Are Neural Stem Cells the end of Glioblastoma Multiform life story?

Is Neural Stem Cell therapy The End of Glioblastoma Multiform Life Story?

Glioma is the most common form of central nervous system (CNS) neoplasm that originates from glial cells (astrocytes, oligodendrocyte cells). Grade IV astrocytoma termed glioblastoma multiform (GBM), is one of the most common, severe, and aggressive forms of malignant glioma known to man. Despite intensive therapies, the median survival has remained approximately 15 months. (1-4)

One of the major challenges to the treatment of GBM is the blood-brain barrier (BBB). This barrier is a highly specialized structure in the brain. It acts as a selective physical barrier for maintaining the homeostasis of the brain by regulating immune cell transport, passive diffusion of chemicals, and etc. physiologically, the BBB selectively allows only certain substance to pass between brain tissue and blood; therefore the BBB protects the brain from possible toxic elements and also prevents drugs from getting into the tumor site, so few amounts of the drugs can get to the site of malignancy. (4–10)

Importantly, as glioblastoma has an aggressive nature through infiltration and invasion, surgical resection is frequently unable to remove all of the glioblastoma foci. This is supported by the fact that most patients die within a year from a reoccurring secondary tumor foci near the resected area. (11)

Fortunately, research has shown stem cells can cross the blood-brain barrier(12). Some other studies found that neural stem cells (NSCs) can reach tumor foci, meaning they have tumor tropism. (13)

It seems that tumor tropism ability of NSC is based on tissue hypoxia caused by tumor cells activity, During hypoxia, glioblastoma cells up-regulate the expression of several chemo attractants and pro-angiogenic factors, such as hypoxia-inducible factor-1 alpha and its downstream targets stromal-cell-derived factor-1 and vascular endothelial growth factor, that attract stem cells to migrate towards the tumor foci.(14,15) Also, Chemokines expressed by glioma stem cells, such as vascular endothelial growth factor, epidermal growth factor, and basic fibroblast growth factor, contributed to the hypoxia-enhanced NSC-tropic migration. (16)

According to the explanations, it can be concluded that stem cells (especially NSC) can be used to treat GBM patients.

But how?

1. 1.     Using genetic engineering to alter the genetic structure of stem cells to produce proteins that kill tumor cells. (17)
2. 2.     Using stem cells as a carrier of therapeutic particles such as chemotaxis drugs, nanoparticles, and oncolytic viruses, to transfer them to the tumor foci and destroy tumor cells. (18–20)

The route of delivery of NSC is so essential because the number of NSCs that can reach the tumor foci is dependent on the tumor delivery routes; now, what are the routes of delivery of stem cells to the patient’s body?

In murine models, GBM injection of NSCs, contralateral to the tumor site, leads to migration and efficient delivery of therapy(20), but the problem of this route of delivery to human patients is its invasive nature and the trouble repeating injections;. At the same time, intravenous administration of NSCs can still cause migration to the tumor site, the efficacy of this route remains controversial. Recently, as a way to curtail these limitations, it has been demonstrated that NSC can be delivered intra-nasally and efficiently migrate to the tumor foci. The intranasal route allows to repeat administration and has higher amounts of NSC migration(21)

In the end, it must be expressed that Stem cell vectors may, by their capacity to target infiltrative tumor cells, provide a powerful treatment modality for GBM. However, many issues, including the choice of cell vector and the therapeutic transgene, the optimal route of administration, and biosafety, need to be addressed. (22)

BY Mohammad Klantary Khandani

References:

1.       Jiang H, Cui Y, Wang J, Lin S. Impact of epidemiological characteristics of supratentorial gliomas in adults brought about by the 2016 world health organization classification of tumors of the central nervous system. Oncotarget [Internet]. 2017 Mar 21;8(12):20354–61. Available from: https://pubmed.ncbi.nlm.nih.gov/27888628

2.       Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar;352(10):987–96.

3.       Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009 May;10(5):459–66.

4.       Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS. Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol. 2015 Mar;17 Suppl 2(Suppl 2):ii24–36.

5.       Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006 Jan;7(1):41–53.

6.       Luissint A-C, Artus C, Glacial F, Ganeshamoorthy K, Couraud P-O. Tight junctions at the blood-brain barrier: physiological architecture and disease-associated dysregulation. Fluids Barriers CNS [Internet]. 2012;9(1):23. Available from: https://doi.org/10.1186/2045-8118-9-23

7.       Obermeier B, Daneman R, Ransohoff RM. Development, maintenance, and disruption of the blood-brain barrier. Nat Med [Internet]. 2013;19(12):1584–96. Available from: https://doi.org/10.1038/nm.3407

8.       Liu H-L, Fan C-H, Ting C-Y, Yeh C-K. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. 2014;4(4):432–44.

9.       Pardridge WM. Drug and gene delivery to the brain: the vascular route. Neuron. 2002 Nov;36(4):555–8.

10.          Ewing JR, Brown SL, Lu M, Panda S, Ding G, Knight RA, et al. Model selection in magnetic resonance imaging measurements of vascular permeability:  Gadomer in a 9L model of rat cerebral tumor. J Cereb blood flow Metab  Off J  Int Soc Cereb Blood Flow Metab. 2006 Mar;26(3):310–20.

11.          Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980 Sep;30(9):907–11.

12.          Aleynik A, Gernavage KM, Mourad YS, Sherman LS, Liu K, Gubenko YA, et al. Stem cell delivery of therapies for brain disorders. Clin Transl Med. 2014;3(1):24.

13.          Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A. 2000 Nov;97(23):12846–51.

14.          Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA, et al. Neural stem cell tropism to glioma: Critical role of tumor hypoxia. Mol Cancer Res. 2008;6(12):1819–29.

15.          Zhang S, Luo X, Wan F, Lei T. The roles of hypoxia-inducible factors in regulating neural stem cells migration to glioma stem cells and determinating their fates. Neurochem Res. 2012 Dec;37(12):2659–66.

16.          Zhang S, Xie R, Zhao T, Yang X, Han L, Ye F, et al. Neural stem cells preferentially migrate to glioma stem cells and reduce their stemness phenotypes. Int J Oncol. 2014 Nov;45(5):1989–96.

17.          Aboody KS, Najbauer J, Metz MZ, D’Apuzzo M, Gutova M, Annala AJ, et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci Transl Med. 2013 May;5(184):184ra59.

18.          Cheng Y, Morshed R, Cheng S-H, Tobias A, Auffinger B, Wainwright DA, et al. Nanoparticle-programmed self-destructive neural stem cells for glioblastoma targeting and therapy. Small. 2013 Dec;9(24):4123–9.

19.          Mooney R, Roma L, Zhao D, Van Haute D, Garcia E, Kim SU, et al. Neural stem cell-mediated intratumoral delivery of gold nanorods improves photothermal therapy. ACS Nano. 2014 Dec;8(12):12450–60.

20.          Ahmed AU, Thaci B, Tobias AL, Auffinger B, Zhang L, Cheng Y, et al. A preclinical evaluation of neural stem cell-based cell carrier for targeted anti-glioma oncolytic virotherapy. J Natl Cancer Inst. 2013 Jul;105(13):968–77.

21.          Schmidt N, Dührsen L, Reitz M, Henze M, Sedlacik J, Riecken K, et al. Repeated intranasal application of neural stem cell-mediated enzyme/prodrug therapy using a novel Hsv-thymidine kinase variant improves therapeutic efficiency in an intracranial glioblastoma model. Neuro Oncol. 2014;16 Suppl 3:iii50.

22.          Bexell D, Svensson A, Bengzon J. Stem cell-based therapy for malignant glioma. Cancer Treat Rev [Internet]. 2013;39(4):358–65. Available from: http://dx.doi.org/10.1016/j.ctrv.2012.06.006