Insight Into T-ALL Leukaemia Initiating Cells, Clonal Evolution and Impact of Treatment In Vivo Using Immune-Compromised Mouse Model,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3577-3577
Author(s):  
Victoria J Weston ◽  
Tracey A Perry ◽  
Helen Roberts ◽  
Katie Brown ◽  
Shaun R Wilson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Rearrangement ◽  
Clonal Evolution ◽  
Human Cells ◽  
Stem Cell Markers ◽  
Drug Resistant ◽  
Cessation Of Treatment ◽  
Cd34 Positivity

Abstract Abstract 3577 T-ALL constitutes 15% of ALL in children, requires more aggressive treatment, and exhibits a 5 year cure rate of around 75%. Relapsed T-ALL has a dismal salvage rate. Understanding the leukaemic stem cells responsible for clonal evolution and the emergence of treatment resistance may facilitate the treatment. We used immuno-compromised NOD/Shi-scid/IL-2Rγnull (NOG) mice to study in vivo engraftment kinetics and clonal evolution of a SIL-TAL+ primary T-ALL. Initially, we compared the pre-injection immunophenotype with that after primary transplantation. While 18% of the pre-injection cells were CD34+, 14% of human cells (hCD45+) at termination of the first passage were CD34+. Although the leukaemia-specific TCRγ gene rearrangement was stable throughout, cells following transplantation exhibited greater resistance to vincristine in vitro indicating the emergence of drug resistant cells. We next engrafted cells from the primary recipient into a second cohort of mice and evaluated the impact of vincristine in vivo on leukaemic subpopulations in different organs. Four weeks post-injection, vincristine treatment (1mg/kg once weekly by IV injection) was initiated. Control animals from this time exhibited increasing spleen weight compared with vincristine-treated mice whose spleen sizes decreased throughout treatment. One week following initiation of vincristine treatment, cells from the control animals predominantly comprised of more mature CD34-CD7+CD5+CD3- or CD34-CD7-CD5+CD3- cells in the BM, liver and spleen as well as small populations of more immature CD34+CD7-CD5-CD3-, CD34+CD7+CD5-CD3-, CD34+CD7+CD5+CD3- cells. An hCD34+CD34-CD7-CD5-CD3- subpopulation was also evident in all organs. In contrast, vincristine-treated mice revealed a reduction in the proportions of CD34-CD7+CD5+CD3- and CD34-CD7-CD5+CD3- cells in all organs, with a concomitant increase in CD34+CD7-CD5-CD3-, CD34+CD7+CD5-CD3- and CD34+CD7+CD5+CD3- as well as a dramatic increase in the proportion of hCD45+CD34-CD7-CD5-CD3- cells. After 4 weeks following treatment-initiation, cells from the control mice again significantly comprised CD34-CD7+CD5+CD3- and, to a greater proportion than week 1, CD34-CD7-CD5+CD3- cells. The proportion of hCD45+CD34-CD7-CD5-CD3- cells was also slightly elevated in all organs compared with week 1. The TCRγ gene rearrangement was easily detectable. In contrast, residual cells from the organs of vincristine-treated animals almost entirely comprised hCD45+CD34-CD7-CD5-CD3- and no TCRγ gene rearrangement could be detected, suggesting these residual cells were both drug resistant and very immature. Finally, we harvested cells from animals 6 weeks after initiation and 2 weeks after cessation of treatment which coincided with leukaemia presentation in control animals. At this time-point, cells from both the control and treated mice significantly comprised CD34-CD7+CD5+CD3-, CD34-CD7-CD5+CD3- (which was reduced in proportion compared with week 4), as well as an emergent CD34-CD7+CD5-CD3- population. The proportion of hCD45+CD34-CD7-CD5-CD3- cells was lower in all organs compared with week 4. Vincristine treated cells were, therefore, able to rapidly repopulate the organs following cessation of treatment. At the end of the second passage (untreated), immunophenotyping of human cells revealed a further dramatic reduction in CD34 positivity to <1% compared with 18% and 14% at pre-injection and end of first engraftment, respectively. There was also significant emergence of hCD45+CD34-CD7-CD5-CD3- cells. We are currently investigating the sensitivity of these cells to vincristine in vitro. Intriguingly, the concomitant loss of CD34 positivity, reduction in vincristine sensitivity and increase in hCD45+CD34-CD7-CD5-CD3- cells indicates the outgrowth of a very immature population of drug resistant leukaemia stem cells during serial transplantations in mice. We are currently characterising these hCD45+CD34-CD7-CD5-CD3- cells by immunophenotyping with additional stem cell markers, gene expression analysis, SIL-TAL+ PCR, and cell sorting to investigate their ability to engraft and reconstitute leukaemia in mice. We are addressing the possibility that they can give rise to relapse over a prolonged period following treatment cessation. These findings have important implications for the development of novel therapies for T-ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Adenovirus infection promotes the formation of glioma stem cells by glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

2020 ◽  
Author(s):  
Jian Zang ◽  
Min-hua Zheng ◽  
Xiu-li Cao ◽  
Yi-zhe Zhang ◽  
Yu-fei Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Glioma Cells ◽  
Tumor Model ◽  
Glioma Stem Cells ◽  
Stem Cell Markers ◽  
Qrt Pcr ◽  
Lineage Differentiation ◽  
Stat3 Signaling

Abstract BackgroundGlioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells, but the identity of the signaling molecules and underlying mechanisms have been incompletely elucidated.MethodsHuman samples and glioma cell lines were cultured in vitro to determine the effects of viral infection by sphere formation, qRT-PCR, Western blot, FACS and immunofluorescence; for in vivo analysis, mice subcutaneous tumor model was carried; while bioinformatics analysis and qRT-PCR were applied for further mechanistic studies.ResultsIn this study, we show that infection of patient-derived glioma cells with adenovirus (ADV) increases the formation of tumor spheres. ADV infection upregulated stem cell markers, and the resultant tumor spheres held the capacities of self-renewal and multi-lineage differentiation, and had stronger potential to form xenograft tumors in immune-compromised mice. ADV promoted GSC formation likely via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1, which is downstream to TLRs and play important roles in cancer stem cells via multiple mechanisms including strengthening STAT3 signaling. Indeed, knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, we show that HMGB1, a damage associated molecular pattern (DAMP) that also triggers TLR signaling, upregulated stemness markers in glioma cells.ConclusionsIn summary, our data indicate that ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

scholarly journals Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Chao Sun ◽  
Xingliang Dai ◽  
Dongliang Zhao ◽  
Haiyang Wang ◽  
Xiaoci Rong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Tumor Growth ◽  
Glioma Cells ◽  
Stem Cell Markers ◽  
Xenograft Tumor ◽  
Angiogenic Effect

Abstract Background and objective Tumor angiogenesis is vital for tumor growth. Recent evidence indicated that bone marrow-derived mesenchymal stem cells (BMSCs) can migrate to tumor sites and exert critical effects on tumor growth through direct and/or indirect interactions with tumor cells. However, the effect of BMSCs on tumor neovascularization has not been fully elucidated. This study aimed to investigate whether fusion cells from glioma stem cells and BMSCs participated in angiogenesis. Methods SU3-RFP cells were injected into the right caudate nucleus of NC-C57Bl/6 J-GFP nude mice, and the RFP+/GFP+ cells were isolated and named fusion cells. The angiogenic effects of SU3-RFP, BMSCs and fusion cells were compared in vivo and in vitro. Results Fusion cells showed elevated levels of CD31, CD34 and VE-Cadherin (markers of VEC) as compared to SU3-RFP and BMSCs. The MVD-CD31 in RFP+/GFP+ cell xenograft tumor was significantly greater as compared to that in SU3-RFP xenograft tumor. In addition, the expression of CD133 and stem cell markers Nanog, Oct4 and Sox2 were increased in fusion cells as compared to the parental cells. Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Conclusion Fusion cells exhibited enhanced angiogenic effect as compared to parental glioma cells in vivo and in vitro, which may be related to their stem cell properties. Hence, cell fusion may contribute to glioma angiogenesis.

A Unique Pre-Clinical Model Providing Access to a Drug Resistant Population within the Multiple Myeloma Stem Cell Niche in a Novel 3-D Culture System for Bone Marrow.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 547-547
Author(s):  
Julia Kirshner ◽  
Kyle J. Thulien ◽  
Lorri D. Martin ◽  
Carina Debes Marun ◽  
Tony Reiman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Culture System ◽  
Hematopoietic Cells ◽  
Drug Resistant ◽  
Culture Model

Abstract Bone marrow (BM), a site of hematopoiesis, is a multicellular tissue with a complex architecture. Multiple myeloma (MM) is an incurable plasma cell malignancy where even patients in remission succumb to an inevitable relapse. While considerable progress has been made towards understanding and treating MM, to date, there is no culture system which can recapitulate the complex interactions within the BM microenvironment. Current failure to grow the MM clone within the context of human microenvironment hampers progress into the understanding of the biology of MM and design of biologically relevant therapies. Here we present an in vitro three-dimensional (3-D) tissue culture model which recapitulates the human BM microenvironment allowing for the growth and expansion of the MM clone. Cells from the BM aspirates are grown in a fibronectin, laminin and collagen rich ECM designed to reconstruct in vitro endosteum and central marrow, mimicking the in vivo microenvironment of the BM. Proliferation and redistribution of cells within reconstructed ECM results in stratification of the culture, mimicking the in vivo condition where cells occupy individual niches. Cellular composition of the culture is maintained in accordance with the proliferation properties of the BM where osteoblasts, osteoclasts, adipocytes and stromal cells differentiate along with the full complement of the hematopoietic cells. BM cultures from normal donors are well-organized with osteoclasts and hematopoietic cells occupying distinct positions in the ECM. In contrast, reconstructed BM from MM patients is disorganized in 3-D where osteoclasts intermingle with the hematopoietic compartment. The MM malignant clone is expanded in 3-D cultures as measured by real-time quantitative PCR (rqPCR) for genomic clonotypic VDJ sequences. Malignant B and plasma cells proliferate in these cultures and FISH analysis reveals that their progeny harbor chromosomal abnormalities identical to those that mark the malignant clone prior to culture. Preclinical testing of emerging therapeutics targeted for multiple myeloma is hindered by the failure of the current models to sustain growth of the myeloma clone. In the 3-D culture, myeloma clone expands within its native environment providing an ideal preclinical model where conventional (Melphalan) and novel (Velcade) therapeutics efficiently and selectively kill their target cells. In the 3-D BM culture model, non-proliferating, label retaining cells (LRC) concentrate at a putative endosteum-marrow junction, where hematopoietic stem cells have been shown to localize in vivo, suggesting that the drug-resistant myeloma stem cells localize to the endosteal niche. In a colony-forming assay, drug-resistant LRC purified from the 3-D cultures form clonal colonies composed of malignant cells with patient specific clonotypic VDJ sequences. Recapitulation of the BM architecture in vitro is a first step towards the identification and therapeutic targeting of the elusive myeloma stem cell.

scholarly journals Identification of a novel population of muscle stem cells in mice

2002 ◽  
Vol 157 (5) ◽  
pp. 851-864 ◽  
Author(s):  
Zhuqing Qu-Petersen ◽  
Bridget Deasy ◽  
Ron Jankowski ◽  
Makato Ikezawa ◽  
James Cummins ◽  
...  
Keyword(s):  
Stem Cells ◽  
Normal Karyotype ◽  
Stem Cell Markers ◽  
Proliferating Cells ◽  
Dystrophic Muscle ◽  
Myogenic Cells ◽  
Hematopoietic Stem ◽  
Long Time

Three populations of myogenic cells were isolated from normal mouse skeletal muscle based on their adhesion characteristics and proliferation behaviors. Although two of these populations displayed satellite cell characteristics, a third population of long-time proliferating cells expressing hematopoietic stem cell markers was also identified. This third population comprises cells that retain their phenotype for more than 30 passages with normal karyotype and can differentiate into muscle, neural, and endothelial lineages both in vitro and in vivo. In contrast to the other two populations of myogenic cells, the transplantation of the long-time proliferating cells improved the efficiency of muscle regeneration and dystrophin delivery to dystrophic muscle. The long-time proliferating cells' ability to proliferate in vivo for an extended period of time, combined with their strong capacity for self-renewal, their multipotent differentiation, and their immune-privileged behavior, reveals, at least in part, the basis for the improvement of cell transplantation. Our results suggest that this novel population of muscle-derived stem cells will significantly improve muscle cell–mediated therapies.

Extracellular Vesicles of Stem Cells to Prevent BRONJ

2020 ◽  
Vol 99 (5) ◽  
pp. 552-560 ◽  
Author(s):  
J. Watanabe ◽  
K. Sakai ◽  
Y. Urata ◽  
N. Toyama ◽  
E. Nakamichi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Bone Marrow Cells ◽  
Treated Group ◽  
Osteonecrosis Of The Jaw ◽  
Oral Epithelium ◽  
Stem Cell Markers

Extracellular vesicles (EVs), several tens to hundreds of nanometers in size, are vesicles secreted by cells for intercellular communication. EVs released from mesenchymal stem cells (MSC-EVs) have the potential to treat multiple diseases. This study aimed to determine the effects of MSC-EVs on bisphosphonate-related osteonecrosis of the jaw (BRONJ), whose pathogenesis and treatment are not yet established. To this end, zoledronic acid (ZOL) was administered to bone marrow cells and fibroblasts in vitro. In vivo, a BRONJ model was produced by administering ZOL to rats and extracting teeth. Each MSC-EV-treated and nontreated group was compared histologically and molecularly. In vitro, the nontreated group showed an increased number of β-galactosidase-positive cells and expression of senescence-associated genes p21, pRB and senescence-related inflammatory cytokines. Conversely, MSC-EV administration decreased the number of senescent cells and expression levels of p21, pRB and inflammatory cytokines. In vivo, in the nontreated group, the socket was partially uncovered by the oral epithelium, leaving an exposed bone. Conversely, in the MSC-EV-treated group, the socket was healed. Besides, in the nontreated group, β-galactosidase-positive cells existed in the socket and colocalized with the CD90 and periostin-positive cells. However, there were few β-galactosidase-positive cells in the MSC-EV-treated group. Furthermore, gene expression of stem cell markers Bmi1 and Hmga2 and the vascular endothelial marker VEGF was significantly increased in the MSC-EV-treated group, compared with that in the nontreated group. These results indicate that MSC-EVs prevent ZOL-induced senescence in stem cells, osteoblasts, and fibroblasts and reduce inflammatory cytokines. Furthermore, administration of MSC-EVs prevented senescence of cells involved in wound healing and the spread of chronic inflammation around senescent cells, thereby promoting angiogenesis and bone regeneration and preventing BRONJ.

scholarly journals High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1373
Author(s):  
Melanie Generali ◽  
Sampoorna Satheesha ◽  
Peter K. Bode ◽  
Debora Wanner ◽  
Beat W. Schäfer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
High Frequency ◽  
Cell Clone ◽  
Hierarchical Organization ◽  
Stem Cell Markers ◽  
Worse Prognosis

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Fusion-positive RMS (FPRMS), expressing the PAX3/7-FOXO1, has a worse prognosis compared to the more common fusion-negative RMS (FNRMS). Although several studies reported hierarchical organization for FNRMS with the identification of cancer stem cells, the cellular organization of FPRMS is not yet clear. In this study we investigated the expression of key stem cell markers, developed a sphere assay, and investigated the seven most common FPRMS cell lines for subpopulations of tumor propagating cancer stem-like cells, also called cancer stem cells (CSCs). Moreover, loss- and gain-of-functions of the stem cell genes SOX2, OCT4, and NANOG were investigated in the same cells. Single-cell clonal analysis was performed in vitro as well as in vivo. We found that no stable CSC subpopulation could be enriched in FPRMS. Unlike depletion of PAX3-FOXO1, neither overexpression nor siRNA-mediated downregulation of SOX2, OCT4, and NANOG affected physiology of RMS cells. Every single subclone-derived cell clone initiated tumor growth in mice, despite displaying considerable heterogeneity in gene expression. FPRMS appears to contain a high frequency of tumor propagating stem-like cells, which could explain their higher propensity for metastasis and relapse. Their dependency on PAX3-FOXO1 activity reinforces the importance of the fusion protein as the key therapeutic target.

scholarly journals Soluble JAM-C Ectodomain Serves as the Niche for Adipose-Derived Stromal/Stem Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 278
Author(s):  
Morio Yamazaki ◽  
Kotaro Sugimoto ◽  
Yo Mabuchi ◽  
Rina Yamashita ◽  
Naoki Ichikawa-Tomikawa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Adhesion ◽  
Progenitor Cells ◽  
Soluble Form ◽  
Interstitial Tissue ◽  
Stem Cell Markers ◽  
Stem And Progenitor Cells ◽  
Stromal Stem Cells

Junctional adhesion molecules (JAMs) are expressed in diverse types of stem and progenitor cells, but their physiological significance has yet to be established. Here, we report that JAMs exhibit a novel mode of interaction and biological activity in adipose-derived stromal/stem cells (ADSCs). Among the JAM family members, JAM-B and JAM-C were concentrated along the cell membranes of mouse ADSCs. JAM-C but not JAM-B was broadly distributed in the interstitial spaces of mouse adipose tissue. Interestingly, the JAM-C ectodomain was cleaved and secreted as a soluble form (sJAM-C) in vitro and in vivo, leading to deposition in the fat interstitial tissue. When ADSCs were grown in culture plates coated with sJAM-C, cell adhesion, cell proliferation and the expression of five mesenchymal stem cell markers, Cd44, Cd105, Cd140a, Cd166 and Sca-1, were significantly elevated. Moreover, immunoprecipitation assay showed that sJAM-C formed a complex with JAM-B. Using CRISPR/Cas9-based genome editing, we also demonstrated that sJAM-C was coupled with JAM-B to stimulate ADSC adhesion and maintenance. Together, these findings provide insight into the unique function of sJAM-C in ADSCs. We propose that JAMs contribute not only to cell–cell adhesion, but also to cell–matrix adhesion, by excising their ectodomain and functioning as a niche-like microenvironment for stem and progenitor cells.

scholarly journals Notch pathway inhibition targets chemoresistant insulinoma cancer stem cells

2018 ◽  
Vol 25 (2) ◽  
pp. 131-144 ◽  
Author(s):  
Y Capodanno ◽  
F O Buishand ◽  
L Y Pang ◽  
J Kirpensteijn ◽  
J A Mol ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Targeted Therapies ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Treatment Modalities ◽  
Stem Cell Markers ◽  
Gamma Secretase

Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies. Highly invasive and tumourigenic human and canine INS CSC-like cells were successfully isolated. These cells expressed stem cell markers (OCT4,SOX9, SOX2, CD133 and CD34), exhibited greater resistance to 5-fluorouracil (5-FU) and demonstrated a more invasive and tumourigenic phenotypein vivocompared to bulk INS cells. Here, we demonstrated that Notch-signalling-related genes (NOTCH2andHES1)were overexpressed in INS CSC-like cells. Protein analysis showed an active NOTCH2-HES1 signalling in INS cell lines, especially in cells resistant to 5-FU. Inhibition of the Notch pathway, using a gamma secretase inhibitor (GSI), enhanced the sensitivity of INS CSC-like cells to 5-FU. When used in combination GSI and 5-FU, the clonogenicityin vitroand the tumourigenicityin vivoof INS CSC-like cells were significantly reduced. These findings suggested that the combined strategy of Notch signalling inhibition and 5-FU synergistically attenuated enriched INS CSC populations, providing a rationale for future therapeutic exploitation.

scholarly journals Adenovirus infection promotes the formation of glioma stem cells from glioblastoma cells through the TLR9/NEAT1/STAT3 pathway

2020 ◽  
Author(s):  
Jian Zang ◽  
Min-hua Zheng ◽  
Xiu-li Cao ◽  
Yi-zhe Zhang ◽  
Yu-fei Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Western Blotting ◽  
Glioma Cells ◽  
Tumor Model ◽  
Glioma Stem Cells ◽  
Stem Cell Markers ◽  
Lineage Differentiation ◽  
Infected Tumor

Abstract Background Glioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells. However, identification of the signaling molecules and underlying mechanisms has not been completely elucidated. Methods Human samples and glioma cell lines were cultured in vitro to determine the effects of adenovirus (ADV) infection by sphere formation, RT-qPCR, western blotting, FACS and immunofluorescence. For in vivo analysis, mouse intracranial tumor model was applied. Bioinformatics analysis, gene knockdown by siRNA, RT-qPCR and western blotting were applied for further mechanistic studies. Results Infection of patient-derived glioma cells with ADV increases the formation of tumor spheres. ADV infection upregulated stem cell markers and in turn promoted the capacities of self-renewal and multi-lineage differentiation of the infected tumor spheres. These ADV infected tumor spheres had stronger potential to form xenograft tumors in immune-compromised mice. GSCs formation could be promoted by ADV infection via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1. Knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, HMGB1, a damage associated molecular pattern (DAMP) that triggers TLR signaling, also upregulated stemness markers in glioma cells. Conclusion ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

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