Stem Cell Therapy for Glioblastoma

   

Abby Lin and Vincent S Gallicchio*

Citation: Lin A, Gallicchio VS. (2023) Stem Cell Therapy for Glioblastoma. J Stem Cell Res. 4(1):1-12.

Received: March 28, 2023 | Published: April 19, 2023

Copyright© 2023 by Lin A. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.52793/JSCR.2023.4(1)-45

Abstract

Glioblastoma is a devastating grade IV cancer that affects the central nervous system and the spinal cord primarily in older adults but can also affect youth. The progression of the disease causes symptoms such as headaches and epilepsy. With such a severe and devasting prognosis and little ability to extend or cure the disease, researchers have been trying to find the best treatments to help patients suffering from Glioblastoma. Although the goal of Glioblastoma is not only to treat the disease but to cure it, current animal in vivo studies have shown promising therapeutic effects in mesenchymal stem cells, induced neural stem cells, and induced pluripotent stem cells. These stem cells have self-renewal capabilities, and stem cells, like the mesenchymal stem cells, can differentiate into various lineages from the mesoderm. While research has shown that each stem cell poses its own risk to the disease, their therapeutic effects have also shown encouraging and promising results. This review outlines the research, progress, and potential therapeutic effects different stem cells have on Glioblastoma. This study aimed to review the current progress researchers have made regarding stem cell therapeutic effects for Glioblastoma, how it is applied, and to discover the potential future progress and treatments these stem cells can create.

Keywords

Glioblastoma; Neural stem cells; Mesenchymal stem cells; Treatment; Tumor

List of Abbreviations

CD133+: heightened tumorgenicity, cRGD: Cyclic arginyl glycyl aspartic acid

CRISPR/Cas 9: Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 C6 cell: rat glioma cell line

DNA: deoxyribonucleic acid

EGFR: Epidermal growth factor receptor ESC: Embryonic stem cell

FADD: Fas-associated proteins with death domain GB: Glioblastoma

GBM8: Glioblastoma multiforme 8 GSC: Glioblastoma stem cell

iNSC: Human-induced neural stem cell HSC: Hematopoietic stem cell

HSPC: Hematopoietic and progenitor cell iNSC: Induced neural stem cell

iNSC-sTR: Induced neural stem cell-short tandem repeat iPSC: Induced pluripotent stem cells

MRI: Magnetic resonance imaging MSC: Mesenchymal stem cell NSC: Neural stem cell

PET: Positron emission tomography PTEN: Phosphatase and tensin homolog P13K: Phosphatidylinositol 3-kinase

scRNA-seq: Single-celled ribonucleic acid sequence

TD: Transdifferentiated

TGFβ: Transforming growth factor beta

TK: Thymidine kinase

TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand

Introduction

 

What is Glioblastoma?

Glioblastoma (GB) is considered a grade IV cancer of the central nervous system, according to the World Health Organization [1]. While secondary GBs can arise in children, primary GB is the most common, fatal brain tumor in adults [2, 3]. GB works aggressively, with the most common prognosis averaging 12-15 months [1]. While there are lower-grade gliomas where coincide chemotherapy is not always part of the treatment, the aggressive nature of the malignant gliomas obligates chemotherapy usage [4]. Malignant, or grade IV, gliomas are the invasive and lethal form with the shortest prognosis [4].

Along with the aggression of the disease, GB is also predisposed to necrosis, and the tumor is mitotically active [5]. Scientists debate whether GBs arise from a subculture of neural stem cells or from the transformation of differentiated astrocytes [6]. Further, recurrent tumors differ from the original tumor due to mutations and evolutions, limiting the information gathered from the initial biopsy when treating the recurred disease [7].

How do doctors differentiate between different glioblastomas? Gliomas often originate from three types of glial cells: oligodendrocytes, ependymal cells, and astrocytes - however, astrocytic gliomas hold 70% of all glioma origins [4]. The classification of each glioma is based on its cell origin and molecular characteristics, which includes acquired mutations [4].

Pathology of Glioblastoma

What drives GB and its progression? An epidermal growth factor receptor (EGFR) is a typical influencer, where phenotypic changes occur by over expression, amplification, and mutation [5]. Amplification of the EGFR happens through reverse transcription, which is then accompanied by EGFR over expression [5]. While the most common GB tumors reside in the frontal, temporal, and parietal lobes, there are rare GBs that can reside in the occipital lobe or the spinal cord [8]. A brainstem GB tumor is a rare form of GBs in adults that is not as rare in pediatric GBs [13]. Although it is not common, GB does not always stay local to the origin of the cancer - it can metastasize to other locations: the lungs, the lymph nodes, the bone, and the liver [8].

Changes in patients’ personalities and moods can occur due to GB; However, it can be mistaken as a psychogenic disorder or part of the “aging process,” which delays diagnosis - negatively affecting the prognosis [8]. Other symptoms of GB, such as epilepsy, headaches, intracranial pressure, nausea, and a slow neurocognitive function, are often experienced post-diagnosis [8] (Figure 1).

 

 

Current Treatments for Glioblastoma

Different therapy options can increase the cancer's survival the cancer; however, they are rendered ineffective when it pertains to patients with grade IV GB [1]. Factors that cause the current therapy treatments to be weak are the blood-brain barrier, cancer stem cells, and the infiltration into the brain parenchyma [1]. Standard treatments, such as maximal safe surgical resection, followed by paired radiotherapy and chemotherapy with temozolomide (a first-line chemotherapy drug that causes apoptosis in GB), allow the average survival rate to stand between 14-16 months [7]. However, the surgical removal of the entire tumor mass is not feasible because the cells sit 2-3 cm from the original site, which could lead to a more aggressive regrowth post-removal [7].

While surgical resection is the current standard of care, it is case-specific based on the tumor’s size and shape, the location of blood vessels and arteries, and the sensitivity of the brain region [4]. Fortunately, patients with a 90% tumor resection have a one-year survival compared to patients that undergo less than 90% tumor resection [4]. Therefore, the vital ability to resect as much of the tumor mass as possible can significantly increase GB survival [4] (Figure 2).

 

Figure 2: Current therapy treatment approaches [13].

 

 

What are stem cells, and why are they being investigated?

Stem cells self-replicate, differentiate, and trope tumors, along with various other factors that could make them attractive therapeutic candidates for GB [5]. Further, they are pluripotent and give rise to various lineages of daughter cells [9]. For example, neural stem cells (NSCs) make cells differentiate into neurons, astrocytes, and oligodendrocytes [9]. NSCs reside in the subventricular zone and the hippocampus, giving them the preference to migrate to tumor masses [3]. These abilities are advantageous as they can simultaneously minimize the side effects of radiotherapy and chemotherapy while maximizing the drug delivery to the tumor site [3]. Due to stem cells’ ability to regenerate in the central nervous system after tissue injury from surgery or chemotherapy, scientists and doctors believe they can provide direct or indirect anti-tumor effects [5].

Stem cells are currently being studied as a standard of care for GB since they can be genetically modified to express various immunomodulatory substances to prevent tumor growth [3]. In addition, they are used for trafficking oncolytic viral vectors to fight against the tumor mass [3]. Another approach for stem cells is to combine them with prodrugs to convert them into an active form that will migrate toward the tumor [3].

 

Discussion

 

Glioblastoma stem cells (cancer stem cells)

Glioblastoma stem cells (GSCs) are found in human brain tumors [6]. GSCs were discovered to play essential roles in therapeutic resistance: radio resistance, chemoresistance, angiogenesis, invasion, and recurrence [6]. The resistance to radiotherapy and chemotherapy is potentially caused by a high capacity for extensive DNA repair, quiescence, higher mitochondrial reserve, and localization in the hypoxic niche [6]. GSCs are unstable mutationally, transcriptionally, and metabolically [10]. The instability causes these stem cells to metastasize and become unresectable able to adapt to new environmental factors [10]. While there are no indications about the tumor cell of origin for GSCs, it is inferred that the presence of GSCs could cause the malignant transformation of a normal tissue stem cell [6]. GSCs are not characterized by the presence or absence of particular molecular markers as they are not sensitive nor specific to a GSC population [6]. However, GSC characterization does not state that the activity of the stem cell is dormant but instead exists in different cellular versions of the tumor, which allows interconversion between GSC and non-GSC states [6]. Certain microenvironmental factors like nutrient deprivation, hypoxia, and radiation can change the dynamic of the regulation of interconversions and phenotypes like proliferation and quiescence [6].

Studies in GSCs

Primary tumor specimens' single-celled RNA sequences (scRNA-seq) have found intertumoral heterogeneity and a slow-divided quiescent population of stem-like cells in GB tumors [6]. For oligodendrogliomas, scRNA-seq has uncovered the presence of undifferentiated stem-like cells, indicating these cells promote tumor growth [6]. In a study with mutant astrocytomas and oligodendrogliomas, the stem cell and cell cycle genes had a positive correlation at the single-cell level [6]. Unlike NSCs which contain discrete self-renewing populations with the ability to multiply highly or cause inactivation [6].

Therapeutic stem cells

Mesenchymal stem cells

Mesenchymal stem cells (MSCs) are currently one of the most applied somatic stem cells in experimental therapies for regenerating damaged tissues [10]. MSCs are multipotent stem cells with self-renewal abilities and differentiate into osteoblasts, chondrocytes, and adipocytes - cell lineages of the mesoderm [10]. MSCs can be found and obtained from the bone marrow, adipose tissue, dental pulp, spleen, umbilical cord, etc. [10]. Experimental studies have shown that these stem cells have strong tumor tropism and can migrate to primary or metastatic cancers after infusion [10]. Their anti-tumor demonstrations exert anti-glioblastoma activity by controlling angiogenesis, regulating the cell cycle, and inducing apoptosis [10]. However, some experiments have found risks of tumor enhancement, cell proliferation, invasion, and aggressiveness after MSC therapy [10].

What are the anti-tumor effects of MSCs? They are considered the potential delivery of therapeutic agents for GB [5]. Tumor-associated MSCs are taken into the glioma’s microenvironment to promote tumor growth via cytokines, chemokines, and growth factors, acting as a trojan horse to deliver antitumor proteins, immune factors, long non-coding RNAs (or antitumor microRNAs), oncolytic viruses, or suicide genes as a result of tropism of the MSCs [5]. How does this induce tumor cell death? Cell death can occur by transducing MSCs with mRNA, which is then used to encode a pro-drug activating enzyme to function as a suicide protein [5]. The regression of the tumor occurs when the MSCs and suicide protein are injected into the tumor site [5]. This suicide protein changes non-toxic pro-drugs into toxic pro-drugs at the site, resulting in a synergistic effect to cause cell death [5]. It was found that phosphatase and tensin homolog engineered MSCs can also cause cytotoxic effects, and microRNAs can stimulate apoptosis or cell senescence when MSCs deliver them [5]. Consequences such as angiogenesis inhibition and apoptosis have decreased the GB tumor’s volume [10]. Still, the relation of whether it is due to the MSC source, the timing of experiments conducted, or the delivery route of the MSC is unknown [10].

What are the risks of MSC therapy? Could they pose a risk for tumor promotion? The short answer is yes, as the modulation, migration, and invasion of tumor cells have been found in MSC-conditioned media [5]. This conditioned media found the expression of six different types of proteins in the presence of C6 cells, which are closely related to cell differentiation and proliferation - indicating that MSCs may infiltrate the GB tumor but promote tumor growth at the secretion of exosomes [5]. MSCs that secrete chemokines can promote tumorigenesis via angiogenesis, proliferation, epithelial-mesenchymal transition, senescence, immune evasion, and metastasis [5] (Figure 3).