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The Subventricular Zone Neural Progenitor Cell Hypothesis in Glioblastoma: Epiphany, Trojan Horse, or Cheshire Fact?

2013; Elsevier BV; Volume: 86; Issue: 4 Linguagem: Inglês

10.1016/j.ijrobp.2013.03.002

1879-355X

Iris C. Gibbs, Daphne A. Haas‐Kogan, Stephanie A. Terezakis, Brian D. Kavanagh,

Axon Guidance and Neuronal Signaling

In the current issue of this journal are 2 reports concerning a provocative and controversial theory on the genesis and treatment of glioblastoma multiforme (GBM). First, Lee and colleagues (1Lee P. Eppinga W. Lagerwaard F. et al.Evaluation of high ipsilateral subventricular zone radiotherapy dose in glioblastoma: a pooled analysis.Int J Rad Onc Biol Phys. 2013 Feb 22; ([Epub ahead of print])http://dx.doi.org/10.1016/j.ijrobp.2013.01.009Google Scholar) report a pooled analysis at 2 institutions that included 173 GBM patients treated with intensity modulated radiation therapy (IMRT) and temozolomide (TMZ) showing that progression-free survival (PFS) was improved by an ipsilateral subventricular zone (SVZ) dose above 59.4 Gy. Next, in a largely concordant fashion, Chen and colleagues (2Chen L. Guerrero-Cazares H. Ye X. et al.Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection.Int J Rad Onc Biol Phys. 2013 Mar 26; ([Epub ahead of print])http://dx.doi.org/10.1016/j.ijrobp.2013.02.014Google Scholar) evaluate 116 patients with GBM treated by IMRT and TMZ and observe that among the 41 patients undergoing gross total resection, SVZ dose above 40 Gy correlated with improved PFS and overall survival (OS). The putative mechanism for this benefit involves an effect upon neural progenitor cells (NPCs) residing in the SVZ. We all agree that current management strategies for high-grade primary brain tumors are unsatisfactory, to say the least. GBM, along with unresectable pancreatic cancer and anaplastic thyroid cancer, remains among the nastiest scourges we face in all of oncology. We applaud any new insight that sets us on a path toward meaningful clinical benefits beyond the limited success we currently achieve. Nevertheless, as with any propitious proposition that promises prosperous progress, we must ask ourselves: is it real, is it a trap, or is it just an illusion? Legend has it that Archimedes got very excited when he suddenly conceived the intellectual insight about how to measure the volume of an object by the water it displaces and immediately jumped out of his bath in his birthday suit and ran around town to share the news. Ordinances in most municipalities prevent that particular form of public celebration, but maybe we should consider at least some level of curbed enthusiasm about the SVZ-NPC-GBM axis connection. After all, there is some good science and logic behind the notion of eradicating the GBM by choking off a possible root cause of the problem. The published investigations that provide credibility for the findings of Chen et al and Lee et al establish the following: (1) The adult human SVZ constitutes the largest area of neurogenesis and houses the greatest concentration of NPCs (3Quinones-Hinojosa A. Sanai N. Soriano-Navarro M. et al.Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells.J Comp Neurol. 2006; 494: 415-434Crossref PubMed Scopus (459) Google Scholar); (2) NPCs contribute to GBM initiation, promotion, and recurrence as their oncogenic activation in rodents increases cellular proliferation, survival, and migration and ultimately the development of infiltrating gliomas (4Abel T.W. Clark C. Bierie B. et al.GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma.Mol Cancer Res. 2009; 7: 645-653Crossref PubMed Scopus (42) Google Scholar, 5Ayuso-Sacido A. Moliterno J.A. Kratovac S. et al.Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells.J Neurooncol. 2010; 97: 323-337Crossref PubMed Scopus (97) Google Scholar); and (3) NPCs can be particularly radioresistant because of preferential activation of the DNA damage checkpoint and DNA repair responses (6Bao S. Wu Q. McLendon R.E. et al.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.Nature. 2006; 444: 756-760Crossref PubMed Scopus (5084) Google Scholar). Thus, it is logical to conclude that the SVZ contains a significant proportion of NPCs that can migrate to gliomas, support recalcitrant tumor behavior, and exhibit marked resistance to standard glioma treatment. It also follows that aggressive therapy directed at the SVZ might enhance glioma control, prolonging patient PFS and OS. Indeed, 2 prior small retrospective studies have suggested that higher radiation doses to the SVZ in adults with high-grade gliomas might enhance patient survival (7Evers P. Lee P.P. DeMarco J. et al.Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma.BMC Cancer. 2010; 10: 384Crossref PubMed Scopus (99) Google Scholar, 8Gupta T. Nair V. Paul S.N. et al.Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma?.J Neurooncol. 2012; 109: 195-203Crossref PubMed Scopus (71) Google Scholar). Therefore, it makes sense to eradicate NPCs in the SVZ to improve PFS and OS for GBM. Q.E.D. In today's cyber parlance, the image of a wooden horse filled with Greek soldiers sneaking into Troy morphs into a program downloaded from the internet that is supposed to enhance your laptop's processing speed or remove viruses but in reality deletes files and steals your identity. You only learn of the infiltration when your credit card is rejected at a fancy restaurant and suddenly that last bite of Baked Alaska tastes like a jalapeno soufflé. The Trojan Horse metaphor is applied here to ask whether a strategy that might at first glance be appealing (who would argue against improving PFS and OS for patients with GBM?) might in other ways be deleterious. The pediatric brain tumor literature is replete with reports that radiation therapy is associated with the development of long-term neurocognitive impairment. Of direct relevance to our current discussion are data suggesting that NPCs residing in regions such as the SVZ and hippocampus are, in fact, exquisitely radiosensitive (9Fike J.R. Rola R. Limoli C.L. Radiation response of neural precursor cells.Neurosurg Clin N Am. 2007; 18: 115-127Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar) and that injury to NPCs contributes to neurocognitive complications (10Rola R. Raber J. Rizk A. et al.Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice.Exp Neurol. 2004; 188: 316-330Crossref PubMed Scopus (580) Google Scholar, 11Winocur G. Wojtowicz J.M. Sekeres M. et al.Inhibition of neurogenesis interferes with hippocampus-dependent memory function.Hippocampus. 2006; 16: 296-304Crossref PubMed Scopus (504) Google Scholar). Several studies have linked radiation dose to specific brain regions, notably the hippocampus, to the development of neurocognitive deficits in children who received cranial radiation (12Armstrong G.T. Jain N. Liu W. et al.Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies.Neuro Oncol. 2010; 12: 1173-1186Crossref PubMed Scopus (105) Google Scholar, 13Jalali R. Mallick I. Dutta D. et al.Factors influencing neurocognitive outcomes in young patients with benign and low-grade brain tumors treated with stereotactic conformal radiotherapy.Int J Radiat Oncol Biol Phys. 2010; 77: 974-979Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 14Redmond K.J. Mahone E.M. Terezakis S. et al.Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: a prospective study.Neuro Oncol. 2013; 15: 360-369Crossref PubMed Scopus (73) Google Scholar). Preclinical evidence with clinical histopathologic correlation lends strong support to the association between NPC injury and cognitive sequelae after brain radiation therapy (15Panagiotakos G. Alshamy G. Chan B. et al.Long-term impact of radiation on the stem cell and oligodendrocyte precursors in the brain.PLoS One. 2007; 2: e588Crossref PubMed Scopus (147) Google Scholar). The dose–volume effect in these structures is still unknown and needs to be defined, given the potential impact on neurogenesis. Nevertheless, the avoidance of radiation dose to NPC-containing niches holds promise as a means to reduce the significant neurocognitive sequelae experienced by pediatric survivors after cranial radiation. To be fair, we acknowledge that in adults with GBM, long-term toxicity considerations might be a lower priority than anything that lengthens OS. However, as with all new hypotheses directing new avenues for treatment, one must consider the potential costs, particularly in the most vulnerable populations, where finding the best balance between quantity and quality of life is not a straightforward task. Chen et al (2Chen L. Guerrero-Cazares H. Ye X. et al.Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection.Int J Rad Onc Biol Phys. 2013 Mar 26; ([Epub ahead of print])http://dx.doi.org/10.1016/j.ijrobp.2013.02.014Google Scholar) do offer a primum non nocere defense insofar as patients' functional status, as assessed in a limited manner by Karnofsky Performance Scale, was not hindered by an SVZ dose above 40 Gy. Interestingly, the same group has investigated dose-painting strategies to protect against neurotoxicity by limiting dose to regions of neurogenesis in the SVZ of patients with various brain tumors, including GBM (16Redmond K.J. Achanta P. Grossman S.A. et al.A radiotherapy technique to limit dose to neural progenitor cell niches without compromising tumor coverage.J Neurooncol. 2011; 104: 579-587Crossref PubMed Scopus (23) Google Scholar). Alas, it is impossible to have it both ways: we can't simultaneously limit and escalate dose to the same regions, so something has to give."[The Cheshire Cat] vanished quite slowly, beginning with the end of the tail, and ending with the grin, which remained some time after the rest of it had gone" (Lewis Carroll, Alice in Wonderland). The term "Cheshire fact" has been coined to represent "the datum solemnly recorded, earnestly explained, vehemently defended, and then never seen again" (17Huber P. Galileo's Revenge: Junk Science in the Court Room. Basic Books, New York1991Google Scholar). Like the fantastic fading feline, what appears at first to be a solid truth is later understood to be only a mirage, a phantom, a trompe-l'oeil. In his famous lecture on the topic, the Nobel Laureate Irving Langmuir cited examples such as Blondlot's N rays and the Davis-Barnes effect as instances in which "there is no dishonesty involved but where people are tricked into false results …by subjective effects, wishful thinking, or threshold interactions" (18Langmuir I. Hall R.N. Pathological science.Phys Today. 1989; 42: 36-48Crossref Scopus (78) Google Scholar). We have to be careful here, because our inclination toward schadenfreude can sometimes steer us first to try to disprove any new theory that is not our own or is otherwise not palatable and to enjoy a smug sneer rather than applaud creativity and effort. For example, skeptics of the impact of nutritional intervention on cancer outcomes routinely feast on the low-hanging fruit of failed dietary intervention trials, which, in 1 case, took the actual form of low-hanging fruit: to wit, the trial that failed to show a reduced rate of breast cancer recurrence among patients randomized to increase their consumption of fruit and vegetables (19Pierce J.P. Natarajan L. Caan B.J. et al.Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial.JAMA. 2007; 298: 289-298Crossref PubMed Scopus (582) Google Scholar). We would bet that many of those same Doubting Thomases are quick to toast the studies showing a protective effect of red wine on the incidence of heart disease (20Chiva-Blanch G. Arranz S. Lamuela-Raventos R.M. et al.Effects of wine, alcohol and polyphenols on cardiovascular disease risk factors: evidences from human studies.Alcohol Alcohol. 2013 Feb 13; (Epub ahead of print)PubMed Google Scholar) …but we digress… Back to the effect of the SVZ NPC dose on outcome in GBM and the pressing question: can this phenomenon still be just a Cheshire fact, now that 2 groups have seen it? In fact, a correlation between ipsilateral SVZ dose and improved PFS or OS has not been uniformly observed. Although in one of the current series, Lee et al combine data from 2 institutions (1Lee P. Eppinga W. Lagerwaard F. et al.Evaluation of high ipsilateral subventricular zone radiotherapy dose in glioblastoma: a pooled analysis.Int J Rad Onc Biol Phys. 2013 Feb 22; ([Epub ahead of print])http://dx.doi.org/10.1016/j.ijrobp.2013.01.009Google Scholar), some of these patients were included in an earlier report of 55 patients (38 with GBM, 17 with anaplastic astrocytoma), which curiously showed that higher bilateral SVZ dose –and not ipsilateral SVZ dose –correlated with improved PFS (7Evers P. Lee P.P. DeMarco J. et al.Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma.BMC Cancer. 2010; 10: 384Crossref PubMed Scopus (99) Google Scholar). A possible explanation is that irradiation of the SVZ initiates a migratory signal to the corpus callosum in response to injury, thus illustrating the importance of bilateral SVZ dose over ipsilateral SVZ dose (21Goings G.E. Sahni V. Szele F.G. Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury.Brain Res. 2004; 996: 213-226Crossref PubMed Scopus (195) Google Scholar). In the current series, however, the opposite finding was shown. Muddying the waters further, Gupta et al (8Gupta T. Nair V. Paul S.N. et al.Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma?.J Neurooncol. 2012; 109: 195-203Crossref PubMed Scopus (71) Google Scholar) observed that although higher ipsilateral SVZ dose was favorable, a higher contralateral SVZ dose was associated with worse outcome. Maybe these observations are all true, but for reasons we don't yet completely understand. Maybe tumors located close to the SVZ present at an earlier point, on average, in their natural history. Maybe it is actually the incidental dose to nearby thalamic substructures that delays harmful corticospinal tract dissemination in some cases. Maybe a contralateral SVZ dose sometimes stimulates migration of reparative stem cells, whereas in other cases the sheer burden of a tumor requiring irradiation covering the contralateral SVZ is simply overwhelming. Maybe the thing we can all agree on, though, is that with our modern arsenal of sophisticated dose delivery technology, with which we can modulate the dose to substructures of the brain, we need to move beyond the simple enhancement-plus-margin target concept in the treatment of GBM and explore more nuanced approaches. Prospective studies of nonstandard target design should, of course, include neurocognitive and other quality of life metrics along the way to be sure we don't achieve small quantitative gains for the price of large qualitative losses. Nevertheless, we have been stuck in a rut with the treatment of GBM for quite a while now, and provocative studies that generate innovative hypotheses are a welcome contribution. Increased Subventricular Zone Radiation Dose Correlates With Survival in Glioblastoma Patients After Gross Total ResectionInternational Journal of Radiation Oncology, Biology, PhysicsVol. 86Issue 4PreviewNeural progenitor cells in the subventricular zone (SVZ) have a controversial role in glioblastoma multiforme (GBM) as potential tumor-initiating cells. The purpose of this study was to examine the relationship between radiation dose to the SVZ and survival in GBM patients. Full-Text PDF Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled AnalysisInternational Journal of Radiation Oncology, Biology, PhysicsVol. 86Issue 4PreviewCancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. Full-Text PDF