Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. DiI Labeling of F3.CD and F3.CD-TK
2.3. In Vitro Assay for the Tumoricidal Effect of F3.CD and F3.CD-TK Formulas
- The dose–response oncolytic effect of 5FC on G55 converted by F3.CD or F3.CD-TK: G55 cells (1.5 × 104/well) and F3.CD or F3.CD-TK cells (0.75 × 104/well) were sequentially seeded in 24-well plates (BD Falcon; BD Biosciences, San Jose, CA, USA). After 24 h, a bolus dose of 5FC (0, 0.7 mM, 2.1 mM, or 7 mM) (Sigma-Aldrich) was added into the culture medium, and the culture was kept for another 72 h (total: 96 h).
- The dose–response effect of 5FC and GCV on G55 cells converted by F3.CD-TK cells: G55 cells (1.5 × 104/well) and F3.CD-TK cells (0.75 × 104/well) were sequentially seeded in 24-well plates (n = 5/group). After 24 h, a combinatorial dose of 5-FC (0, 0.7 mM, 2.1 mM, or 7 mM) and GCV (0, 4 µM, 12 µM, or 40 µM) (Sigma-Aldrich) was applied to the culture medium, and the culture was maintained for another 72 h (total: 96 h).
- Comparison of the oncolytic potency of individually or combinatorially applied 5FC and GCV in F3.CD-TK and G55 cocultures: G55 cells (1.5 × 104 per well) and F3.CD-TK cells (0.75 × 104 per well) were sequentially seeded in 24-well plates. After 24 h, a single dose of 5FC at 2.1 mM or GCV at 12 µM, or a combination of 2.1 mM 5FC + 12 µM GCV (i.e., optimal single doses determined in Steps i and ii), was applied to the culture medium to continue incubation for an additional 72 h.
- Evaluation of the oncolytic effect of consecutive prodrug administration on G55 cells converted by F3.CD-TK cells: G55 cells (1.5 × 104/well) and F3.CD-TK cells (0.75 × 104/well) were sequentially seeded in 24-well plates. After 24 h, 5FC or GCV was administered according to the following formulas: (1) 2.1 mM 5FC for 72 h; (2) 12 µM GCV for 72 h; (3) 2.1 mM 5FC for the first 36 h followed with 12 µM GCV for another 36 h; (4) 2.1 mM 5FC for the first 24 h with subsequent medium change with no precursor drug for 24 h (i.e., a washout period), followed by another 24 h treatment of 12 µM GCV; (5) 12 µM GCV for the first 36 h followed with 2.1 mM 5FC for another 36 h; (6) 12 µM GCV for 24 h with a subsequent 24 h washout period (see above), followed by another 24 h treatment of 2.1 mM 5FC; (7) combinatorial treatment of 2.1 mM 5FC and 12 µM GCV for 72 h; (8) no prodrug culturing for 72 h. At the end of each experiment, cell counting was conducted using the standard trypan blue method [5]. Each independent assay was performed in triplicate.
2.4. Immunocytochemical (ICC) Analysis of Activated Caspase 3
2.5. Enzyme-Linked Immunosorbent Assay (ELISA) of VEGF and BDNF
2.6. In Vivo Study Design
2.7. Intramedullary Spinal Cord Tumor Model
2.8. Administration of F3.hNSCs and Prodrugs
2.9. Functional Evaluation and Termination Criteria
2.10. Histopathological and Immunohistochemical (IHC) Procedures
2.11. Image Analysis
2.12. Statistical Analysis
3. Results
3.1. Expressions of VEGF and BDNF by F3.CD-TK and F3.CD Cells In Vitro
3.2. Connexins Expression and Gap Junction Formation by F3.CD-TK, F3.CD, and G55 Cells In Vitro
3.3. A stronger Cytotoxic Effect of F3.CD-TK (vs. F3.CD) Regimen on G55 Cells and Its Dependence on Gap Junction Channels
3.4. F3.CD-TK Regimen Robustly Improved Hindlimb Locomotion and Overall Survival of C6-ISCG Animals
3.5. F3.CD-TK Regimen Markedly Enhanced Wellbeing and Forelimb Motosensory Function of C6-ISCG Animals
3.6. Autonomic Improvements in C6-ISCG Animals following the F3.CD-TK Therapy
3.7. The Robust Effect of F3.CD-TK Regimen on Tumor Growth in C6-ISCG Animals
3.8. The Modifying Effect of F3.CD-TK Regimen on the Histopathological Feature of C6-ISCG
3.9. The Effect of F3.CD-TK Regimen on Inducing Apoptosis of C6-ISCG Cells
3.10. F3.CD-TK Regimen Rescued Host Neurites within the Interface Space between the Tumor and Spinal Cord
3.11. F3.CD-TK Treatment Improved Intraparenchymal Microenvironment via Neuroinflammation/Neuroimmune Modulation and GJIC Formation
3.12. The In Vivo Self-Clearance Rate Difference between F3.CD-TK and F3.CD Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Hsu, S.; Quattrone, M.; Ostrom, Q.; Ryken, T.C.; Sloan, A.E.; Barnholtz-Sloan, J.S. Incidence patterns for primary malignant spinal cord gliomas: A Surveillance, Epidemiology, and End Results (SEER) Study. J. Neurosurg. Spine 2011, 14, 742–747. [Google Scholar] [CrossRef] [PubMed]
- Liu, A.; Sankey, E.W.; Bettegowda, C.; Burger, P.C.; Jallo, G.I.; Groves, M.L. Poor prognosis despite aggressive treatment in adults with intramedullary spinal cord glioblastoma. J. Clin. Neurosci. 2015, 22, 1628–1631. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D.; Abd-El-Barr, M.; Wang, L.; Hajiali, H.; Wu, L.; Zafonte, R.D. Spinal cord astrocytomas: Progresses in experimental and clinical investigations for developing recovery neurobiology-based novel therapies. Exp. Neurol. 2019, 311, 135–147. [Google Scholar] [CrossRef] [PubMed]
- Capo, G.; Vandenbulcke, A.; Barreyet, C.Y. “Intramedullary Spinal Tumors” in Central Nervous System Tumors—Primary and Secondary; IntechOpen: London, UK, 2022. [Google Scholar]
- Ropper, A.E.; Zeng, X.; Haragopal, H.; Anderson, J.E.; Aljuboori, Z.; Han, I.; Abd-El-Barr, M.; Kim, S.U.; Chi, J.H.; Teng, Y.D. Targeted Treatment of Experimental Spinal Cord Glioma With Dual Gene-Engineered Human Neural Stem Cells. Neurosurgery 2016, 79, 481–491. [Google Scholar] [CrossRef] [PubMed]
- Zeng, X.; Han, I.; Abd-El-Barr, M.; Aljuboori, Z.; Anderson, J.E.; Chi, J.H.; Zafonte, R.D.; Teng, Y.D. The Effects of Thermal Preconditioning on Oncogenic and Intraspinal Cord Growth Features of Human Glioma Cells. Cell Transplant. 2016, 25, 2099–2109. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.Y.; Lee, D.H.; Kim, H.A.; Choi, S.A.; Lee, H.J.; Park, C.K.; Phi, J.H.; Wang, K.C.; Kim, S.U.; Kim, S.K. Double suicide gene therapy using human neural stem cells against glioblastoma: Double safety measures. J. Neurooncol 2014, 116, 49–57. [Google Scholar] [CrossRef] [PubMed]
- Aboody, K.S.; Brown, A.; Rainov, N.G.; Bower, K.A.; Liu, S.; Yang, W.; Small, J.E.; Herrlinger, U.; Ourednik, V.; Black, P.M.; et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc. Natl. Acad. Sci. USA 2000, 97, 12846–12851. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.-H.; Lee, J.-E.; Kim, S.U.; Cho, K.-G. Stereological analysis on migration of human neural stem cells in the brain of rats bearing glioma. Neurosurgery 2010, 66, 333–342. [Google Scholar] [CrossRef] [PubMed]
- Portnow, J.; Synold, T.W.; Badie, B.; Tirughana, R.; Lacey, S.F.; D’Apuzzo, M.; Metz, M.Z.; Najbauer, J.; Bedell, V.; Vo, T.; et al. Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients. Clin. Cancer Res. 2017, 23, 2951–2960. [Google Scholar] [CrossRef] [PubMed]
- Portnow, J.; Badie, B.; Suzette Blanchard, M.; Kilpatrick, J.; Tirughana, R.; Metz, M.; Mi, S.; Tran, V.; Ressler, J.; D’Apuzzo, M.; et al. Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients. Cancer Gene Ther. 2021, 28, 294–306. [Google Scholar] [CrossRef] [PubMed]
- Ropper, A.E.; Thakor, D.K.; Han, I.; Yu, D.; Zeng, X.; Anderson, J.E.; Aljuboori, Z.; Kim, S.W.; Wang, H.; Sidman, R.L.; et al. Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation. Proc. Natl. Acad. Sci. USA 2017, 114, E820–E829. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D. Functional Multipotency of Stem Cells and Recovery Neurobiology of Injured Spinal Cords. Cell Transplant. 2019, 28, 451–459. [Google Scholar] [CrossRef] [PubMed]
- Westphal, M.; Hänsel, M.; Hamel, W.; Kunzmann, R.; Hölzel, F. Karyotype analyses of 20 human glioma cell lines. Acta Neurochir 1994, 126, 17–26. [Google Scholar] [CrossRef] [PubMed]
- Heinzen, D.; Divé, I.; Lorenz, N.I.; Luger, A.L.; Steinbach, J.P.; Ronellenfitsch, M.W. Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment. Int. J. Mol. Sci. 2019, 20, 4474. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.; Phillips, H.S.; Ferrara, N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993, 362, 841–844. [Google Scholar] [CrossRef] [PubMed]
- Rubenstein, J.L.; Kim, J.; Ozawa, T.; Zhang, M.; Westphal, M.; Deen, D.F.; Shuman, M.A. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2000, 2, 306–314. [Google Scholar] [CrossRef] [PubMed]
- Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro Oncol 2021, 23, 1231–1251. [Google Scholar] [CrossRef]
- Claes, A.; Idema, A.J.; Wesseling, P. Diffuse glioma growth: A guerilla war. Acta Neuropathol. 2007, 114, 443–458. [Google Scholar] [CrossRef] [PubMed]
- Kim, S.K.; Kim, S.U.; Park, I.H.; Bang, J.H.; Aboody, K.S.; Wang, K.C.; Cho, B.K.; Kim, M.; Menon, L.G.; Black, P.M.; et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin. Cancer Res. 2006, 12, 5550–5556. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Natsume, A.; Lee, H.J.; Motomura, K.; Nishimira, Y.; Ohno, M.; Ito, M.; Kinjo, S.; Momota, H.; Iwami, K.; et al. Neural stem cell-based dual suicide gene delivery for metastatic brain tumors. Cancer Gene Ther. 2012, 19, 796–801. [Google Scholar] [PubMed]
- Wang, L.; Gunduz, M.A.; Semeano, A.T.; Yılmaz, E.C.; Alanazi, F.A.H.; Imir, O.B.; Yener, U.; Arbelaez, C.A.; Usuga, E.; Teng, Y.D. Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: A systematic approach to profiling neuropathic pain. J. Neuroinflammation 2022, 19, 264. [Google Scholar] [CrossRef] [PubMed]
- Basso, D.M.; Beattie, M.S.; Bresnahan, J.C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 1995, 12, 1–21. [Google Scholar] [CrossRef] [PubMed]
- Martinez, M.; Brezun, J.M.; Bonnier, L.; Xerri, C. A new rating scale for open-field evaluation of behavioral recovery after cervical spinal cord injury in rats. J. Neurotrauma 2009, 26, 1043–1053. [Google Scholar] [CrossRef]
- Feng, M.; Whitesall, S.; Zhang, Y.; Beibel, M.; D’Alecy, L.; DiPetrillo, K. Validation of volume-pressure recording tail-cuff blood pressure measurements. Am. J. Hypertens. 2008, 21, 1288–1291. [Google Scholar] [CrossRef] [PubMed]
- Choi, H.; Liao, W.-L.; Newton, K.M.; Onario, R.C.; King, A.M.; Desilets, F.C.; Woodard, E.J.; Frontera, W.R.; Sabharwal, S.; Teng, Y.D. Respiratory abnormalities resulting from midcervical spinal cord injury and their reversal by serotonin 1A agonists in conscious rats. J. Neurosci. 2005, 25, 4550–4559. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D. Method for Improving Respiratory Function and Inhibiting Muscular Degeneration. United. U.S. Patent 7,071,194, 4 July 2006. [Google Scholar]
- Schmidt, N.O.; Przylecki, W.; Yang, W.; Ziu, M.; Teng, Y.D.; Kim, S.U.; Black, P.M.; Aboody, K.S.; Carroll, R.S. Brain tumor tropism of transplanted human neural stem cells is induced by vascular endothelial growth factor. Neoplasia 2005, 7, 623–629. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D.; Benn, S.C.; Kalkanis, S.N.; Shefner, J.M.; Onario, R.C.; Cheng, B.; Lachyankar, M.B.; Marconi, M.; Li, J.; Yu, D.; et al. Multimodal actions of neural stem cells in a mouse model of ALS: A meta-analysis. Sci. Transl. Med. 2012, 4, 165ra164. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D. Functional multipotency of stem cells: Biological traits gleaned from neural progeny studies. Semin. Cell Dev. Biol. 2019, 95, 74–83. [Google Scholar] [CrossRef] [PubMed]
- Noble, M. Can neural stem cells be used to track down and destroy migratory brain tumor cells while also providing a means of repairing tumor-associated damage? Proc. Natl. Acad. Sci. USA 2000, 97, 12393–12395. [Google Scholar] [CrossRef] [PubMed]
- Elshami, A.A.; Saavedra, A.; Zhang, H.; Kucharczuk, J.C.; Spray, D.C.; Fishman, G.I.; Amin, K.M.; Kaiser, L.R.; Albelda, S.M. Gap junctions play a role in the “bystander effect” of the herpes simplex virus thymidine kinase/ganciclovir system in vitro. Gene Ther. 1996, 3, 85–92. [Google Scholar]
- Cottin, S.; Gould, P.V.; Cantin, L.; Caruso, M. Gap junctions in human glioblastomas: Implications for suicide gene therapy. Cancer Gene Ther. 2011, 18, 674–681. [Google Scholar] [CrossRef] [PubMed]
- Zhang, M.; Song, T.; Yang, L.; Chen, R.; Wu, L.; Yang, Z.; Fang, J. Nestin and CD133: Valuable stem cell-specific markers for determining clinical outcome of glioma patients. J. Exp. Clin. Cancer Res. 2008, 27, 85. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D.; Wang, L.; Kabatas, S.; Ulrich, H.; Zafonte, R.D. Cancer Stem Cells or Tumor Survival Cells? Stem Cells Dev. 2018, 27, 1466–1478. [Google Scholar] [CrossRef] [PubMed]
- Ghosh, B.; Wang, Z.; Nong, J.; Urban, M.W.; Zhang, Z.; Trovillion, V.A.; Wright, M.C.; Zhong, Y.; Lepore, A.C. Local BDNF Delivery to the Injured Cervical Spinal Cord using an Engineered Hydrogel Enhances Diaphragmatic Respiratory Function. J. Neurosci. 2018, 38, 5982–5995. [Google Scholar] [CrossRef] [PubMed]
- Jecko, V.; Roblot, P.; Mongardi, L.; Ollivier, M.; Piccoli, N.D.; Charleux, T.; Wavasseur, T.; Gimbert, E.; Liguoro, D.; Chotard, G.; et al. Intramedullary Spinal Cord Lesions: A Single-Center Experience. Neurospine 2022, 19, 108–117. [Google Scholar] [CrossRef] [PubMed]
- Bhimani, A.D.; Rosinski, C.L.; Denyer, S.; Hobbs, J.G.; Patel, S.; Shah, K.; Mudreac, A.; Diamond, R.; Behbahani, M.; Mehta, A.I. Acute Surgical Risk Profile of Intramedullary Spinal Cord Tumor Resection in Pediatric Patients: A Pediatric National Surgical Quality Improvement Program Analysis. World Neurosurg. 2019, 121, e389–e397. [Google Scholar] [CrossRef] [PubMed]
- Szucs, P.; Luz, L.L.; Pinho, R.; Aguiar, P.; Antal, Z.; Tiong, S.Y.; Todd, A.J.; Safronov, B.V. Axon diversity of lamina I local-circuit neurons in the lumbar spinal cord. J. Comp. Neurol. 2013, 521, 2719–2741. [Google Scholar] [CrossRef] [PubMed]
- Laliberte, A.M.; Goltash, S.; Lalonde, N.R.; Bui, T.V. Propriospinal Neurons: Essential Elements of Locomotor Control in the Intact and Possibly the Injured Spinal Cord. Front. Cell Neurosci. 2019, 13, 512. [Google Scholar] [CrossRef] [PubMed]
- Diep, Y.N.; Hyeon, S.J.; McQuade, A.; Tran, M.; Ko, H.Y.; Jo, H.; Kim, J.; Chung, J.I.; Kim, T.Y.; Kim, D.; et al. Astrocytic scar restricting glioblastoma via glutamate-MAO-B activity in glioblastoma-microglia assembloid. Biomater. Res. 2023, 27, 71. [Google Scholar] [CrossRef] [PubMed]
- Perez, J.-C.; Gerber, Y.N.; Perrin, F.E. Dynamic Diversity of Glial Response Among Species in Spinal Cord Injury. Front. Aging Neurosci. 2021, 13, 769548. [Google Scholar] [CrossRef]
- Warawdekar, U.M. An Assay to Assess Gap Junction Communication in Cell Lines. J. Biomol. Tech. 2019, 30, 1–6. [Google Scholar] [CrossRef] [PubMed]
- Hopperton, K.E.; Mohammad, D.; Trépanier, M.O.; Giuliano, V.; Bazinet, R.P. Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: A systematic review. Mol. Psychiatry 2018, 23, 177–198. [Google Scholar] [CrossRef] [PubMed]
- Kuntzel, T.; Bagnard, D. Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis. Pharmaceutics 2022, 14, 344. [Google Scholar] [CrossRef] [PubMed]
- Kisucká, A.; Bimbová, K.; Bačová, M.; Gálik, J.; Lukáčová, N. Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury. Cells 2021, 10, 1943. [Google Scholar] [CrossRef] [PubMed]
- Lesniak, M.S.; Langer, R.; Brem, H. Drug delivery to tumors of the central nervous system. Curr. Neurol. Neurosci. Rep. 2001, 1, 210–216. [Google Scholar] [CrossRef] [PubMed]
- Sontheimer, H. Malignant gliomas: Perverting glutamate and ion homeostasis for selective advantage. Trends Neurosci. 2003, 26, 543–549. [Google Scholar] [CrossRef] [PubMed]
- Sontheimer, H. Ion channels and amino acid transporters support the growth and invasion of primary brain tumors. Mol. Neurobiol. 2004, 29, 61–71. [Google Scholar] [CrossRef]
- Di Nunno, V.; Aprile, M.; Gatto, L.; Tosoni, A.; Ranieri, L.; Bartolini, S.; Franceschi, E. Tumor Microenvironment in Gliomas: A Treatment Hurdle or an Opportunity to Grab? Cancers 2023, 15, 1042. [Google Scholar] [CrossRef] [PubMed]
- Gerardi, R.M.; Giammalva, G.R.; Basile, L.; Gulì, C.; Pino, M.A.; Messina, D.; Umana, G.E.; Graziano, F.; di Bonaventura, R.; Sturiale, C.L.; et al. White Cord Syndrome After Cervical or Thoracic Spinal Cord Decompression. Hemodynamic Complication or Mechanical Damage? An Underestimated Nosographic Entity. World Neurosurg. 2022, 164, 243–250. [Google Scholar] [CrossRef] [PubMed]
- López-Gómez, L.; Abalo, R.; Vera, G. Central Neurotoxicity of Chemotherapy. In Handbook of Cancer and Immunology; Rezaei, N., Ed.; Springer International Publishing: New York, NY, USA, 2022; pp. 1–27. [Google Scholar]
- Amelchenko, E.M.; Bezriadnov, D.V.; Chekhov, O.A.; Ivanova, A.A.; Kedrov, A.V.; Anokhin, K.V.; Lazutkin, A.A.; Enikolopov, G. Cognitive Flexibility Is Selectively Impaired by Radiation and Is Associated with Differential Recruitment of Adult-Born Neurons. J. Neurosci. 2023, 43, 6061–6083. [Google Scholar] [CrossRef] [PubMed]
- Teng, Y.D.; Yu, D.; Ropper, A.E.; Wakeman, D.R.; Wang, J.; Sullivan, M.P.; Redmond, D.E., Jr.; Langer, R.; Snyder, E.Y.; Sidman, R.L. Functional multipotency of stem cells: A conceptual review of neurotrophic factor-based evidence and its role in translational research. Curr. Neuropharmacol. 2011, 9, 574–585. [Google Scholar]
- Park, K.I.; Teng, Y.D.; Snyder, E.Y. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat. Biotechnol. 2002, 20, 1111–1117. [Google Scholar] [CrossRef] [PubMed]
- Cao, Q.-L.; Howard, R.M.; Dennison, J.B.; Whittemore, S.R. Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp. Neurol. 2002, 177, 349–359. [Google Scholar] [CrossRef] [PubMed]
- Blurton-Jones, M.; Kitazawa, M.; Martinez-Coria, H.; Castello, N.A.; Müller, F.J.; Loring, J.F.; Yamasaki, T.R.; Poon, W.W.; Green, K.N.; LaFerla, F.M. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 2009, 106, 13594–13599. [Google Scholar] [CrossRef] [PubMed]
- Wielińska, J.; Nowacki, A.; Liberek, B. 5-Fluorouracil-Complete Insight into Its Neutral and Ionised Forms. Molecules 2019, 24, 3683. [Google Scholar] [CrossRef] [PubMed]
- Wohlhueter, R.M.; McIvor, R.S.; Plagemann, P.G. Facilitated transport of uracil and 5-fluorouracil, and permeation of orotic acid into cultured mammalian cells. J. Cell Physiol. 1980, 104, 309–319. [Google Scholar] [CrossRef] [PubMed]
- Ladd, B.; O’Konek, J.J.; Ostruszka, L.J.; Shewach, D.S. Unrepairable DNA double-strand breaks initiate cytotoxicity with HSV-TK/ganciclovir. Cancer Gene Ther. 2011, 18, 751–759. [Google Scholar] [CrossRef] [PubMed]
- Shanker, A.J.; Yamada, K.; Green, K.G.; Yamada, K.A.; Saffitz, J.E. Matrix-protein-specific regulation of Cx43 expression in cardiac myocytes subjected to mechanical load. Circ. Res. 2005, 96, 558–566. [Google Scholar] [CrossRef] [PubMed]
- VanSlyke, J.K.; Musil, L.S. Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol. Biol. Cell 2005, 16, 5247–5257. [Google Scholar] [CrossRef] [PubMed]
- Bai, D.; del Corsso, C.; Srinivas, M.; Spray, D.C. Block of specific gap junction channel subtypes by 2-aminoethoxydiphenyl borate (2-APB). J. Pharmacol. Exp. Ther. 2006, 319, 1452–1458. [Google Scholar] [CrossRef] [PubMed]
- Luo, E.W.-C.; Liao, M.-L.; Chien, C.-L. Neural differentiation of glioblastoma cell lines via a herpes simplex virus thymidine kinase/ganciclovir system driven by a glial fibrillary acidic protein promoter. PLoS ONE 2021, 16, e0253008. [Google Scholar] [CrossRef] [PubMed]
- Theodoric, N.; Bechberger, J.F.; Naus, C.C.; Sin, W.-C. Role of gap junction protein connexin43 in astrogliosis induced by brain injury. PLoS ONE 2012, 7, e47311. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Liu, C.F.; Chen, A.B.; Yao, Z.; Li, W.G.; Xu, S.J.; Ma, X.Y. Prognostic and Clinic Pathological Value of Cx43 Expression in Glioma: A Meta-Analysis. Front. Oncol. 2019, 9, 1209. [Google Scholar] [CrossRef] [PubMed]
- Jäderstad, J.; Jäderstad, L.M.; Li, J.; Chintawar, S.; Salto, C.; Pandolfo, M.; Ourednik, V.; Teng, Y.D.; Sidman, R.L.; Arenas, E.; et al. Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host. Proc. Natl. Acad. Sci. USA 2010, 107, 5184–5189. [Google Scholar] [CrossRef] [PubMed]
- Okolie, O.; Bago, J.R.; Schmid, R.S.; Irvin, D.M.; Bash, R.E.; Miller, C.R.; Hingtgen, S.D. Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model. Neuro Oncol. 2016, 18, 1622–1633. [Google Scholar] [CrossRef] [PubMed]
- Bikfalvi, A.; da Costa, C.A.; Avril, T.; Barnier, J.V.; Bauchet, L.; Brisson, L.; Cartron, P.F.; Castel, H.; Chevet, E.; Chneiweiss, H.; et al. Challenges in glioblastoma research: Focus on the tumor microenvironment. Trends Cancer 2023, 9, 9–27. [Google Scholar] [CrossRef] [PubMed]
- Geribaldi-Doldán, N.; Fernández-Ponce, C.; Quiroz, R.N.; Sánchez-Gomar, I.; Escorcia, L.G.; Velásquez, E.P.; Quiroz, E.N. The Role of Microglia in Glioblastoma. Front. Oncol. 2021, 10, 603495. [Google Scholar] [CrossRef] [PubMed]
- Bashyal, N.; Lee, T.Y.; Chang, D.Y.; Jung, J.H.; Kim, M.G.; Acharya, R.; Kim, S.S.; Oh, I.H.; Suh-Kim, H. Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase. Mol. Cells 2022, 45, 479–494. [Google Scholar] [CrossRef] [PubMed]
- Chang, D.Y.; Jung, J.H.; Kim, A.A.; Marasini, S.; Lee, Y.J.; Paek, S.H.; Kim, S.S.; Suh-Kim, H. Combined effects of mesenchymal stem cells carrying cytosine deaminase gene with 5-fluorocytosine and temozolomide in orthotopic glioma model. Am. J. Cancer Res. 2020, 10, 1429–1441. [Google Scholar] [PubMed]
- Boucher, P.D.; Im, M.M.; Freytag, S.O.; Shewach, D.S. A novel mechanism of synergistic cytotoxicity with 5-fluorocytosine and ganciclovir in double suicide gene therapy. Cancer Res. 2006, 66, 3230–3237. [Google Scholar] [CrossRef] [PubMed]
- Markowicz-Piasecka, M.; Huttunen, J.; Montaser, A.; Adla, S.K.; Auriola, S.; Lehtonen, M.; Huttunen, K.M. Ganciclovir and Its Hemocompatible More Lipophilic Derivative Can Enhance the Apoptotic Effects of Methotrexate by Inhibiting Breast Cancer Resistance Protein (BCRP). Int. J. Mol. Sci. 2021, 22, 7727. [Google Scholar] [CrossRef] [PubMed]
- Kim, B.H.; Oh, H.K.; Kim, D.W.; Kang, S.B.; Choi, Y.; Shin, E. Clinical Implications of Cancer Stem Cell Markers and ABC Transporters as a Predictor of Prognosis in Colorectal Cancer Patients. Anticancer Res. 2020, 40, 4481–4489. [Google Scholar] [CrossRef] [PubMed]
- Demuth, T.; Berens, M.E. Molecular mechanisms of glioma cell migration and invasion. J. Neurooncol. 2004, 70, 217–228. [Google Scholar] [CrossRef] [PubMed]
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Zeng, X.; Ropper, A.E.; Aljuboori, Z.; Yu, D.; Teng, T.W.; Kabatas, S.; Usuga, E.; Anderson, J.E.; Teng, Y.D. Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma. Cells 2024, 13, 1522. https://doi.org/10.3390/cells13181522
Zeng X, Ropper AE, Aljuboori Z, Yu D, Teng TW, Kabatas S, Usuga E, Anderson JE, Teng YD. Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma. Cells. 2024; 13(18):1522. https://doi.org/10.3390/cells13181522
Chicago/Turabian StyleZeng, Xiang, Alexander E. Ropper, Zaid Aljuboori, Dou Yu, Theodore W. Teng, Serdar Kabatas, Esteban Usuga, Jamie E. Anderson, and Yang D. Teng. 2024. "Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma" Cells 13, no. 18: 1522. https://doi.org/10.3390/cells13181522