis to lungs (39.0%). Osteosarcomas of the hand and wrist were less likely to be high-grade when compared to osteosarcomas of the forearm, arm, and shoulder., Conclusion: The results of this study help us to approach patients promptly and avoid total amputation, increasing functionality and prognosis of the disease., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2019
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22. Aqueductal Cerebrospinal Fluid Stroke Volume Flow in a Rodent Model of Chronic Communicating Hydrocephalus: Establishing a Homogeneous Study Population for Cerebrospinal Fluid Dynamics Exploration.
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Vivas-Buitrago T, Lokossou A, Jusué-Torres I, Pinilla-Monsalve G, Blitz AM, Herzka DA, Robison J, Xu J, Guerrero-Cazares H, Mori S, Quiñones-Hinojosa A, Baledént O, and Rigamonti D
- Subjects
- Animals, Cerebral Aqueduct diagnostic imaging, Contrast Media, Disease Progression, Hydrocephalus diagnostic imaging, Kaolin, Magnetic Resonance Imaging, Organ Size, Rats, Sprague-Dawley, Cerebral Aqueduct physiopathology, Cerebrospinal Fluid diagnostic imaging, Disease Models, Animal, Hydrocephalus physiopathology, Hydrodynamics
- Abstract
Background: Idiopathic normal pressure hydrocephalus (iNPH) is a cause of dementia that can be reversed when treated timely with cerebrospinal fluid (CSF) diversion. Understanding CSF dynamics throughout the development of hydrocephalus is crucial to identify prognostic markers to estimate benefit/risk to shunts., Objective: To explore the cerebral aqueduct CSF flow dynamics with phase-contrast magnetic resonance imaging (MRI) in a novel rodent model of adult chronic communicating hydrocephalus., Methods: Kaolin was injected into the subarachnoid space at the convexities in Sprague-Dawley adult rats. 11.7-T Bruker MRI was used to acquire T2-weighted images for anatomic identification and phase-contrast MRI at the cerebral aqueduct. Aqueductal stroke volume (ASV) results were compared with the ventricular volume (VV) at 15, 60, 90, and 120 days., Results: Significant ventricular enlargement was found in kaolin-injected animals at all times (P < 0.001). ASV differed between cases and controls/shams at every time point (P = 0.004, 0.001, 0.001, and <0.001 at 15, 60, 90, and 120 days, respectively). After correlation between the ASV and the VV, there was a significant correlation at 15 (P = 0.015), 60 (P = 0.001), 90 (P < 0.001), and 120 days. Moreover, there was a significant positive correlation between the VV expansion and the aqueductal CSF stroke between 15 and 60 days., Conclusions: An initial active phase of rapid ventricular enlargement shows a strong correlation between the expansion of the VV and the increment in the ASV during the first 60 days, followed by a second phase with less ventricular enlargement and heterogeneous behavior in the ASV. Further correlation with complementary data from intracranial pressure and histologic/microstructural brain parenchyma assessments are needed to better understand the ASV variations after 60 days., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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23. Potential influence of IDH1 mutation and MGMT gene promoter methylation on glioma-related preoperative seizures and postoperative seizure control.
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Feyissa AM, Worrell GA, Tatum WO, Chaichana KL, Jentoft ME, Guerrero Cazares H, Ertekin-Taner N, Rosenfeld SS, ReFaey K, and Quinones-Hinojosa A
- Subjects
- Adult, Aged, Brain physiopathology, Brain surgery, Brain Neoplasms physiopathology, Brain Neoplasms surgery, DNA Methylation, DNA Modification Methylases metabolism, DNA Repair Enzymes metabolism, Female, Glioma physiopathology, Glioma surgery, Humans, Male, Middle Aged, Postoperative Complications genetics, Postoperative Complications therapy, Preoperative Period, Promoter Regions, Genetic, Retrospective Studies, Seizures etiology, Seizures physiopathology, Tumor Suppressor Proteins metabolism, Young Adult, Brain Neoplasms genetics, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Glioma genetics, Isocitrate Dehydrogenase genetics, Seizures genetics, Seizures therapy, Tumor Suppressor Proteins genetics
- Abstract
Purpose: To examine the occurrence of glioma-related preoperative seizures (GPS) and post-operative seizure control (PSC) with respect to patients characteristics including five commonly tested tumor molecular markers (TMMs)., Methods: A single-center retrospective cohort study of patients with glioma evaluated at the Mayo Clinic, Florida between 2016 and 2018., Results: 68 adult patients (mean age = 51-years, 45-males) were included. 46 patients had GPS. 57 patients underwent intra-operative electrocorticography during awake craniotomy-assisted glioma resection. All patients underwent glioma resection (53, gross-total resection) with histologies of pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 4), oligodendroglioma (n = 14), anaplastic astrocytoma (n = 16), anaplastic oligodendroglioma (n = 1), and glioblastoma (n = 31). 31 (67%) patients had PSC (median follow-up = 14.5 months; IQR = 7-16.5 months). IDH1 mutation (IDH1
mut ) was present in 32, ARTX retention in 53, MGMT gene promotor methylation in 15, 1p/19q co-deletion in 15, and over-expression of p53 in 19 patients. Patients with IDH1mut were more likely to have GPS (p = 0.037) and PSC (p = 0.035) compared to patients with IDH1 wild-type. Patients with MGMT gene promoter methylation were also likely to have PSC (p = 0.032). GPS or PSC did not differ by age, sex, extent of surgery, glioma grade, location, and histopathological subtype, p53 expression, ARTX retention, or 1p/19q co-deletion status., Conclusions: GPS and PSC may be associated with IDH1 mutation and MGMT gene promoter methylation status but not other glioma characteristics including tumor grade, location, or histopathology. Prospective studies with larger sample size are needed to clarify the exact mechanisms of GPS and PSC by the various TMMs to identify new treatment targets., (Published by Elsevier Ltd.)- Published
- 2019
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24. Ventricular Volume Dynamics During the Development of Adult Chronic Communicating Hydrocephalus in a Rodent Model.
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Vivas-Buitrago T, Pinilla-Monsalve G, Jusué-Torres I, Oishi K, Robison J, Crawford JA, Pletnikov M, Xu J, Baledént O, Lokossou A, Hung AL, Blitz AM, Lu J, Herzka DA, Guerrero-Cazares H, Oishi K, Mori S, Quiñones-Hinojosa A, and Rigamonti D
- Subjects
- Animals, Cerebral Ventricles pathology, Disease Models, Animal, Disease Progression, Female, Hydrocephalus pathology, Kaolin, Magnetic Resonance Imaging, Organ Size, Rats, Sprague-Dawley, Cerebral Ventricles diagnostic imaging, Cerebral Ventricles physiopathology, Hydrocephalus diagnostic imaging, Hydrocephalus physiopathology
- Abstract
Introduction: The pathophysiology of normal-pressure hydrocephalus and the correlation with its symptomatology is not well understood., Objective: To monitor and evaluate the enlargement patterns of the ventricular system for each ventricle and its correlation with the presenting symptoms., Methods: Bilateral kaolin injection into the subarachnoid space overlying the cranial convexities was done in 18 adult rats. Magnetic resonance imaging was performed on an 11.7-T scanner 15, 60, 90, and 120 days after injection. Volumes of the ventricular system were measured for each ventricle and correlated with biweekly behavioral findings., Results: There was a progressive increase in the ventricular volume for the lateral ventricles since day 15 in the kaolin-injected animals. There was a nonsignificant trend in volume growth for the third ventricle, but its enlargement was synchronous with the lateral ventricles. No significant change for the fourth ventricle. No symptoms were detected in the first 60 days. Association was found between the ventricular volume and locomotor changes. In addition, the odds of locomotor symptoms increased by 3% for every additional cubic millimeter of volume in the left (P < 0.001) and right (P = 0.023) ventricles, and for the total magnetic resonance imaging volume by 1% (P = 0.013)., Conclusions: Expansion of the lateral ventricles maintained similar proportions over time, accompanied by a synchronous third ventricular expansion with less proportion and a nonsignificant fourth enlargement. Lateral ventricles enlarged most in those animals that were to develop late locomotor deterioration. Further research using this animal model combined with different radiologic imaging techniques, such as diffusion tensor imaging and perfusion studies, is recommended., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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25. Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents.
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Sarabia-Estrada R, Ruiz-Valls A, Guerrero-Cazares H, Ampuero AM, Jimenez-Estrada I, De Silva S, Bernhardt LJ, Goodwin CR, Ahmed AK, Li Y, Phillips NA, Gokaslan ZL, Quiñones-Hinojosa A, and Sciubba DM
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Hyperalgesia pathology, Hyperalgesia physiopathology, Rats, Spinal Cord pathology, Spinal Cord physiopathology, Spinal Neoplasms secondary, Adenocarcinoma pathology, Gait, Hyperalgesia etiology, Mammary Neoplasms, Experimental pathology, Spinal Neoplasms pathology
- Abstract
Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques., Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats., Study Design/setting: This is a basic science study., Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining., Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups., Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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26. Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model.
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Sarabia-Estrada R, Ruiz-Valls A, Shah SR, Ahmed AK, Ordonez AA, Rodriguez FJ, Guerrero-Cazares H, Jimenez-Estrada I, Velarde E, Tyler B, Li Y, Phillips NA, Goodwin CR, Petteys RJ, Jain SK, Gallia GL, Gokaslan ZL, Quinones-Hinojosa A, and Sciubba DM
- Subjects
- Animals, Cell Line, Tumor, Chordoma diagnostic imaging, Chordoma pathology, Female, Gait physiology, Humans, Immunocompromised Host, Neoplasm Recurrence, Local physiopathology, Neoplasm Transplantation, Random Allocation, Rats, Sacrum, Spinal Cord diagnostic imaging, Spinal Cord pathology, Spinal Cord physiopathology, Spinal Neoplasms diagnostic imaging, Spinal Neoplasms pathology, Chordoma physiopathology, Disease Models, Animal, Hindlimb physiopathology, Motor Activity physiology, Nociception physiology, Spinal Neoplasms physiopathology
- Abstract
OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100β, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma-engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.
- Published
- 2017
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27. Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells.
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Huang YJ, Schiapparelli P, Kozielski K, Green J, Lavell E, Guerrero-Cazares H, Quinones-Hinojosa A, and Searson P
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- Cell Line, Tumor, Humans, Neuroglia cytology, Cell Membrane chemistry, Cell Movement, Electrophoresis, Heparitin Sulfate chemistry, Neuroglia metabolism
- Abstract
Endogenous electric fields modulate many physiological processes by promoting directional migration, a process known as galvanotaxis. Despite the importance of galvanotaxis in development and disease, the mechanism by which cells sense and migrate directionally in an electric field remains unknown. Here, we show that electrophoresis of cell surface heparan sulfate (HS) critically regulates this process. HS was found to be localized at the anode-facing side in fetal neural progenitor cells (fNPCs), fNPC-derived astrocytes and brain tumor-initiating cells (BTICs), regardless of their direction of galvanotaxis. Enzymatic removal of HS and other sulfated glycosaminoglycans significantly abolished or reversed the cathodic response seen in fNPCs and BTICs. Furthermore, Slit2, a chemorepulsive ligand, was identified to be colocalized with HS in forming a ligand gradient across cellular membranes. Using both imaging and genetic modification, we propose a novel mechanism for galvanotaxis in which electrophoretic localization of HS establishes cell polarity by functioning as a co-receptor and provides repulsive guidance through Slit-Robo signaling., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
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28. NKCC1 Regulates Migration Ability of Glioblastoma Cells by Modulation of Actin Dynamics and Interacting with Cofilin.
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Schiapparelli P, Guerrero-Cazares H, Magaña-Maldonado R, Hamilla SM, Ganaha S, Goulin Lippi Fernandes E, Huang CH, Aranda-Espinoza H, Devreotes P, and Quinones-Hinojosa A
- Subjects
- Cell Line, Tumor, Cell Movement genetics, Cytoskeleton metabolism, Gene Expression, Humans, Protein Binding, Protein Transport, rac1 GTP-Binding Protein metabolism, rhoA GTP-Binding Protein metabolism, Actin Depolymerizing Factors metabolism, Actins metabolism, Glioblastoma genetics, Glioblastoma metabolism, Solute Carrier Family 12, Member 2 genetics, Solute Carrier Family 12, Member 2 metabolism
- Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. The mechanisms that confer GBM cells their invasive behavior are poorly understood. The electroneutral Na
+ -K+ -2Cl- co-transporter 1 (NKCC1) is an important cell volume regulator that participates in cell migration. We have shown that inhibition of NKCC1 in GBM cells leads to decreased cell migration, in vitro and in vivo. We now report on the role of NKCC1 on cytoskeletal dynamics. We show that GBM cells display a significant decrease in F-actin content upon NKCC1 knockdown (NKCC1-KD). To determine the potential actin-regulatory mechanisms affected by NKCC1 inhibition, we studied NKCC1 protein interactions. We found that NKCC1 interacts with the actin-regulating protein Cofilin-1 and can regulate its membrane localization. Finally, we analyzed whether NKCC1 could regulate the activity of the small Rho-GTPases RhoA and Rac1. We observed that the active forms of RhoA and Rac1 were decreased in NKCC1-KD cells. In summary, we report that NKCC1 regulates GBM cell migration by modulating the cytoskeleton through multiple targets including F-actin regulation through Cofilin-1 and RhoGTPase activity. Due to its essential role in cell migration NKCC1 may serve as a specific therapeutic target to decrease cell invasion in patients with primary brain cancer., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2017
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29. Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development.
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Guerrero-Cazares H, Lavell E, Chen L, Schiapparelli P, Lara-Velazquez M, Capilla-Gonzalez V, Clements AC, Drummond G, Noiman L, Thaler K, Burke A, and Quiñones-Hinojosa A
- Subjects
- Animals, Cell Movement, Fetus, Humans, Intercellular Signaling Peptides and Proteins metabolism, Lateral Ventricles cytology, Lateral Ventricles growth & development, Median Eminence cytology, Median Eminence growth & development, Median Eminence metabolism, Mice, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins metabolism, Neural Stem Cells cytology, Neural Stem Cells transplantation, Neurogenesis genetics, Neurons cytology, Neurons metabolism, Olfactory Bulb cytology, Olfactory Bulb growth & development, Primary Cell Culture, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic metabolism, Signal Transduction, Roundabout Proteins, Gene Expression Regulation, Developmental, Intercellular Signaling Peptides and Proteins genetics, Lateral Ventricles metabolism, Nerve Tissue Proteins genetics, Neural Stem Cells metabolism, Olfactory Bulb metabolism, Receptors, Immunologic genetics
- Abstract
Human neural progenitor cell (NPC) migration within the subventricular zone (SVZ) of the lateral ganglionic eminence is an active process throughout early brain development. The migration of human NPCs from the SVZ to the olfactory bulb during fetal stages resembles what occurs in adult rodents. As the human brain develops during infancy, this migratory stream is drastically reduced in cell number and becomes barely evident in adults. The mechanisms regulating human NPC migration are unknown. The Slit-Robo signaling pathway has been defined as a chemorepulsive cue involved in axon guidance and neuroblast migration in rodents. Slit and Robo proteins expressed in the rodent brain help guide neuroblast migration from the SVZ through the rostral migratory stream to the olfactory bulb. Here, we present the first study on the role that Slit and Robo proteins play in human-derived fetal neural progenitor cell migration (hfNPC). We describe that Robo1 and Robo2 isoforms are expressed in the human fetal SVZ. Furthermore, we demonstrate that Slit2 is able to induce a chemorepellent effect on the migration of hfNPCs derived from the human fetal SVZ. In addition, when Robo1 expression is inhibited, hfNPCs are unable to migrate to the olfactory bulb of mice when injected in the anterior SVZ. Our findings indicate that the migration of human NPCs from the SVZ is partially regulated by the Slit-Robo axis. This pathway could be regulated to direct the migration of NPCs in human endogenous neural cell therapy. Stem Cells 2017;35:1860-1865., (© 2017 AlphaMed Press.)
- Published
- 2017
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30. Abstracts from Hydrocephalus 2016.
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Adam A, Robison J, Lu J, Jose R, Badran N, Vivas-Buitrago T, Rigamonti D, Sattar A, Omoush O, Hammad M, Dawood M, Maghaslah M, Belcher T, Carson K, Hoffberger J, Jusué Torres I, Foley S, Yasar S, Thai QA, Wemmer J, Klinge P, Al-Mutawa L, Al-Ghamdi H, Carson KA, Asgari M, de Zélicourt D, Kurtcuoglu V, Garnotel S, Salmon S, Balédent O, Lokossou A, Page G, Balardy L, Czosnyka Z, Payoux P, Schmidt EA, Zitoun M, Sevestre MA, Alperin N, Baudracco I, Craven C, Matloob S, Thompson S, Haylock Vize P, Thorne L, Watkins LD, Toma AK, Bechter K, Pong AC, Jugé L, Bilston LE, Cheng S, Bradley W, Hakim F, Ramón JF, Cárdenas MF, Davidson JS, García C, González D, Bermúdez S, Useche N, Mejía JA, Mayorga P, Cruz F, Martinez C, Matiz MC, Vallejo M, Ghotme K, Soto HA, Riveros D, Buitrago A, Mora M, Murcia L, Bermudez S, Cohen D, Dasgupta D, Curtis C, Domínguez L, Remolina AJ, Grijalba MA, Whitehouse KJ, Edwards RJ, Eleftheriou A, Lundin F, Fountas KN, Kapsalaki EZ, Smisson HF, Robinson JS, Fritsch MJ, Arouk W, Garzon M, Kang M, Sandhu K, Baghawatti D, Aquilina K, James G, Thompson D, Gehlen M, Schmid Daners M, Eklund A, Malm J, Gomez D, Guerra M, Jara M, Flores M, Vío K, Moreno I, Rodríguez S, Ortega E, Rodríguez EM, McAllister JP, Guerra MM, Morales DM, Sival D, Jimenez A, Limbrick DD, Ishikawa M, Yamada S, Yamamoto K, Junkkari A, Häyrinen A, Rauramaa T, Sintonen H, Nerg O, Koivisto AM, Roine RP, Viinamäki H, Soininen H, Luikku A, Jääskeläinen JE, Leinonen V, Kehler U, Lilja-Lund O, Kockum K, Larsson EM, Riklund K, Söderström L, Hellström P, Laurell K, Kojoukhova M, Sutela A, Vanninen R, Vanha KI, Timonen M, Rummukainen J, Korhonen V, Helisalmi S, Solje E, Remes AM, Huovinen J, Paananen J, Hiltunen M, Kurki M, Martin B, Loth F, Luciano M, Luikku AJ, Hall A, Herukka SK, Mattila J, Lötjönen J, Alafuzoff I, Jurjević I, Miyajima M, Nakajima M, Murai H, Shin T, Kawaguchi D, Akiba C, Ogino I, Karagiozov K, Arai H, Reis RC, Teixeira MJ, Valêncio CG, da Vigua D, Almeida-Lopes L, Mancini MW, Pinto FCG, Maykot RH, Calia G, Tornai J, Silvestre SSS, Mendes G, Sousa V, Bezerra B, Dutra P, Modesto P, Oliveira MF, Petitto CE, Pulhorn H, Chandran A, McMahon C, Rao AS, Jumaly M, Solomon D, Moghekar A, Relkin N, Hamilton M, Katzen H, Williams M, Bach T, Zuspan S, Holubkov R, Rigamonti A, Clemens G, Sharkey P, Sanyal A, Sankey E, Rigamonti K, Naqvi S, Hung A, Schmidt E, Ory-Magne F, Gantet P, Guenego A, Januel AC, Tall P, Fabre N, Mahieu L, Cognard C, Gray L, Buttner-Ennever JA, Takagi K, Onouchi K, Thompson SD, Thorne LD, Tully HM, Wenger TL, Kukull WA, Doherty D, Dobyns WB, Moran D, Vakili S, Patel MA, Elder B, Goodwin CR, Crawford JA, Pletnikov MV, Xu J, Blitz A, Herzka DA, Guerrero-Cazares H, Quiñones-Hinojosa A, Mori S, Saavedra P, Treviño H, Maitani K, Ziai WC, Eslami V, Nekoovaght-Tak S, Dlugash R, Yenokyan G, McBee N, and Hanley DF
- Published
- 2017
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31. A Novel Experimental Animal Model of Adult Chronic Hydrocephalus.
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Jusué-Torres I, Jeon LH, Sankey EW, Lu J, Vivas-Buitrago T, Crawford JA, Pletnikov MV, Xu J, Blitz A, Herzka DA, Crain B, Hulbert A, Guerrero-Cazares H, Gonzalez-Perez O, McAllister JP 2nd, Quiñones-Hinojosa A, and Rigamonti D
- Subjects
- Animals, Female, Fibrosis, Hydrocephalus chemically induced, Hydrocephalus diagnostic imaging, Hydrocephalus pathology, Hydrocephalus physiopathology, Hydrocephalus, Normal Pressure chemically induced, Hydrocephalus, Normal Pressure diagnostic imaging, Hydrocephalus, Normal Pressure pathology, Inflammation, Kaolin toxicity, Magnetic Resonance Imaging, Radiography, Rats, Sprague-Dawley, Subarachnoid Space diagnostic imaging, Subarachnoid Space pathology, Cognition, Disease Models, Animal, Gait, Hydrocephalus, Normal Pressure physiopathology, Locomotion, Rats
- Abstract
Background: The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown., Objective: To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus., Methods: Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed., Results: Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement., Conclusion: Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus., Abbreviation: NPH, normal pressure hydrocephalus.
- Published
- 2016
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32. Brain-on-a-chip model enables analysis of human neuronal differentiation and chemotaxis.
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Kilic O, Pamies D, Lavell E, Schiapparelli P, Feng Y, Hartung T, Bal-Price A, Hogberg HT, Quinones-Hinojosa A, Guerrero-Cazares H, and Levchenko A
- Subjects
- Cell Line, Tumor, Humans, Neuroglia cytology, Brain cytology, Cell Differentiation, Chemotaxis, Microchip Analytical Procedures, Neurons cytology
- Abstract
Migration of neural progenitors in the complex tissue environment of the central nervous system is not well understood. Progress in this area has the potential to drive breakthroughs in neuroregenerative therapies, brain cancer treatments, and neurodevelopmental studies. To a large extent, advances have been limited due to a lack of controlled environments recapitulating characteristics of the central nervous system milieu. Reductionist cell culture models are frequently too simplistic, and physiologically more relevant approaches such as ex vivo brain slices or in situ experiments provide little control and make information extraction difficult. Here, we present a brain-on-chip model that bridges the gap between cell culture and ex vivo/in vivo conditions through recapitulation of self-organized neural differentiation. We use a new multi-layer silicone elastomer device, over the course of four weeks to differentiate pluripotent human (NTERA2) cells into neuronal clusters interconnected with thick axonal bundles and interspersed with astrocytes, resembling the brain parenchyma. Neurons within the device express the neurofilament heavy (NF200) mature axonal marker and the microtubule-associated protein (MAP2ab) mature dendritic marker, demonstrating that the devices are sufficiently biocompatible to allow neuronal maturation. This neuronal-glial environment is interfaced with a layer of human brain microvascular endothelial cells showing characteristics of the blood-brain barrier including the expression of zonula occludens (ZO1) tight junctions and increased trans-endothelial electrical resistance. We used this device to model migration of human neural progenitors in response to chemotactic cues within a brain-tissue setting. We show that in the presence of an environment mimicking brain conditions, neural progenitor cells show a significantly enhanced chemotactic response towards shallow gradients of CXCL12, a key chemokine expressed during embryonic brain development and in pathological tissue regions of the central nervous system. Our brain-on-chip model thus provides a convenient and scalable model of neural differentiation and maturation extensible to analysis of complex cell and tissue behaviors.
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- 2016
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33. Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes.
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Smith CL, Kilic O, Schiapparelli P, Guerrero-Cazares H, Kim DH, Sedora-Roman NI, Gupta S, O'Donnell T, Chaichana KL, Rodriguez FJ, Abbadi S, Park J, Quiñones-Hinojosa A, and Levchenko A
- Subjects
- Animals, Glioblastoma pathology, Humans, Mice, Nanoparticles chemistry, Neoplasm Invasiveness, Phenotype, Platelet-Derived Growth Factor pharmacology, Treatment Outcome, Tumor Microenvironment, Brain Neoplasms pathology, Cell Movement
- Abstract
Glioblastoma multiforme is a heterogeneous and infiltrative cancer with dismal prognosis. Studying the migratory behavior of tumor-derived cell populations can be informative, but it places a high premium on the precision of in vitro methods and the relevance of in vivo conditions. In particular, the analysis of 2D cell migration may not reflect invasion into 3D extracellular matrices in vivo. Here, we describe a method that allows time-resolved studies of primary cell migration with single-cell resolution on a fibrillar surface that closely mimics in vivo 3D migration. We used this platform to screen 14 patient-derived glioblastoma samples. We observed that the migratory phenotype of a subset of cells in response to platelet-derived growth factor was highly predictive of tumor location and recurrence in the clinic. Therefore, migratory phenotypic classifiers analyzed at the single-cell level in a patient-specific way can provide high diagnostic and prognostic value for invasive cancers., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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34. Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells.
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Ravin R, Blank PS, Busse B, Ravin N, Vira S, Bezrukov L, Waters H, Guerrero-Cazares H, Quinones-Hinojosa A, Lee PR, Fields RD, Bezrukov SM, and Zimmerberg J
- Subjects
- Animals, Blast Injuries, Cells, Cultured, Central Nervous System cytology, Explosions, Female, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Humans, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Rats, Sprague-Dawley, Receptors, Purinergic metabolism, Signal Transduction, Stress, Mechanical, Astrocytes metabolism, Calcium metabolism, Calcium Signaling, Central Nervous System metabolism
- Abstract
In a recent study of the pathophysiology of mild, blast-induced traumatic brain injury (bTBI) the exposure of dissociated, central nervous system (CNS) cells to simulated blast resulted in propagating waves of elevated intracellular Ca(2+). Here we show, in dissociated human CNS cultures, that these calcium waves primarily propagate through astrocyte-dependent, purinergic signaling pathways that are blocked by P2 antagonists. Human, compared to rat, astrocytes had an increased calcium response and prolonged calcium wave propagation kinetics, suggesting that in our model system rat CNS cells are less responsive to simulated blast. Furthermore, in response to simulated blast, human CNS cells have increased expressions of a reactive astrocyte marker, glial fibrillary acidic protein (GFAP) and a protease, matrix metallopeptidase 9 (MMP-9). The conjoint increased expression of GFAP and MMP-9 and a purinergic ATP (P2) receptor antagonist reduction in calcium response identifies both potential mechanisms for sustained changes in brain function following primary bTBI and therapeutic strategies targeting abnormal astrocyte activity.
- Published
- 2016
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35. Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer.
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Feng Y, Zhu M, Dangelmajer S, Lee YM, Wijesekera O, Castellanos CX, Denduluri A, Chaichana KL, Li Q, Zhang H, Levchenko A, Guerrero-Cazares H, and Quiñones-Hinojosa A
- Published
- 2015
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36. Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix.
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Placone AL, McGuiggan PM, Bergles DE, Guerrero-Cazares H, Quiñones-Hinojosa A, and Searson PC
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- Animals, Astrocytes drug effects, Cell Shape drug effects, Cells, Cultured, Collagen pharmacology, Drug Combinations, Elastic Modulus drug effects, Endothelial Cells cytology, Endothelial Cells drug effects, Glial Fibrillary Acidic Protein metabolism, Humans, Hyaluronic Acid pharmacology, Hydrogel, Polyethylene Glycol Dimethacrylate pharmacology, Laminin pharmacology, Microscopy, Electron, Scanning, Proteoglycans pharmacology, Rats, Time Factors, Astrocytes cytology, Astrocytes physiology, Cellular Microenvironment drug effects
- Abstract
Astrocytes are the most abundant glial cells in the brain and are responsible for diverse functions, from modulating synapse function to regulating the blood-brain barrier. In vivo, these cells exhibit a star-shaped morphology with multiple radial processes that contact synapses and completely surround brain capillaries. In response to trauma or CNS disease, astrocytes become activated, a state associated with profound changes in gene expression, including upregulation of intermediate filament proteins, such as glial fibrillary acidic protein (GFAP). The inability to recapitulate the complex structure of astrocytes and maintain their quiescent state in vitro is a major roadblock to further developments in tissue engineering and regenerative medicine. Here, we characterize astrocyte morphology and activation in various hydrogels to assess the feasibility of developing a matrix that mimics key aspects of the native microenvironment. We show that astrocytes seeded in optimized matrix composed of collagen, hyaluronic acid, and matrigel exhibit a star-shaped morphology with radial processes and do not upregulate GFAP expression, hallmarks of quiescent astrocytes in the brain. In these optimized gels, collagen I provides structural support, HA mimics the brain extracellular matrix, and matrigel provides endothelial cell compatibility and was found to minimize GFAP upregulation. This defined 3D microenvironment for maintaining human astrocytes in vitro provides new opportunities for developing improved models of the blood-brain barrier and studying their response to stress signals., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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37. Regulation of subventricular zone-derived cells migration in the adult brain.
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Capilla-Gonzalez V, Lavell E, Quiñones-Hinojosa A, and Guerrero-Cazares H
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- Adult, Animals, Humans, Neural Stem Cells physiology, Neurogenesis physiology, Neurons physiology, Stem Cell Niche, Brain Injuries pathology, Cell Movement physiology, Lateral Ventricles cytology, Neural Stem Cells cytology, Olfactory Bulb cytology
- Abstract
The subventricular zone of the lateral ventricles (SVZ) is the largest source of neural stem cells (NSCs) in the adult mammalian brain. Newly generated neuroblasts from the SVZ form cellular chains that migrate through the rostral migratory stream (RMS) into the olfactory bulb (OB), where they become mature neurons. Migration through the RMS is a highly regulated process of intrinsic and extrinsic factors, orchestrated to achieve direction and integration of neuroblasts into OB circuitry. These factors include internal cytoskeletal and volume regulators, extracellular matrix proteins, and chemoattractant and chemorepellent proteins. All these molecules direct the cells away from the SVZ, through the RMS, and into the OB guaranteeing their correct integration. Following brain injury, some neuroblasts escape the RMS and migrate into the lesion site to participate in regeneration, a phenomenon that is also observed with brain tumors. This review focuses on factors that regulate the migration of SVZ precursor cells in the healthy and pathologic brain. A better understanding of the factors that control the movement of newly generated cells may be crucial for improving the use of NSC-replacement therapy for specific neurological diseases.
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- 2015
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38. Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer.
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Feng Y, Zhu M, Dangelmajer S, Lee YM, Wijesekera O, Castellanos CX, Denduluri A, Chaichana KL, Li Q, Zhang H, Levchenko A, Guerrero-Cazares H, and Quiñones-Hinojosa A
- Subjects
- Adipose Tissue metabolism, Adult, Aged, Brain Neoplasms metabolism, Cell Differentiation, Cell Hypoxia, Cell Line, Cell Survival, Cells, Cultured, Female, Humans, Male, Mesenchymal Stem Cells metabolism, Middle Aged, Oxygen analysis, Adipose Tissue cytology, Brain Neoplasms physiopathology, Cell Movement, Mesenchymal Stem Cells cytology, Oxygen metabolism, Tropism
- Abstract
Adult human adipose-derived mesenchymal stem cells (hAMSCs) are multipotent cells, which are abundant, easily collected, and bypass the ethical concerns that plague embryonic stem cells. Their utility and accessibility have led to the rapid development of clinical investigations to explore their autologous and allogeneic cellular-based regenerative potential, tissue preservation capabilities, anti-inflammatory properties, and anticancer properties, among others. hAMSCs are typically cultured under ambient conditions with 21% oxygen. However, physiologically, hAMSCs exist in an environment of much lower oxygen tension. Furthermore, hAMSCs cultured in standard conditions have shown limited proliferative and migratory capabilities, as well as limited viability. This study investigated the effects hypoxic culture conditions have on primary intraoperatively derived hAMSCs. hAMSCs cultured under hypoxia (hAMSCs-H) remained multipotent, capable of differentiation into osteogenic, chondrogenic, and adipogenic lineages. In addition, hAMSCs-H grew faster and exhibited less cell death. Furthermore, hAMSCs-H had greater motility than normoxia-cultured hAMSCs and exhibited greater homing ability to glioblastoma (GBM) derived from brain tumor-initiating cells from our patients in vitro and in vivo. Importantly, hAMSCs-H did not transform into tumor-associated fibroblasts in vitro and were not tumorigenic in vivo. Rather, hAMSCs-H promoted the differentiation of brain cancer cells in vitro and in vivo. These findings suggest an alternative culturing technique that can enhance the function of hAMSCs, which may be necessary for their use in the treatment of various pathologies including stroke, myocardial infarction, amyotrophic lateral sclerosis, and GBM.
- Published
- 2014
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39. Kruppel-like factor-9 (KLF9) inhibits glioblastoma stemness through global transcription repression and integrin α6 inhibition.
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Ying M, Tilghman J, Wei Y, Guerrero-Cazares H, Quinones-Hinojosa A, Ji H, and Laterra J
- Subjects
- Animals, Antibiotics, Antineoplastic pharmacology, Blotting, Western, Cell Differentiation drug effects, Cell Line, Tumor, Doxorubicin pharmacology, Glioblastoma metabolism, Glioblastoma pathology, Humans, Integrin alpha6 metabolism, Kruppel-Like Transcription Factors metabolism, Mice, SCID, Promoter Regions, Genetic genetics, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Tumor Burden genetics, Cell Differentiation genetics, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Integrin alpha6 genetics, Kruppel-Like Transcription Factors genetics
- Abstract
It is increasingly important to understand the molecular basis for the plasticity of neoplastic cells and their capacity to transition between differentiated and stemlike phenotypes. Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation, and neural development; however, the molecular basis for the diverse contextual functions of KLF9 remains unclear. This study focused on the functions of KLF9 in human glioblastoma stemlike cells. We established for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stemlike cells and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, showed that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation and identify KLF9-regulated molecular targets applicable to cancer therapeutics., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
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40. Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion.
- Author
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Abbadi S, Rodarte JJ, Abutaleb A, Lavell E, Smith CL, Ruff W, Schiller J, Olivi A, Levchenko A, Guerrero-Cazares H, and Quinones-Hinojosa A
- Subjects
- Animals, Astrocytes pathology, Brain Neoplasms enzymology, Cell Differentiation, Cell Line, Tumor, Cell Movement, Cell Survival, Gene Knockdown Techniques, Glioblastoma enzymology, Glycogen metabolism, Glycogen Phosphorylase metabolism, Glycogen Synthase metabolism, Glycolysis, Humans, Male, Mice, Nude, Neoplasm Invasiveness, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Phenotype, RNA, Small Interfering metabolism, Up-Regulation, Brain Neoplasms metabolism, Brain Neoplasms pathology, Glioblastoma metabolism, Glioblastoma pathology, Glucose-6-Phosphatase metabolism
- Abstract
Unlabelled: Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6-phosphatase (G6PC/G6Pase) expression is elevated in GBM when compared with normal brain. Human-derived brain tumor-initiating cells (BTIC) use this enzyme to counteract glycolytic inhibition induced by 2-deoxy-d-glucose (2DG) and sustain malignant progression. Downregulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with promalignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target., Implications: This study is the first to demonstrate a functional relationship between the critical gluconeogenic and glycogenolytic enzyme G6PC with the metabolic adaptations during GBM invasion., (©2014 American Association for Cancer Research.)
- Published
- 2014
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41. HMMR maintains the stemness and tumorigenicity of glioblastoma stem-like cells.
- Author
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Tilghman J, Wu H, Sang Y, Shi X, Guerrero-Cazares H, Quinones-Hinojosa A, Eberhart CG, Laterra J, and Ying M
- Subjects
- Animals, Carcinogenesis genetics, Cell Growth Processes physiology, Cell Line, Tumor, Extracellular Matrix Proteins genetics, Glioblastoma genetics, Humans, Hyaluronan Receptors genetics, Mice, Mice, SCID, Carcinogenesis metabolism, Carcinogenesis pathology, Extracellular Matrix Proteins metabolism, Glioblastoma metabolism, Glioblastoma pathology, Hyaluronan Receptors metabolism, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology
- Abstract
Glioblastoma (GBM) stem cells (GSC) are a subpopulation of tumor cells that display stem-like characteristics (stemness) and play unique roles in tumor propagation, therapeutic resistance, and tumor recurrence. Therapeutic targets in GSCs are a focus of increasing interest to improve GBM therapy. Here we report that the hyaluronan-mediated motility receptor (HMMR) is highly expressed in GBM tumors, where it supports the self-renewal and tumorigenic potential of GSCs. HMMR silencing impairs GSC self-renewal and inhibits the expression of GSC markers and regulators. Furthermore, HMMR silencing suppresses GSC-derived tumor growth and extends the survival of mice bearing GSC xenografts. Conversely, HMMR overexpression promotes GSC self-renewal and intracranial tumor propagation. In human GBM tumor specimens, HMMR expression is correlated positively with the expression of stemness-associated markers and regulators. Our findings identify HMMR as a candidate therapeutic target to GSCs as a GBM treatment strategy., (©2014 American Association for Cancer Research.)
- Published
- 2014
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42. Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival.
- Author
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Li Q, Wijesekera O, Salas SJ, Wang JY, Zhu M, Aprhys C, Chaichana KL, Chesler DA, Zhang H, Smith CL, Guerrero-Cazares H, Levchenko A, and Quinones-Hinojosa A
- Subjects
- Animals, Bone Morphogenetic Protein 4 genetics, Brain Neoplasms mortality, Brain Neoplasms therapy, Cell Differentiation genetics, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation, Disease Models, Animal, Humans, Mesenchymal Stem Cells cytology, Mice, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Transduction, Genetic, Xenograft Model Antitumor Assays, Adipocytes cytology, Bone Morphogenetic Protein 4 biosynthesis, Brain Neoplasms pathology, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism
- Abstract
Purpose: Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor-initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma., Experimental Design: The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model., Results: hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe., Conclusions: Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma., (©2014 AACR.)
- Published
- 2014
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43. Age-related changes in astrocytic and ependymal cells of the subventricular zone.
- Author
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Capilla-Gonzalez V, Cebrian-Silla A, Guerrero-Cazares H, Garcia-Verdugo JM, and Quiñones-Hinojosa A
- Subjects
- Animals, Astrocytes ultrastructure, Cell Differentiation physiology, Cell Proliferation, Ependyma ultrastructure, Lateral Ventricles ultrastructure, Male, Mice, Mice, Inbred C57BL, Neural Stem Cells physiology, Neural Stem Cells ultrastructure, Neurogenesis physiology, Aging physiology, Astrocytes physiology, Ependyma cytology, Ependyma physiology, Lateral Ventricles cytology, Lateral Ventricles physiology
- Abstract
Neurogenesis persists in the adult subventricular zone (SVZ) of the mammalian brain. During aging, the SVZ neurogenic capacity undergoes a progressive decline, which is attributed to a decrease in the population of neural stem cells (NSCs). However, the behavior of the NSCs that remain in the aged brain is not fully understood. Here we performed a comparative ultrastructural study of the SVZ niche of 2-month-old and 24-month-old male C57BL/6 mice, focusing on the NSC population. Using thymidine-labeling, we showed that residual NSCs in the aged SVZ divide less frequently than those in young mice. We also provided evidence that ependymal cells are not newly generated during senescence, as others studies suggest. Remarkably, both astrocytes and ependymal cells accumulated a high number of intermediate filaments and dense bodies during aging, resembling reactive cells. A better understanding of the changes occurring in the neurogenic niche during aging will allow us to develop new strategies for fighting neurological disorders linked to senescence.
- Published
- 2014
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44. Influence of basement membrane proteins and endothelial cell-derived factors on the morphology of human fetal-derived astrocytes in 2D.
- Author
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Levy AF, Zayats M, Guerrero-Cazares H, Quiñones-Hinojosa A, and Searson PC
- Subjects
- Animals, Astrocytes metabolism, Cells, Cultured, Extracellular Matrix metabolism, Humans, Rats, Solubility, Astrocytes cytology, Basement Membrane metabolism, Cell Shape, Endothelial Cells metabolism, Fetus cytology, Membrane Proteins metabolism
- Abstract
Astrocytes are the most prevalent type of glial cell in the brain, participating in a variety of diverse functions from regulating cerebral blood flow to controlling synapse formation. Astrocytes and astrocyte-conditioned media are widely used in models of the blood-brain barrier (BBB), however, very little is known about astrocyte culture in 2D. To test the hypothesis that surface coating and soluble factors influence astrocyte morphology in 2D, we quantitatively analyzed the morphology of human fetal derived astrocytes on glass, matrigel, fibronectin, collagen IV, and collagen I, and after the addition soluble factors including platelet-derived growth factor (PDGF), laminin, basic fibroblast growth factor (bFGF), and leukemia inhibitory factor (LIF). Matrigel surface coatings, as well as addition of leukemia inhibitory factor (LIF) to the media, were found to have the strongest effects on 2D astrocyte morphology, and may be important in improving existing BBB models. In addition, the novel set of quantitative parameters proposed in this paper provide a test for determining the influence of compounds on astrocyte morphology, both to screen for new endothelial cell-secreted factors that influence astrocytes, and to determine in a high-throughput way which factors are important for translation to more complex, 3D BBB models.
- Published
- 2014
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45. The subventricular zone is able to respond to a demyelinating lesion after localized radiation.
- Author
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Capilla-Gonzalez V, Guerrero-Cazares H, Bonsu JM, Gonzalez-Perez O, Achanta P, Wong J, Garcia-Verdugo JM, and Quiñones-Hinojosa A
- Subjects
- Animals, Cell Differentiation physiology, Cell Differentiation radiation effects, Cell Movement physiology, Cell Movement radiation effects, Cell Proliferation, Cerebral Ventricles metabolism, Cerebral Ventricles pathology, Demyelinating Diseases pathology, Humans, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Neural Stem Cells cytology, Cerebral Ventricles radiation effects, Demyelinating Diseases metabolism, Neural Stem Cells radiation effects
- Abstract
Radiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer., (Copyright © 2013 AlphaMed Press.)
- Published
- 2014
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46. The generation of oligodendroglial cells is preserved in the rostral migratory stream during aging.
- Author
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Capilla-Gonzalez V, Cebrian-Silla A, Guerrero-Cazares H, Garcia-Verdugo JM, and Quiñones-Hinojosa A
- Abstract
The subventricular zone (SVZ) is the largest source of newly generated cells in the adult mammalian brain. SVZ-derived neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into mature neurons. Additionally, a small proportion of SVZ-derived cells contribute to the generation of myelinating oligodendrocytes. The production of new cells in the SVZ decreases during aging, affecting the incorporation of new neurons into the OB. However, the age-related changes that occur across the RMS are not fully understood. In this study we evaluate how aging affects the cellular organization of migrating neuroblast chains, the proliferation, and the fate of the newly generated cells in the SVZ-OB system. By using electron microscopy and immunostaining, we found that the RMS path becomes discontinuous and its cytoarchitecture is disorganized in aged mice (24-month-old mice). Subsequently, OB neurogenesis was impaired in the aged brain while the production of oligodendrocytes was not compromised. These findings provide new insight into oligodendrocyte preservation throughout life. Further exploration of this matter could help the development of new strategies to prevent neurological disorders associated with senescence.
- Published
- 2013
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47. Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection.
- Author
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Chen L, Guerrero-Cazares H, Ye X, Ford E, McNutt T, Kleinberg L, Lim M, Chaichana K, Quinones-Hinojosa A, and Redmond K
- Subjects
- Adult, Aged, Aged, 80 and over, Analysis of Variance, Antineoplastic Agents, Alkylating therapeutic use, Brain Neoplasms mortality, Brain Neoplasms surgery, Cerebral Ventricles, Dacarbazine analogs & derivatives, Dacarbazine therapeutic use, Disease-Free Survival, Female, Glioblastoma mortality, Glioblastoma surgery, Humans, Karnofsky Performance Status, Male, Middle Aged, Radiotherapy Dosage, Radiotherapy, Adjuvant, Radiotherapy, Intensity-Modulated, Temozolomide, Brain Neoplasms radiotherapy, Glioblastoma radiotherapy
- Abstract
Purpose: Neural progenitor cells in the subventricular zone (SVZ) have a controversial role in glioblastoma multiforme (GBM) as potential tumor-initiating cells. The purpose of this study was to examine the relationship between radiation dose to the SVZ and survival in GBM patients., Methods and Materials: The study included 116 patients with primary GBM treated at the Johns Hopkins Hospital between 2006 and 2009. All patients underwent surgical resection followed by adjuvant radiation therapy with intensity modulated radiation therapy (60 Gy/30 fractions) and concomitant temozolomide. Ipsilateral, contralateral, and bilateral SVZs were contoured on treatment plans by use of coregistered magnetic resonance imaging and computed tomography. Multivariate Cox regression was used to examine the relationship between mean SVZ dose and progression-free survival (PFS), as well as overall survival (OS). Age, Karnofsky Performance Status score, and extent of resection were used as covariates. The median age was 58 years (range, 29-80 years)., Results: Of the patients, 12% underwent biopsy, 53% had subtotal resection (STR), and 35% had gross total resection (GTR). The Karnofsky Performance Status score was less than 90 in 54 patients and was 90 or greater in 62 patients. The median ipsilateral, contralateral, and bilateral mean SVZ doses were 48.7 Gy, 34.4 Gy, and 41.5 Gy, respectively. Among patients who underwent GTR, a mean ipsilateral SVZ dose of 40 Gy or greater was associated with a significantly improved PFS compared with patients who received less than 40 Gy (15.1 months vs 10.3 months; P=.028; hazard ratio, 0.385 [95% confidence interval, 0.165-0.901]) but not in patients undergoing STR or biopsy. The subgroup of GTR patients who received an ipsilateral dose of 40 Gy or greater also had a significantly improved OS (17.5 months vs 15.6 months; P=.027; hazard ratio, 0.385 [95% confidence interval, 0.165-0.895]). No association was found between SVZ radiation dose and PFS and OS among patients who underwent STR or biopsy., Conclusion: A mean radiation dose of 40 Gy or greater to the ipsilateral SVZ was associated with a significantly improved PFS and OS in patients with GBM after GTR., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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48. Mesenchymal stem cells derived from adipose tissue vs bone marrow: in vitro comparison of their tropism towards gliomas.
- Author
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Pendleton C, Li Q, Chesler DA, Yuan K, Guerrero-Cazares H, and Quinones-Hinojosa A
- Subjects
- Adipose Tissue pathology, Bone Marrow Cells pathology, Cell Line, Coculture Techniques, Female, Glioma pathology, Humans, Male, Mesenchymal Stem Cells pathology, Organ Specificity, Adipose Tissue metabolism, Bone Marrow Cells metabolism, Cell Differentiation, Cell Movement, Glioma metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Introduction: Glioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma., Methods: Under an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures., Results: Commercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines., Conclusions: Adipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting.
- Published
- 2013
- Full Text
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49. Stem cells in gliomas.
- Author
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Guerrero-Cazares H, Attenello FJ, Noiman L, and Quiñones-Hinojosa A
- Subjects
- Animals, Glioma classification, Humans, Magnetic Resonance Imaging, Models, Biological, Cerebral Ventricles pathology, Glioma pathology, Neoplastic Stem Cells physiology
- Published
- 2012
- Full Text
- View/download PDF
50. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.
- Author
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Garzon-Muvdi T, Schiapparelli P, ap Rhys C, Guerrero-Cazares H, Smith C, Kim DH, Kone L, Farber H, Lee DY, An SS, Levchenko A, and Quiñones-Hinojosa A
- Subjects
- Amino Acid Sequence, Animals, Brain Neoplasms metabolism, Bumetanide pharmacology, Cell Size, Cloning, Molecular, Fluorescent Antibody Technique, Focal Adhesions metabolism, Gene Knockdown Techniques, Genetic Vectors genetics, Genetic Vectors metabolism, Glioma metabolism, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, HEK293 Cells, Humans, Male, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Sodium-Potassium-Chloride Symporters genetics, Solute Carrier Family 12, Member 2, Brain Neoplasms pathology, Cell Movement, Focal Adhesions pathology, Gene Expression Regulation, Neoplastic, Glioma pathology, Sodium-Potassium-Chloride Symporters metabolism
- Abstract
Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2012
- Full Text
- View/download PDF
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