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Glioblastoma Therapy: Rationale for a Mesenchymal Stem Cell-based Vehicle to Carry Recombinant Viruses

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Abstract

Evasion of growth suppression is among the prominent hallmarks of cancer. Phosphatase and tensin homolog (PTEN) and p53 tumor-suppressive pathways are compromised in most human cancers, including glioblastoma (GB). Hence, these signaling pathways are an ideal point of focus for novel cancer therapeutics. Recombinant viruses can selectivity kill cancer cells and carry therapeutic genes to tumors. Specifically, oncolytic viruses (OV) have been successfully employed for gene delivery in GB animal models and showed potential to neutralize immunosuppression at the tumor site. However, the associated systemic immunogenicity, inefficient transduction of GB cells, and inadequate distribution to metastatic tumors have been the major bottlenecks in clinical studies. Mesenchymal stem cells (MSCs), with tumor-tropic properties and immune privilege, can improve OVs targeting. Remarkably, combining the two approaches can address their individual issues. Herein, we summarize findings to advocate the reactivation of tumor suppressors p53 and PTEN in GB treatment and use MSCs as a “Trojan horse” to carry oncolytic viral cargo to disseminated tumor beds. The integration of MSCs and OVs can emerge as the new paradigm in cancer treatment.

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Abbreviations

Adv:

Adenovirus

OA:

Oncolytic adenovirus

OVs:

Oncolytic viruses

PTEN:

Phosphatase and tensin homolog

GB:

Glioblastoma

GSC:

Glioma stem cell

MSCs:

Mesenchymal stem cells

PI3Ks:

Phosphatidylinositol 3-kinases

AKT:

a serine/threonine-specific protein kinase

PIP2 :

Phosphatidylinositol-4,5-bisphosphate

CRAds:

Conditionally replicating adenoviruses

RD-Ads:

Replication-defective adenoviral vectors

TCGA:

The Cancer Genome Atlas

MDM2:

Mouse double minute 2 homolog

CDKN2A:

also known as cyclin-dependent kinase inhibitor 2A

YB-1:

Y-box-binding protein-1

ARF:

Alternative reading frame

SOX2:

SRY-Box Transcription Factor 2

FoxO1:

Forkhead Box O1

SHH:

Sonic hedgehog

PAX7:

Paired Box 7

BRAF:

Serine/threonine-protein kinase B-raf

B7-H1:

B7 homolog 1

PD-L1:

Programmed death-ligand 1

E2F1:

E2F Transcription Factor 1

myc:

a proto-oncogene that code for transcription factors

ras:

Rat sarcoma – a proto-oncogene

ATM:

Ataxia Telangiectasia Mutated – a Serine/Threonine Kinase

mTORC1:

Mammalian target of rapamycin complex 1

GCV:

Ganciclovir

HSV-TK:

Herpes Simplex Virus-1 Thymidine Kinase

CD-NSCs:

Cytosine deaminase expressing neural stem cells

optHBS:

Optimized HIF-binding site

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

RNAi:

RNA interference

RISC:

RNA-induced silencing complex

siRNA/shRNA:

Small interfering and short hairpin RNA

TME:

Tumor microenvironment

IFN-β:

Interferon beta

CAR:

Chimeric antigen receptor

TCR-T:

Affinity-enhanced T cell receptor-transgenic T

DOTMA:

N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethyl ammonium chloride

DOTAP:

[1,2-bis (oleoyloxy)-3-(trimethylammonio) propane]

DOPE:

Dioleoylphosphatidylethanolamine

CXCR4:

C-X-C chemokine receptor type 4

ICOVIR-5:

Oncolytic virus

Celyvir:

Autologous mesenchymal stem cells carrying ICOVIR-5

HER2:

Human epidermal growth factor receptor

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Acknowledgements

The authors gratefully acknowledge the support from the Beijing Natural Science Foundation (Z190018), the National Natural Science Foundation of China (81870123), National Science Foundation for Young Scientists of China (81902545), and China Postdoctoral Science Foundation Grant (2018M641206). Figures were drawn using BioRender.com

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Authors and Affiliations

  1. School of Life Science, Beijing Institute of Technology, Beijing, 100811, China

    Sakhawat Ali, Qin Xia, Liqun Liu, Xinyi Meng & Lei Dong

  2. College of Life Sciences and Bio-Engineering, Beijing University of Technology, Beijing, 100022, China

    Tahir Muhammad, Aamir Ali Khan & Yinghui Huang

  3. Animal Genetics and Integrative Biology Department, Paris-Saclay University, INRAE, 78350, Paris, France

    David Bars-Cortina

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All authors took part in the preparation of this manuscript. SA and LD were responsible for determining the topic and idea. XQ and AAK drew figures/tables with the help of SA and performed literature search. XQ, YH, MT and DBC contributed with SA in writing the first draft and furtherly editing/revising the manuscript. LD, LL and XM perform extensive literature search and help to revise the manuscript in the light of queries and suggestions of the reviewers. All authors approved the version of the manuscript published. Overall supervision was done by LD.

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Ali, S., Xia, Q., Muhammad, T. et al. Glioblastoma Therapy: Rationale for a Mesenchymal Stem Cell-based Vehicle to Carry Recombinant Viruses. Stem Cell Rev and Rep 18, 523–543 (2022). https://doi.org/10.1007/s12015-021-10207-w

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