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Review
. 2021 Jun 1;10(2):CNS73.
doi: 10.2217/cns-2020-0026. Epub 2021 May 19.

Stem cells for the treatment of glioblastoma: a 20-year perspective

Anda-Alexandra Calinescu  1 , McKenzie C Kauss  1   2 , Zain Sultan  1   3 , Wajd N Al-Holou  1 , Sue K O'Shea  4
Affiliations
Review

Stem cells for the treatment of glioblastoma: a 20-year perspective

Anda-Alexandra Calinescu et al. CNS Oncol. .

Abstract

Glioblastoma, the deadliest form of primary brain tumor, remains a disease without cure. Treatment resistance is in large part attributed to limitations in the delivery and distribution of therapeutic agents. Over the last 20 years, numerous preclinical studies have demonstrated the feasibility and efficacy of stem cells as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies, discuss mechanisms underlying their beneficial effect and highlight experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages brought by stem cells for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies.

Keywords: enzyme/prodrug; exosomes; glioblastoma; immunologic cell death; mesenchymal stem cells; nanoparticles; neural stem cells; oncolytic virotherapy; stem cells; therapeutic stem cells.

Plain language summary

Lay abstract Glioblastoma is the deadliest and most common form of brain tumor, for which there is no cure. It is very difficult to deliver medicine to the tumor cells, because they spread out widely into the normal brain, and local blood vessels represent a barrier that most medicines cannot cross. It was shown, in many studies over the last 20 years, that stem cells are attracted toward the tumor and that they can deliver many kinds of therapeutic agents directly to brain cancer cells and shrink the tumor. In this review we analyze these studies and present new discoveries that can be used to make stem cell therapies for glioblastoma more effective to prolong the life of patients with brain tumors.

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Conflict of interest statement

Financial & competing interests disclosure

Grant support was provided by NIH/NINDS R21NS107879 (AC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Mechanisms of action employed in enzyme/prodrug strategies for the treatment of glioblastoma.
(A) HSV-TK can phosphorylate not only thymidine but also gancyclovir, generating gancyclovir monophosphate. Cellular kinases convert it into gancyclovir triphosphate, which can be integrated into newly synthesized DNA, arresting further DNA synthesis and inducing cell death. (B) CD converts 5-FC into 5-FU. To exert its cytotoxic function 5-FU is anabolized into fluoropyrimidine nucleotides (FdUMP, FUTP and FdUTP). FdUMP is a suicide inhibitor of TS, binding and inactivating it. TS converts dUMP to dTMP; inhibiting TS results in nucleotide imbalance, excess dUTP and lack of dTMP, leading to DNA damage. FUTP is extensively incorporated into nuclear and cytoplasmic RNA, leading to impaired RNA synthesis, stability, processing and methylation. FdUTP, when incorporated into DNA, inhibits DNA elongation and induces DNA fragmentation. 5-FU is deactivated and converted to FUH2 through the catalytic action of DPD, the initial and rate-limiting step in the catabolism of 5-FU. FUH2 can be further degraded to FUPA and subsequently to the nontoxic amino acid FBAL. (C) CE converts the water-soluble compound CPT-11 into the more potent, lipophilic metabolite SN38. During the DNA synthesis phase of the cell cycle, TOP1 attaches to the 3′ end of the cleaved DNA and forms a reversible DNA-TOP1 cleavage complex (TOP1cc). SN-38 binds to TOP1 and stabilizes this complex, halting DNA synthesis and leading to the accumulation of single-strand DNA breaks which trigger apoptosis. 5-FC: 5-Fluorocytosine; 5-FU: 5-Fluorouracyl; CD: Cytosine deaminase; CE: Carboxyl esterase; dTMP: Deoxythymidine monophosphate; dUMP: Deoxyuridine monophosphate; DPD: Dihydropyrimidine dehydrogenase; FBAL: Fluoro-β-alanine; FdUMP: 5-Fluoro-2′-deoxyuridine 5′-monophosphate; FdUTP: 5-fluoro-2′-deoxyuridine 5′-triphosphate; FUH2: Fluoro-5,6-dihydrouracil; FUPA: Fluoro-β-ureidopropionate; FUTP: 5-Fluorouridine 5′-triphosphate; GCV-P: Gancyclovir monophosphate; HSV-TK: Herpes simplex virus thymidine kinase; TOP1: Topoisomerase 1; TOP1cc: TOP1 cleavage complex; TS: Thymidylate synthase.
Figure 2.
Figure 2.. Stem cells carrying proapoptotic molecules.
Intratumoral delivery of TRAIL activates the extrinsic apoptotic pathway. Binding of TRAIL to the death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) results in formation of DISC and proteolytic cleavage of procaspase 8. This triggers activation of the effector caspase 3, leading to apoptosis. Activation of the initiator caspase 8 results also in activation of Bax and Bak inducing release of cytochrome C from the mitochondria and further activation of the effector caspases. Resistance to TRAIL-induced apoptosis may be caused by excess FLIP. FLIP binds to FADD and caspase-8 and inhibits formation of DISC and activation of caspase 8. The proteasome inhibitor bortezomib increases sensitivity of tumor cells to TRAIL-induced apoptosis by inhibiting recruitment of FLIP to DISC and increasing expression of the two signaling TRAIL receptors (TRAIL-R1 and TRAIL-R2). DISC: Death-inducing signaling complex; FADD: FAS-associated death domain protein; TRAIL: TNF-related apoptosis-inducing ligand.
Figure 3.
Figure 3.. Stem cells and oncolytic virotherapy.
Intratumoral delivery of oncolytic viruses by SCs results in virus-induced glioma tumor cell death and also in immunogenic cell death through activation of the innate and adaptive antitumor immune responses. Dying cells release viral antigens (PAMPs), DAMPs and TAAs. These antigens activate NK cells that induce direct tumor cell killing through production of granzyme and perforin, and also induce apoptosis through the release of TRAIL, TNF-α and IFN-γ. DAMPs and TAA activate antigen-presenting cells that travel to the draining lymph nodes, where they cross-present antigens to naive T lymphocytes and activate them. Activated T helper and cytotoxic T lymphocytes migrate into the tumor and release cytokines, perforin and granzyme that amplify the cytotoxic effect. APC: Antigen presenting cell; DAMP: Damage-associated molecular pattern; NK: Natural killer; PAMP: Pathogen-associated molecular pattern; SC: Stem cell; TAA: Tumor-associated antigen; TRAIL: TNF-related apoptosis-inducing ligand.
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