scholarly journals Fibrinogen in the glioblastoma microenvironment contributes to the invasiveness of brain tumor‐initiating cells

2021 ◽  
Author(s):  
Lauren Dzikowski ◽  
Reza Mirzaei ◽  
Susobhan Sarkar ◽  
Mehul Kumar ◽  
Pinaki Bose ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Initiating Cells ◽  
Brain Tumor Initiating Cells

scholarly journals ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

2021 ◽  
Vol 11 (2) ◽  
pp. 125
Author(s):  
Melis Savasan Sogut ◽  
Chitra Venugopal ◽  
Basak Kandemir ◽  
Ugur Dag ◽  
Sujeivan Mahendram ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Brain Tumor ◽  
Brain Tumors ◽  
System Development ◽  
Nervous System Development ◽  
Stem Cell Population ◽  
Tumor Initiating Cells ◽  
Specific Domain ◽  
Brain Tumor Initiating Cells ◽  
Ets Domain

Elk-1, a member of the ternary complex factors (TCFs) within the ETS (E26 transformation-specific) domain superfamily, is a transcription factor implicated in neuroprotection, neurodegeneration, and brain tumor proliferation. Except for known targets, c-fos and egr-1, few targets of Elk-1 have been identified. Interestingly, SMN, SOD1, and PSEN1 promoters were shown to be regulated by Elk-1. On the other hand, Elk-1 was shown to regulate the CD133 gene, which is highly expressed in brain-tumor-initiating cells (BTICs) and used as a marker for separating this cancer stem cell population. In this study, we have carried out microarray analysis in SH-SY5Y cells overexpressing Elk-1-VP16, which has revealed a large number of genes significantly regulated by Elk-1 that function in nervous system development, embryonic development, pluripotency, apoptosis, survival, and proliferation. Among these, we have shown that genes related to pluripotency, such as Sox2, Nanog, and Oct4, were indeed regulated by Elk-1, and in the context of brain tumors, we further showed that Elk-1 overexpression in CD133+ BTIC population results in the upregulation of these genes. When Elk-1 expression is silenced, the expression of these stemness genes is decreased. We propose that Elk-1 is a transcription factor upstream of these genes, regulating the self-renewal of CD133+ BTICs.

scholarly journals CS-14 * NEUROTROPHIN RECEPTORS TrkB AND TrkC ARE REQUIRED FOR SURVIVAL OF BRAIN TUMOR INITIATING CELLS

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v54-v54
Author(s):  
R. Kenchappa ◽  
S. Lawn ◽  
N. Krishna ◽  
X. Qu ◽  
D. Fenstermacher ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Neurotrophin Receptors ◽  
Tumor Initiating Cells ◽  
Brain Tumor Initiating Cells

scholarly journals Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

2017 ◽  
Vol 114 (30) ◽  
pp. E6147-E6156 ◽  
Author(s):  
Dou Yu ◽  
Omar F. Khan ◽  
Mario L. Suvà ◽  
Biqin Dong ◽  
Wojciech K. Panek ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Therapeutic Potential ◽  
Therapy Resistance ◽  
Tumor Initiating Cells ◽  
Convection Enhanced Delivery ◽  
Individual Gene ◽  
Brain Tumor Initiating Cells ◽  
Novel Therapeutic Strategies

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

scholarly journals Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Susobhan Sarkar ◽  
Candice C. Poon ◽  
Reza Mirzaei ◽  
Khalil S. Rawji ◽  
Walter Hader ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Human Brain ◽  
Tumor Initiating Cells ◽  
Human Brain Tumor ◽  
Brain Tumor Initiating Cells

scholarly journals The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells

2018 ◽  
Vol 1869 (2) ◽  
pp. 175-188 ◽  
Author(s):  
Catherine J. Libby ◽  
Anh Nhat Tran ◽  
Sarah E. Scott ◽  
Corinne Griguer ◽  
Anita B. Hjelmeland
Keyword(s):  
Brain Tumor ◽  
Tumor Initiating Cells ◽  
Metabolic Alterations ◽  
Brain Tumor Initiating Cells

scholarly journals Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

2018 ◽  
Vol 115 (22) ◽  
pp. E5086-E5095 ◽  
Author(s):  
Liang Xu ◽  
Ye Chen ◽  
Anand Mayakonda ◽  
Lynnette Koh ◽  
Yuk Kien Chong ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Acquired Resistance ◽  
Transcriptional Network ◽  
Next Generation ◽  
Transcriptional Program ◽  
Tumor Initiating Cells ◽  
Self Renewal ◽  
Brain Tumor Initiating Cells ◽  
Bet Protein

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

scholarly journals Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

2014 ◽  
Vol 20 (22) ◽  
pp. 5756-5767 ◽  
Author(s):  
H. Artee Luchman ◽  
Owen D.M. Stechishin ◽  
Stephanie A. Nguyen ◽  
Xueqing Q. Lun ◽  
J. Gregory Cairncross ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Initiating Cells ◽  
Orthotopic Xenograft ◽  
Brain Tumor Initiating Cells

scholarly journals Functional Characterization of Brain Tumor-Initiating Cells: Implications for Preclinical Models and Drug Development

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Cesar A Garcia ◽  
Adip Guruprasad Bhargav ◽  
Sujan K Mondal ◽  
Karim ReFaey ◽  
Natanael Zarco ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Critical Role ◽  
Functional Characterization ◽  
Tumor Initiating Cells ◽  
Retroviral Transduction ◽  
Significant Difference ◽  
Brain Tumor Initiating Cells ◽  
Functional Features

Abstract INTRODUCTION Glioblastoma (GBM) is the deadliest and most common primary brain cancer in adults. Brain tumor-initiating cells (BTICs) are a heterogeneous subset of stem-like, invasive cells that play a critical role in treatment failure and recurrence. METHODS Here, we propose a system to functionally characterize patient-derived BTICs to identify features that will guide assessment of therapeutics in a BTIC subpopulation-specific manner. We established and evaluated 5 BTIC populations based on (1) proliferation, (2) stemness, (3) migration, (4) tumorigenesis, (5) clinical characteristics, and (6) therapeutic sensitivity. RESULTS Overall, in Vitro growth trends reflected in Vivo growth rates. However, a significant difference was found between tumor growth in male versus female mice in 3 BTIC lines (QNS108 P = .0011; QNS120 P < .0001; QNS 140 P < .0001). Differences in survival were observed, where BTICs derived from male and female patients produced faster morbidity in mice of the opposite sex (male derived QNS108 male vs female P = .0039; female derived QNS203 male vs female P = .029). QNS203, which was isolated from a tumor in contact with the anterior subventricular zone, decreased survival at a faster rate compared to other cell lines (n = 10 per line, 5 males/5 females, P < .0001). Stem-like properties of BTICs were assessed via differentiation marker expression, sphere-forming capacity, and detection of canonical marker CD133. Higher CD133 expression correlated with faster in Vitro doubling time and greater tumor burden. Histology reflected similar patient tumor features such as migration across the corpus callosum and cystic formation. BTICs revealed varying responses to therapies (TMZ, Radiation, TRAIL, BMP4) and varied competence to retroviral transduction. CONCLUSION By studying the functional features of BTICs within our model of GBM heterogeneity, it was shown that several factors influenced tumorigenesis and survival. These included original tumor location, stemness, variation in therapeutic sensitivity, and a critical finding for the role of sex, an unexplored area for creating next-generation, sex-specific, and BTIC-specific therapeutics.

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