Neural Stem Cells of the Subventricular Zone as the Origin of Human Glioblastoma Stem Cells. Therapeutic Implications

Matarredona, Esperanza R.; Pastor, Ángel M.

doi:10.3389/fonc.2019.00779

Cited by 80 publications

(75 citation statements)

References 138 publications

(146 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glioblastoma, the most common brain cancer in humans, is one of the deadliest human cancers and is considered incurable, despite all efforts and aggressive treatment schemes [92]. Glioblastoma cells harbor numerous genetic aberrations, but the main driving force behind tumor progression and lethality is suggested to be the CSC-subpopulation [93]. The role of LSD1 in these cells has only recently been investigated and has turned out to be a critical one for their maintenance (Figure 2).…”

Section: Lds1 In Glioblastoma Stem Cellsmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

View full text Add to dashboard Cite

A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

show abstract

Section: Lds1 In Glioblastoma Stem Cellsmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

View full text Add to dashboard Cite

show abstract

“…The origin of GBM cells remains unclear. Some studies proposed that GBM was derived from the malignant transformation of neural progenitor cells (NPCs)/neural stem cells (NSCs) 49–51 . No matter what the precursor cells of GBM are, at the aspect of genome, they are normal diploid cells, whereas GBM cells are characterized by trisomy 7 and monosomy 10, as well as some other remarkable CNVs (amplification of EGFR, PDGFRA, MET, and deletion of CNKN2A, PTEN, etc.)…”

Section: Discussionmentioning

confidence: 99%

Genetic characterization of stem cell-like cancer cell in the peri-tumoral regions and proliferative lymphocyte in the peripheral blood of patients with glioblastoma

Yang

Huang

Guo

et al. 2020

Preprint

View full text Add to dashboard Cite

Recurrence is almost inevitable in glioblastoma (GBM) patients even after aggressive multimodal therapies. Most recurrences occur at the resection margin that is outside GBM's contrast-enhancing region (C region) of magnetic resonance imaging (MRI), and always left behind after surgery. Current knowledge about GBM cells outside C region is limited and thus impedes the post-operative therapy. In this study, single cell RNA-sequencing (scRNA-seq) was performed to dissect twelve GBM samples of C regions and outside C regions from four patients. We found a cluster of peculiar GBM cells outside C region different from the GBM cells with typical copy number variations (CNVs), which had only fragmental CNVs in chromosomes 1, 10, 11, 12 and 19, and were termed CNV 4 in this study. Furthermore, transcription factor-cofactor (TF-TCF) interaction network was constructed to uncover the transcriptional regulatory mechanism of GBM cells. The core signature of TF-TCF interaction network of CNV 4 GBM cells shows prognostic significance in GBM patients. Besides, sub-cluster of these peculiar GBM cells possess stem cell-like properties and have potential of tumorigenesis as revealed by in silico and in vitro analyses. To explore whether these peculiar GBM cells exist in the circulation of GBM patients, additional peripheral blood mononuclear cells (PBMC) samples from four GBM patients, three epilepsy patients and three healthy volunteers were analyzed by scRNA-seq. GBM cells were not found in PBMC, but peculiar proliferative immune cells were discovered in the PBMC of GBM patients but epilepsy patients and healthy volunteers. Collectively, these results indicated that peculiar GBM cells 3 outside C region are responsible for recurrence, and proliferative immune cells are specific to the PBMC of GBM patients. This study sheds light on the hidden and neglected parts of GBM, providing a new perspective to understand the nature of GBM recurrence, to develop monitoring strategy or promising immune therapy against GBM.Notably, most GBM cells of CNV patterns 1, 2 and 3 (77.44%, 95.73%, and 98.90%, respectively), whose CNVs were similar with classical GBM hallmarks, came from C regions, whereas GBM cells of CNV pattern 4 were found mainly in P and N regions (59.43% and 35.05%, respectively) (Chi-square test, P < 0.0001) ( Figure 1E). CNV patterns contribute to transcriptomic status of GBM cells in limited extent and show potential transitional relationshipsClassification of GBM cells according to CNV profiles was based on transcriptomic information, so we next analyzed the relationship between CNV patterns and transcriptomic sub-clusters. Totally, 6, 715 GBM cells were divided into 11 sub-clusters ( Figure 2A). Interestingly, sub-cluster 3 accounted for 93.93% of CNV pattern 3, and sub-cluster 5 accounted for 94.31% of CNV pattern 2, while CNV pattern 1 and 4 were made up of diverse sub-clusters in relatively balanced role in four CNV patterns, and MYC in CNV patterns 2, 3 and 4, while TP53 and E2F1 were specific to CNV pattern 1, SMAD2 s...

show abstract

“…Substantial evidence suggests that GSCs originate from NSCs that undergo malignant transformation and migrate from subventricular zone (SVZ) to distant regions of the brain (9)(10)(11). In accordance with this hypothesis, GSCs share many features with NSCs of the SVZ, like high proliferative and migration potential, association with vasculature and reciprocal communication with perivascular niche (12). Interestingly, key signaling pathways responsible for NSC maintenance, proliferation, differentiation and migration, like EGFR, PDGFR, p53 or PTEN, are frequently altered in GBM.…”

Section: Introductionmentioning

confidence: 88%

Potential Therapeutic Effects of the Neural Stem Cell-Targeting Antibody Nilo1 in Patient-Derived Glioblastoma Stem Cells

et al. 2020

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most devastating and least treatable brain tumor with median survival <15 months and extremely high recurrence rates. Promising results of immune checkpoint blockade obtained from pre-clinical studies in mice did not translate to clinic, and new strategies are urgently needed, particularly those targeting GBM stem cells (GSCs) that are held responsible for drug resistance and tumor recurrence. Patientderived GSC cultures are critical for finding effective brain tumor therapies. Here, we investigated the ability of the recently described monoclonal antibody Nilo1 to specifically recognize GSCs isolated from GBM surgical samples. We employed five patient-derived GSC cultures with different stemness marker expression and differentiation potential, able to recapitulate original tumors when xenotransplanted in vivo. To answer whether Nilo1 has any functional effects in patient-derived GSCs lines, we treated the cells with Nilo1 in vitro and analyzed cell proliferation, cell cycle, apoptosis, sphere formation, as well as the expression of stem vs. differentiation markers. All tested GSCs stained positively for Nilo1, and the ability of Nilo1 to recognize GSCs strongly relied on their stem-like phenotype. Our results showed that a subset of patient-derived GSCs were sensitive to Nilo1 treatment. In three GSC lines Nilo1 triggered differentiation accompanied by the induction of p21. Most strikingly, in one GSC line Nilo1 completely abrogated self-renewal and led to Bax-associated apoptosis. Our data suggest that Nilo1 targets a molecule functionally relevant for stemness maintenance and pinpoint Nilo1 as a novel antibody-based therapeutical strategy to be used either alone or in combination with cytotoxic drugs for GSC targeting. Further pre-clinical studies are needed to validate the effectiveness of GSC-specific Nilo1 targeting in vivo.

show abstract

Neural Stem Cells of the Subventricular Zone as the Origin of Human Glioblastoma Stem Cells. Therapeutic Implications

Cited by 80 publications

References 138 publications

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Genetic characterization of stem cell-like cancer cell in the peri-tumoral regions and proliferative lymphocyte in the peripheral blood of patients with glioblastoma

Potential Therapeutic Effects of the Neural Stem Cell-Targeting Antibody Nilo1 in Patient-Derived Glioblastoma Stem Cells

Contact Info

Product

Resources

About