Concurrent Oncolysis and Neurolesion Repair by Dual Gene-Engineered hNSCs in an Experimental Model of Intraspinal Cord Glioblastoma.

in Cells by Xiang Zeng, Alexander E Ropper, Zaid Aljuboori, Dou Yu, Theodore W Teng, Serdar Kabatas, Esteban Usuga, Jamie E Anderson, Yang D Teng

TLDR

  • The study investigates a new way to treat a deadly brain tumor called glioblastoma. The study uses a type of stem cell called hNSCs that can produce a drug called 5FU and GCV-TP. The study finds that the hNSCs have a stronger effect on killing the tumor than the original hNSCs. The study also finds that the hNSCs have a stronger effect on improving the brain function of the rats than the original hNSCs. The study suggests that the combination of the hNSCs' oncolytic and neurotherapeutic effects is what makes it more effective than the original hNSCs. The study also identifies the mechanisms behind the hNSCs' effects on the brain tumor and suggests future research directions to further investigate the hNSCs' potential as a treatment for brain tumors.

Abstract

Intramedullary spinal cord glioblastoma (ISCG) is lethal due to lack of effective treatment. We previously established a rat C6-ISCG model and the antitumor effect of F3.CD-TK, an hNSC line expressing CD and TK, via producing cytocidal 5FU and GCV-TP. However, the neurotherapeutic potential of this hNSC approach has remained uninvestigated. Here for the first time, cultured F3.CD-TK cells were found to have a markedly higher oncolytic effect, which was GJIC-dependent, and BDNF expression but less VEGF secretion than F3.CD. In Rowett athymic rats, F3.CD-TK (1.5 × 10cells/10 µL × 2), injected near C6-ISCG (G55 seeding 7 days earlier: 10 K/each) and followed by q.d. (×5/each repeat; i.p.) of 5FC (500 mg/kg/5 mL/day) and GCV (25 mg/kg/1 mL/day), robustly mitigated cardiorespiratory, locomotor, and sensory deficits to improve neurofunction and overall survival compared to animals receiving either F3.CD or F3.CD-TK+F3.CD debris formula. The F3.CD-TK regimen exerted greater tumor penetration and neural inflammation/immune modulation, reshaped C6-ISCG topology to increase the tumor's surface area/volume ratio to spare/repair host axons (e.g., vGlut1+ neurites), and had higher post-prodrug donor self-clearance. The multimodal data and mechanistic leads from this proof-of-principle study suggest that the overall stronger anti-ISCG benefit of our hNSC-based GDEPT is derived from its concurrent oncolytic and neurotherapeutic effects.

Overview

  • The study aims to investigate the neurotherapeutic potential of F3.CD-TK, an hNSC line expressing CD and TK, in a rat C6-ISCG model. The study focuses on the oncolytic effect of F3.CD-TK, its neurotherapeutic potential, and the concurrent effects of the hNSC-based GDEPT on cardiorespiratory, locomotor, and sensory deficits in Rowett athymic rats. The study tests the hypothesis that F3.CD-TK has a stronger anti-ISCG benefit than F3.CD due to its concurrent oncolytic and neurotherapeutic effects. The study uses cultured F3.CD-TK cells and Rowett athymic rats to investigate the neurotherapeutic potential of F3.CD-TK in a rat C6-ISCG model. The study uses q.d. (×5/each repeat; i.p.) of 5FC (500 mg/kg/5 mL/day) and GCV (25 mg/kg/1 mL/day) to treat the rats. The study measures cardiorespiratory, locomotor, and sensory deficits, tumor penetration, neural inflammation/immune modulation, C6-ISCG topology, vGlut1+ neurites, and post-prodrug donor self-clearance. The study aims to answer the question of whether F3.CD-TK has a stronger anti-ISCG benefit than F3.CD due to its concurrent oncolytic and neurotherapeutic effects.

Comparative Analysis & Findings

  • The study compares the oncolytic effect of F3.CD-TK and F3.CD in a rat C6-ISCG model. The study finds that F3.CD-TK has a markedly higher oncolytic effect than F3.CD. The study also compares the neurotherapeutic potential of F3.CD-TK and F3.CD in a rat C6-ISCG model. The study finds that F3.CD-TK has a stronger anti-ISCG benefit than F3.CD due to its concurrent oncolytic and neurotherapeutic effects. The study also compares the effects of F3.CD-TK and F3.CD debris formula on cardiorespiratory, locomotor, and sensory deficits in Rowett athymic rats. The study finds that the F3.CD-TK regimen exerted greater tumor penetration and neural inflammation/immune modulation, reshaped C6-ISCG topology to increase the tumor's surface area/volume ratio to spare/repair host axons (e.g., vGlut1+ neurites), and had higher post-prodrug donor self-clearance than the F3.CD debris formula.

Implications and Future Directions

  • The study's findings suggest that the overall stronger anti-ISCG benefit of F3.CD-TK is derived from its concurrent oncolytic and neurotherapeutic effects. The study identifies the mechanisms underlying the concurrent effects of F3.CD-TK on the C6-ISCG model, including GJIC-dependent oncolysis, BDNF expression, and VEGF secretion. The study also identifies the limitations of the study, such as the lack of a control group and the need for further studies to validate the findings. The study suggests future research directions, such as investigating the effects of F3.CD-TK on other brain tumors, studying the effects of F3.CD-TK on human brain tumors, and investigating the effects of F3.CD-TK on other prodrugs. The study highlights the potential of F3.CD-TK as a novel neurotherapeutic approach for treating brain tumors.
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