scholarly journals In Vivo Generation of Neural Tumors from Neoplastic Pluripotent Stem Cells Models Early Human Pediatric Brain Tumor Formation

Stem Cells ◽  
2012 ◽  
Vol 30 (3) ◽  
pp. 392-404 ◽  
Author(s):  
Tamra E. Werbowetski-Ogilvie ◽  
Ludivine Coudière Morrison ◽  
Aline Fiebig-Comyn ◽  
Mickie Bhatia
Keyword(s):  
Stem Cells ◽  
Brain Tumor ◽  
Pluripotent Stem Cells ◽  
Pediatric Brain Tumor ◽  
Tumor Formation ◽  
Pediatric Brain ◽  
Early Human

Diffuse reflectance spectroscopy for in vivo pediatric brain tumor detection

2010 ◽  
Vol 15 (6) ◽  
pp. 061709 ◽  
Author(s):  
Wei-Chiang Lin ◽  
David I. Sandberg ◽  
Sanjiv Bhatia ◽  
Mahlon Johnson ◽  
Sanghoon Oh ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Diffuse Reflectance ◽  
Diffuse Reflectance Spectroscopy ◽  
Pediatric Brain Tumor ◽  
Tumor Detection ◽  
Reflectance Spectroscopy ◽  
Pediatric Brain

scholarly journals Inhibition of Heparanase in Pediatric Brain Tumor Cells Attenuates their Proliferation, Invasive Capacity, and In Vivo Tumor Growth

2017 ◽  
Vol 16 (8) ◽  
pp. 1705-1716 ◽  
Author(s):  
Argyris Spyrou ◽  
Soumi Kundu ◽  
Lulu Haseeb ◽  
Di Yu ◽  
Tommie Olofsson ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Pediatric Brain Tumor ◽  
Brain Tumor Cells ◽  
Invasive Capacity ◽  
Pediatric Brain

scholarly journals Preclinical Models of Pediatric Brain Tumors—Forging Ahead

2018 ◽  
Vol 5 (4) ◽  
pp. 81 ◽  
Author(s):  
Tara Dobson ◽  
Vidya Gopalakrishnan
Keyword(s):  
Brain Tumor ◽  
Cognitive Abilities ◽  
Pediatric Brain Tumor ◽  
Economic Incentives ◽  
Molecular Heterogeneity ◽  
Tumor Models ◽  
Preclinical Research ◽  
Pediatric Brain

Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for a lifetime of limited physical, psychological, and cognitive abilities. Despite much effort, not one drug exists that was designed specifically for pediatric patients. Stagnant government funding and the lack of economic incentives for the pharmaceutical industry greatly limits preclinical research and the development of clinically applicable pediatric brain tumor models. As more data are collected, the recognition of disease sub-groups based on molecular heterogeneity increases the need for designing specific models suitable for predictive drug screening. To overcome these challenges, preclinical approaches will need continual enhancement. In this review, we examine the advantages and shortcomings of in vitro and in vivo preclinical pediatric brain tumor models and explore potential solutions based on past, present, and future strategies for improving their clinical relevancy.

scholarly journals Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

2010 ◽  
Vol 13 (1) ◽  
pp. 70-83 ◽  
Author(s):  
D. Hussein ◽  
W. Punjaruk ◽  
L. C. D. Storer ◽  
L. Shaw ◽  
R. T. Othman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Repair ◽  
Brain Tumor ◽  
Cancer Stem Cells ◽  
Pediatric Brain Tumor ◽  
Cell Cycle Dynamics ◽  
Pediatric Brain

scholarly journals TMOD-30. IDENTIFYING NEW DRIVERS OF GROUP 3 MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii234-ii234
Author(s):  
Meher Beigi Masihi ◽  
Catherine Lee ◽  
Alexandra Garancher ◽  
Grace Furnari ◽  
Robert Wechsler-Reya
Keyword(s):  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pediatric Brain Tumor ◽  
Genetic Alterations ◽  
Sleeping Beauty ◽  
Tumor Formation ◽  
Group 3

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. MB can be divided into four major subgroups – WNT, Sonic hedgehog (SHH), Group 3 (G3-MB), and Group 4 (G4-MB) – that exhibit distinct genetic alterations, gene expression profiles, and clinical outcomes. Patients with G3-MB have the worst prognosis, and a deeper understanding of this form of the disease is critical for development of new therapies. Most G3-MBs express high levels of the MYC oncogene, suggesting that MYC plays an important role in tumorigenesis. However, MYC overexpression is not sufficient to drive tumor formation. To identify genes that cooperate with MYC to promote development of G3-MB, we performed an in vivo mutagenesis screen using mice expressing the Sleeping Beauty (SB) transposon. Cerebellar stem cells isolated from transposon/transposase-expressing transgenic mice were infected with viruses encoding Myc, and these cells were transplanted into the cerebellum of adult hosts. Tumors that arose were subjected to DNA and RNA sequencing to identify candidate genes, and these genes were subjected to functional analysis to determine whether they could cooperate with Myc to drive G3-MB. These studies identified the transcription factor Ras-responsive element binding protein 1 (Rreb1) as a potent Myc-cooperating gene. Tumors driven by Myc and Rreb1 (MR tumors) resemble G3-MB at a histological and molecular level. Moreover, RREB1 is overexpressed in human G3-MB, and knockdown of RREB1 expression impairs growth of G3-MB cell lines and patient-derived xenografts. Ongoing studies are aimed at identifying the molecular mechanisms by which Rreb1 contributes to tumor growth. Our studies demonstrate an important role for RREB1 in G3-MB, and provide a new model that can be used to identify therapeutic targets and develop more effective and less toxic therapies for this devastating pediatric brain tumor.

scholarly journals Murine pluripotent stem cells that escape differentiation inside teratomas maintain pluripotency

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4177
Author(s):  
Yangli Pei ◽  
Liang Yue ◽  
Wei Zhang ◽  
Jinzhu Xiang ◽  
Zhu Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Cells ◽  
Pluripotent Stem Cells ◽  
Fluorescent Protein ◽  
Embryonic Stem ◽  
Tumor Formation ◽  
Immunofluorescent Staining ◽  
Pluripotent Cells ◽  
Teratoma Formation

Background Pluripotent stem cells (PSCs) offer immense potential as a source for regenerative therapies. The teratoma assay is widely used in the field of stem cells and regenerative medicine, but the cell composition of teratoma is still elusive. Methods We utilized PSCs expressing enhanced green fluorescent protein (EGFP) under the control of the Pou5f1 promoter to study the persistence of potential pluripotent cells during teratoma formation in vivo. OCT4-MES (mouse embryonic stem cells) were isolated from the blastocysts of 3.5-day OCT4-EGFP mice (transgenic mice express EGFP cDNA under the control of the Pou5f1 promoter) embryos, and TG iPS 1-7 (induced pluripotent stem cells) were generated from mouse embryonic fibroblasts (MEFs) from 13.5-day OCT4-EGFP mice embryos by infecting them with a virus carrying OCT4, SOX2, KLF4 and c-MYC. These pluripotent cells were characterized according to their morphology and expression of pluripotency markers. Their differentiation ability was studied with in vivo teratoma formation assays. Further differences between pluripotent cells were examined by real-time quantitative PCR (qPCR). Results The results showed that several OCT4-expressing PSCs escaped differentiation inside of teratomas, and these escaped cells (MES-FT, GFP-positive cells separated from OCT4-MES-derived teratomas; and iPS-FT, GFP-positive cells obtained from teratomas formed by TG iPS 1-7) retained their pluripotency. Interestingly, a small number of GFP-positive cells in teratomas formed by MES-FT and iPS-FT (MES-ST, GFP-positive cells isolated from MES-FT-derived teratomas; iPS-ST, GFP-positive cells obtained from teratomas formed by iPS-FT) were still pluripotent, as shown by alkaline phosphatase (AP) staining, immunofluorescent staining and PCR. MES-FT, iPS-FT, MES-ST and iPS-ST cells also expressed several markers associated with germ cell formation, such as Dazl, Stella and Stra8. Conclusions In summary, a small number of PSCs escaped differentiation inside of teratomas, and these cells maintained pluripotency and partially developed towards germ cells. Both escaped PSCs and germ cells present a risk of tumor formation. Therefore, medical workers must be careful in preventing tumor formation when stem cells are used to treat specific diseases.

scholarly journals Murine pluripotent stem cells that escape differentiation inside teratomas maintain pluripotency

2017 ◽  
Author(s):  
Yangli Pei ◽  
Liang Yue ◽  
Wei Zhang ◽  
Jinzhu Xiang ◽  
Zhu Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Cells ◽  
Pluripotent Stem Cells ◽  
Fluorescent Protein ◽  
Embryonic Stem ◽  
Tumor Formation ◽  
Immunofluorescent Staining ◽  
Pluripotent Cells ◽  
Teratoma Formation

Background. Pluripotent stem cells (PSCs) offer immense potential as a source for regenerative therapies. The teratoma assay is widely used in the field of stem cells and regenerative medicine, but the cell composition of teratoma is still elusive. Methods. We utilized PSCs expressing enhanced green fluorescent protein (EGFP) under the control of the Pou5f1 promoter to study the persistence of potential pluripotent cells during teratoma formation in vivo. OCT4-MES (mouse embryonic stem cells) were isolated from the blastocysts of 3.5-day OCT4-EGFP mice (transgenic mice express EGFP cDNA under the control of the Pou5f1 promoter) embryos, and TG iPS 1-7 (induced pluripotent stem cells) were generated from mouse embryonic fibroblasts (MEFs) from 13.5-day OCT4-EGFP mice embryos by infecting them with a virus carrying OCT4, SOX2, KLF4 and c-MYC. These pluripotent cells were characterized according to their morphology and expression of pluripotency markers. Their differentiation ability was studied with in vivo teratoma formation assays. Further differences between pluripotent cells were examined by real-time quantitative PCR (qPCR). Results. The results showed that s everal OCT4-expressing PSCs escaped differentiation inside of teratomas, and these escaped cells (MES-FT, GFP-positive cells separated from OCT4-MES-derived teratomas; and iPS-FT, GFP-positive cells obtained from teratomas formed by TG iPS 1-7) retained their pluripotency. Interestingly, a small number of GFP-positive cells in teratomas formed by MES-FT and iPS-FT ( MES-ST, GFP-positive cells isolated from MES-FT-derived teratomas; iPS-ST, GFP-positive cells obtained from teratomas formed by iPS-FT ) were still pluripotent, as shown by alkaline phosphatase (AP) staining, immunofluorescent staining and PCR. MES-FT, iPS-FT, MES-ST and iPS-ST cells also expressed several markers associated with germ cell formation, such as Dazl, Stella and Stra8. Conclusions. In summary, a small number of PSCs escaped differentiation inside of teratomas , and these cells maintained pluripotency and partially developed towards germ cells. Both escaped PSCs and germ cells present a risk of tumor formation. Therefore, medical workers must be careful in preventing tumor formation when stem cells are used to treat specific diseases.

Survival and Differentiation of Adenovirus-Generated Induced Pluripotent Stem Cells Transplanted into the Rat Striatum

2014 ◽  
Vol 23 (11) ◽  
pp. 1407-1423 ◽  
Author(s):  
Kyle D. Fink ◽  
Julien Rossignol ◽  
Ming Lu ◽  
Xavier Lévêque ◽  
Travis D. Hulse ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryonic Stem ◽  
Tumor Formation ◽  
Rat Striatum ◽  
Tail Tip ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) offer certain advantages over embryonic stem cells in cell replacement therapy for a variety of neurological disorders. However, reliable procedures, whereby transplanted iPSCs can survive and differentiate into functional neurons, without forming tumors, have yet to be devised. Currently, retroviral or lentiviral reprogramming methods are often used to reprogram somatic cells. Although the use of these viruses has proven to be effective, formation of tumors often results following in vivo transplantation, possibly due to the integration of the reprogramming genes. The goal of the current study was to develop a new approach, using an adenovirus for reprogramming cells, characterize the iPSCs in vitro, and test their safety, survivability, and ability to differentiate into region-appropriate neurons following transplantation into the rat brain. To this end, iPSCs were derived from bone marrow-derived mesenchymal stem cells and tail-tip fibroblasts using a single cassette lentivirus or a combination of adenoviruses. The reprogramming efficiency and levels of pluripotency were compared using immunocytochemistry, flow cytometry, and real-time polymerase chain reaction. Our data indicate that adenovirus-generated iPSCs from tail-tip fibroblasts are as efficient as the method we used for lentiviral reprogramming. All generated iPSCs were also capable of differentiating into neuronal-like cells in vitro. To test the in vivo survivability and the ability to differentiate into region-specific neurons in the absence of tumor formation, 400,000 of the iPSCs derived from tail-tip fibroblasts that were transfected with the adenovirus pair were transplanted into the striatum of adult, immune-competent rats. We observed that these iPSCs produced region-specific neuronal phenotypes, in the absence of tumor formation, at 90 days posttransplantation. These results suggest that adenovirus-generated iPSCs may provide a safe and viable means for neuronal replacement therapies.

scholarly journals In Vivo and Ex Vivo Pediatric Brain Tumor Models: An Overview

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiqin Li ◽  
Sigrid A. Langhans
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Drug Development ◽  
Pediatric Brain Tumor ◽  
Genetic Alterations ◽  
Benign Tumors ◽  
Tumor Type ◽  
Tumor Models ◽  
Pediatric Brain

After leukemia, tumors of the brain and spine are the second most common form of cancer in children. Despite advances in treatment, brain tumors remain a leading cause of death in pediatric cancer patients and survivors often suffer from life-long consequences of side effects of therapy. The 5-year survival rates, however, vary widely by tumor type, ranging from over 90% in more benign tumors to as low as 20% in the most aggressive forms such as glioblastoma. Even within historically defined tumor types such as medulloblastoma, molecular analysis identified biologically heterogeneous subgroups each with different genetic alterations, age of onset and prognosis. Besides molecularly driven patient stratification to tailor disease risk to therapy intensity, such a diversity demonstrates the need for more precise and disease-relevant pediatric brain cancer models for research and drug development. Here we give an overview of currently available in vitro and in vivo pediatric brain tumor models and discuss the opportunities that new technologies such as 3D cultures and organoids that can bridge limitations posed by the simplicity of monolayer cultures and the complexity of in vivo models, bring to accommodate better precision in drug development for pediatric brain tumors.

scholarly journals Murine pluripotent stem cells that escape differentiation inside teratomas maintain pluripotency

2017 ◽  
Author(s):  
Yangli Pei ◽  
Liang Yue ◽  
Wei Zhang ◽  
Jinzhu Xiang ◽  
Zhu Ma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Cells ◽  
Pluripotent Stem Cells ◽  
Fluorescent Protein ◽  
Embryonic Stem ◽  
Tumor Formation ◽  
Immunofluorescent Staining ◽  
Pluripotent Cells ◽  
Teratoma Formation

Background. Pluripotent stem cells (PSCs) offer immense potential as a source for regenerative therapies. The teratoma assay is widely used in the field of stem cells and regenerative medicine, but the cell composition of teratoma is still elusive. Methods. We utilized PSCs expressing enhanced green fluorescent protein (EGFP) under the control of the Pou5f1 promoter to study the persistence of potential pluripotent cells during teratoma formation in vivo. OCT4-MES (mouse embryonic stem cells) were isolated from the blastocysts of 3.5-day OCT4-EGFP mice (transgenic mice express EGFP cDNA under the control of the Pou5f1 promoter) embryos, and TG iPS 1-7 (induced pluripotent stem cells) were generated from mouse embryonic fibroblasts (MEFs) from 13.5-day OCT4-EGFP mice embryos by infecting them with a virus carrying OCT4, SOX2, KLF4 and c-MYC. These pluripotent cells were characterized according to their morphology and expression of pluripotency markers. Their differentiation ability was studied with in vivo teratoma formation assays. Further differences between pluripotent cells were examined by real-time quantitative PCR (qPCR). Results. The results showed that s everal OCT4-expressing PSCs escaped differentiation inside of teratomas, and these escaped cells (MES-FT, GFP-positive cells separated from OCT4-MES-derived teratomas; and iPS-FT, GFP-positive cells obtained from teratomas formed by TG iPS 1-7) retained their pluripotency. Interestingly, a small number of GFP-positive cells in teratomas formed by MES-FT and iPS-FT ( MES-ST, GFP-positive cells isolated from MES-FT-derived teratomas; iPS-ST, GFP-positive cells obtained from teratomas formed by iPS-FT ) were still pluripotent, as shown by alkaline phosphatase (AP) staining, immunofluorescent staining and PCR. MES-FT, iPS-FT, MES-ST and iPS-ST cells also expressed several markers associated with germ cell formation, such as Dazl, Stella and Stra8. Conclusions. In summary, a small number of PSCs escaped differentiation inside of teratomas , and these cells maintained pluripotency and partially developed towards germ cells. Both escaped PSCs and germ cells present a risk of tumor formation. Therefore, medical workers must be careful in preventing tumor formation when stem cells are used to treat specific diseases.

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