To the Editor: In 2007, Chicoine et al1 showed that the antitumoral effects of lipopolysaccharide (LPS) against glioblastoma might be orchestrated TLR4.1 A decade ago, embryologic studies also revealed that toll-like receptors (TLRs) modulate the development of neural systems and control adult hippocampal neurogenesis.2 More recently, the role of TLRs has become of interest for a wide range of diseases. In 2001, Reya et al3 introduced the “cancer stem cells hypothesis,” suggesting that cancer stem cells (CSCs) orchestrate the indefinite ability to self-renew in cancer based on similar signaling pathways known from stem cells. In 2004, Singh et al4 identified such CSC as “human brain tumor initiating cells.” Since then, manifold studies have aimed at targeting glioblastoma CSC with therapeutic intent, yet glioblastoma has remained an incurable disease. Lathia et al5 showed that in addition to CSCs, the tumor's environment significantly impacts glioblastoma biology. In part, this environment appears to be influenced by hypoxic and necrotic tissue, which prevents the immune system from intervening effectively.5,6 Yet, an active immune system appears to play an important role in restricting tumor growth and invasion,7 and clinical trials currently aim at stimulating glioblastoma patients’ immune defense, for example with LPS.8 In order to define innate immunologic factors responsible for glioblastoma CSCs’ invasiveness and malignant proliferation rates, Alvarado et al6 recently analyzed TLR4 expression in glioblastoma CSCs. They found a negative correlation between the expression of stem cell markers and TLR4 expression in glioblastoma CSCs, and demonstrated that glioblastoma CSCs show higher proliferation rates in populations with low TLR4 expression through downstream interactions. TLR4 expression as a part of the immune system signaling cascade appears to reduce some oncogenic effects in glioblastoma CSCs. These cells’ propensity ability for invasion leads to brain edema in glioblastoma patients. Therefore, as a complicating factor, the immunosuppressive glucocorticoid dexamethasone is often used to relieve clinical symptoms, although recent evidence revealed severe side effects in an orthotopic glioblastoma model.9 Given the fact that dexamethasone is routinely used in glioblastoma patients, we aimed to identify the impact of TLR4’s natural ligand LPS on both glioblastoma CSC and normal human astrocytes (NHA, as a surrogate for the tumor microenvironment) in the presence of dexamethasone in Vitro. We assessed TLR4 expression upon stimulation with 50 μM dexamethasone and 500 ng/ml LPS for 7 d with fluorescence-activated cell sorting using an R-phycoerythrin mouse anti-human TLR4 (CD284) antibody 1:20) in both glioblastoma CSC and NHA. Strikingly, when compared to controls, TLR4 expression in glioblastoma CSCs was nonresponsive to dexamethasone (normalized mean expression 77, P > .99) or to LPS and dexamethasone (103, P > .99). Likewise, NHA cells did not show any significant change in TLR4 expression in response to LPS treatment alone, but surprisingly, they did show a significant increase in TLR4 expression in response to both stimulation with dexamethasone alone (187, P < .05) and to LPS in combination with dexamethasone (218, P < .05). Although dexamethasone is known for its immunosuppressive effects, it showed seemingly paradoxical effects in our experiments. Our findings underline the potentially underestimated effect of the cells composing a tumor's microenvironment with respect to exposure to isolated dexamethasone or to dexamethasone with LPS. The importance of glioblastoma's surrounding microenvironment should be taken into account when considering immunologic dimensions. Disclosures Funded by the Mach-Gaensslen Neurology Grant 2017 (Markus Luedi) Mach-Gaensslen Foundation, Unteraegeri, Switzerland. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Chicoine MR , Zahner M , Won EK et al. The in vivo antitumoral effects of lipopolysaccharide against glioblastoma multiforme are mediated in part by toll-like receptor 4 . Neurosurgery . 2007 ; 60 ( 2 ): 372 - 381 . Google Scholar CrossRef Search ADS PubMed 2. Rolls A , Shechter R , London A et al. Toll-like receptors modulate adult hippocampal neurogenesis . Nat Cell Biol . 2007 ; 9 ( 9 ): 1081 - 1088 . Google Scholar CrossRef Search ADS PubMed 3. Reya T , Morrison SJ , Clarke MF , Weissman IL . Stem cells, cancer, and cancer stem cells . Nature . 2001 ; 414 ( 6859 ): 105 - 111 . Google Scholar CrossRef Search ADS PubMed 4. Singh SK , Hawkins C , Clarke ID et al. Identification of human brain tumour initiating cells . Nature . 2004 ; 432 ( 7015 ): 396 - 401 . Google Scholar CrossRef Search ADS PubMed 5. Lathia JD , Mack SC , Mulkearns-Hubert EE , Valentim CL , Rich JN . Cancer stem cells in glioblastoma . Genes Dev . 2015 ; 29 ( 12 ): 1203 - 1217 . Google Scholar CrossRef Search ADS PubMed 6. Alvarado AG , Thiagarajan PS , Mulkearns-Hubert EE et al. Glioblastoma cancer stem cells evade innate immune suppression of self-renewal through reduced TLR4 expression . Cell Stem Cell . 2017 ; 20 ( 4 ): 450 - 461 . e454 . Google Scholar CrossRef Search ADS PubMed 7. Hanahan D , Weinberg RA . The hallmarks of cancer . Cell . 2000 ; 100 ( 1 ): 57 - 70 . Google Scholar CrossRef Search ADS PubMed 8. Hawkins LD , Ishizaka ST , McGuinness P et al. A novel class of endotoxin receptor agonists with simplified structure, toll-like receptor 4-dependent immunostimulatory action, and adjuvant activity . J Pharmacol Exp Ther . 2002 ; 300 ( 2 ): 655 - 661 . Google Scholar CrossRef Search ADS PubMed 9. Luedi MM , Singh SK , Mosley JC et al. Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma . J Neurosurg . 2018 : 1 - 10 . doi: 10.3171/2017.7.JNS17668 [published online ahead of print] . Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Neurosurgery – Oxford University Press
Published: May 23, 2018
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