Targeting glioblastoma stem-cells: a recurrent challenge in neuro-oncology

Targeting glioblastoma stem-cells: a recurrent challenge in neuro-oncology

Giulia Berzero1,2, Alberto Picca1,2, Marc Sanson1,3

1AP-HP Groupe Hospitalier Pitié-Salpêtrière, service de Neurologie 2-Mazarin, Paris, France; 2Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino, Italy; 3Université Pierre et Marie Curie, Paris VI; Institut du Cerveau et de la Moelle Epinière, CNRS U1127, UMR 7225, Paris, France

Correspondence to: Giulia Berzero. C. Mondino National Institute of Neurology, IRCCS, via Mondino 2, 27100 Pavia, Italy. Email:

Provenance: This is an invited Editorial commissioned by the Section Editor Ning Huang (Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China).

Comment on: Yan H, Romero-López M, Benitez LI, et al. 3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy. Cancer Res 2017;77:4171-84.

Submitted Sep 01, 2017. Accepted for publication Sep 18, 2017.

doi: 10.21037/tcr.2017.09.39

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. To date, this tumor remains rapidly fatal despite treatment, median overall survival not exceeding 15 months from diagnosis (1). The resistance of GBM to the current standard of care is thought to derive, at least in part, from cancer stem-cells located in intratumoral niches (2). Glioblastoma stem-cells (GSC) have in fact the potential to differentiate into committed tumor cells, replacing the cells depleted by cytotoxic treatments and leading to tumor recurrence (2).

In their article (3), Yan and colleagues proposed a sophisticated three-dimensional mathematical model simulating the dynamics of growth and evolution of human GBM. This model accounted for the proliferation, apoptosis, motility and differentiation of different types of tumor cells, including GCS. The dynamic interactions between cell subpopulations, occurring upon intercellular signaling, were recapitulated. The supply of oxygen and nutrients to different tumor areas were estimated based on blood vessel density, substrate concentration and diffusivity. The process of neoangiogenesis induced by hypoxic signals was integrated in the model, together with the interactions between newly-formed vessels and existing vasculature. The authors also entered in their model the transdifferentiation of GCS into endothelial cells. Therefore, this model accounted for all the main features of GBM, including intense proliferation, invasiveness, necrosis and neovascularization, as well as for their reciprocal interactions.

The model was then used to simulate the response of human GBM to different antineoplastic treatments, administered alone or in combination. This model predicted that cytotoxic therapies alone are bound to fail in controlling tumor growth, since additional therapies targeting GSC are mandatory to achieve durable tumor response. Based on these results, the authors ultimately proposed a treatment combination based on cytotoxic compounds, antiangiogenics, differentiating agents, and drugs targeting transdifferentiated GCS to test in clinical practice. The assumption of the authors is that administering a treatment combination active on all the subsets of tumor cells, for an appropriate amount of time, could potentially lead to GBM eradication.

GSC were first described over 15 years ago (4,5). Similarly to other cancer stem-cells, GSC are defined by functional characteristics such tumor initiation upon secondary transplantation, persistent proliferation, and sustained self-renewal (2). In some circumstances, GSC can also transdifferentiate, giving rise to committed stromal cells (2), pericytes (6), or even endothelial cells (7-9). This accounts for the plasticity of GBM, its remarkable capacity for adaptation and self-sustenance.

GSC reside in protective niches localized in close proximity to blood vessels within the hypoxic core, along perivascular spaces, and at tumor margins (10-12). Each niche has its own microenvironment, supporting GSC and modulating their activity (13). GSC niches have specific functions that include, but are not limited to, GSC maintenance (11,12). The perivascular niche is responsible for tumor neoangiogenesis, which is promoted by proangiogenic factors secreted by resident GSC (10,11,14). The hypoxic niche, located in GBM necrotic core, is the main reservoir of GSC, whose survival and stemness is promoted by hypoxia signaling pathways (10,11). The invasive niche, located at tumor margins, is responsible for the invasion of surrounding tissue carried on by GSC following mesenchymal transition (10,11).

Therefore, GSC are involved into tumor initiation, progression and neoangiogenesis, and participate to GBM resistance to antineoplastic agents. Being intrinsically resistant to radiochemotherapy (15,16), GSC will survive cytotoxic treatments and will eventually drive tumor recurrence by differentiating into committed tumor progenitors. It has also been proposed that GSC may be responsible for GBM resistance to antiangiogenics by transdifferentiating into endothelial cells to form new blood vessels (17).

Endothelial transdifferentiation is clearly operant in xenograft models, where human GSC differentiate into bona fide blood vessels to supply tumor growth (7-9). However, this is an artificial model, and studies conducted on fresh GBM samples suggest that, in normal conditions, the phenomenon rarely occurs (18,19). Endothelial transdifferentiation may instead be more frequent at recurrence, operating as a mechanism of resistance to antiangiogenics. The same has been suggested for vascular mimicry, which has been documented in a patient presenting with tumor recurrence after antiangiogenic therapy (20). Indeed, we still do not know to which extent endothelial transdifferentiation may be involved in secondary resistance to antiangiogenics, since the number of patients undergoing surgery after bevacizumab is very limited. In addition, several other mechanisms of resistance to antiangiogenics have been reported (21,22), and their relative contribution in determining treatment resistance is still unclear.

Since GSC are possibly involved in the resistance to both cytotoxic and antiangiogenic agents, specifically targeting these cells seems a rational treatment strategy to counteract the escape of GBM to the current standard of care. In the neuro-oncological community, efforts are being made to identify therapies capable of inhibiting the stemness and self-renewal of GSC. Although several compounds are being investigated as pro-differentiating agents, current data are limited to pre-clinical models and there is still no evidence of efficacy in humans.

Indeed, how sophisticated a mathematical model may be, it is always an oversimplification, and results should therefore be taken with caution. The model adopted by Yan et al. (3) is based on a priori assumptions that may not entirely reflect biological complexity, as discussed above for endothelial transdifferentiation. In addition, the hierarchical model adopted here postulates the existence of distinct types of tumor cells, only a subset of which has the ability to initiate tumor growth: GSC can give rise to committed cells but committed cells should not dedifferentiate into GSC. In fact, this last point remains controversial. In vitro experiments have shown that the induction of few transcription factors (POU3F2, SOX2, SALL2, OLIG2) is sufficient through epigenetic changes to reprogram differentiated GBM into stem-like cells capable of in vivo tumor propagation (23). Whether this bidirectional plasticity between GSC and differentiated tumor cell works in vivo, and to which extent, remains to be investigated. In this case, the specific targeting of GSC would be less relevant. Lastly, the model by Yan et al. (3) operates under the assumption that treatments can actually eradicate the totality of targeted cells and does not account for acquired drug resistance.

Despite these limitations, the mathematical model of human GBM proposed by Yan and colleagues (3) remains an appealing and elegant tool for predicting the effects of novel agents and for orienting treatment strategies, at the condition that it is implemented with the most accurate assumptions.




Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. [Crossref] [PubMed]
  2. Lathia JD, Mack SC, Mulkearns-Hubert EE, et al. Cancer stem cells in glioblastoma. Genes Dev 2015;29:1203-17. [Crossref] [PubMed]
  3. Yan H, Romero-López M, Benitez LI, et al. 3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy. Cancer Res 2017;77:4171-84. [Crossref] [PubMed]
  4. Ignatova TN, Kukekov VG, Laywell ED, et al. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 2002;39:193-206. [Crossref] [PubMed]
  5. Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64:7011-21. [Crossref] [PubMed]
  6. Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 2013;153:139-52. [Crossref] [PubMed]
  7. Ricci-Vitiani L, Pallini R, Biffoni M, et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010;468:824-8. [Crossref] [PubMed]
  8. Wang R, Chadalavada K, Wilshire J, et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010;468:829-33. [Crossref] [PubMed]
  9. Soda Y, Marumoto T, Friedmann-Morvinski D, et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci U S A 2011;108:4274-80. [Crossref] [PubMed]
  10. Brooks LJ, Parrinello S. Vascular regulation of glioma stem-like cells: a balancing act. Curr Opin Neurobiol 2017;47:8-15. [Crossref] [PubMed]
  11. Hambardzumyan D, Bergers G. Glioblastoma: Defining Tumor Niches. Trends Cancer 2015;1:252-65. [Crossref] [PubMed]
  12. Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11:69-82. [Crossref] [PubMed]
  13. Roos A, Ding Z, Loftus JC, et al. Molecular and Microenvironmental Determinants of Glioma Stem-Like Cell Survival and Invasion. Front Oncol 2017;7:120. [Crossref] [PubMed]
  14. Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006;66:7843-8. [Crossref] [PubMed]
  15. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012;488:522-6. [Crossref] [PubMed]
  16. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756-60. [Crossref] [PubMed]
  17. Angara K, Borin TF, Arbab AS. Vascular Mimicry: A Novel Neovascularization Mechanism Driving Anti-Angiogenic Therapy (AAT) Resistance in Glioblastoma. Transl Oncol 2017;10:650-60. [Crossref] [PubMed]
  18. Kulla A, Burkhardt K, Meyer-Puttlitz B, et al. Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature. Acta Neuropathol 2003;105:328-32. [PubMed]
  19. Rodriguez FJ, Orr BA, Ligon KL, et al. Neoplastic cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106. [Crossref] [PubMed]
  20. El Hallani S, Boisselier B, Peglion F, et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain 2010;133:973-82. [Crossref] [PubMed]
  21. Tamura R, Tanaka T, Miyake K, et al. Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 2017;34:62-77. [Crossref] [PubMed]
  22. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592-603. [Crossref] [PubMed]
  23. Suvà ML, Rheinbay E, Gillespie SM, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 2014;157:580-94. [Crossref] [PubMed]
Cite this article as: Berzero G, Picca A, Sanson M. Targeting glioblastoma stem-cells: a recurrent challenge in neuro-oncology. Transl Cancer Res 2017;6(Suppl 7):S1197-S1199. doi: 10.21037/tcr.2017.09.39