Abstract

BackgroundHuman mesenchymal stem cell (MSC)-based tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene delivery is regarded as an effective treatment for glioblastoma (GBM). However, adverse-free target site homing of the delivery vehicles to the tumor microsatellite nests is challenging, leading to erroneously sustained released of this suicide protein into the normal brain parenchyma; therefore, limiting off-target cytotoxicity and controlled expression of the suicide inductor is a prerequisite for the safe use of therapeutic stem cells.MethodsUtilizing the intrinsic expression profile of GBM and its elevated expression of TGF-β relative to normal brain tissue, we sought to engineer human adipose-derived MSCs (hAMSC-SBE4-TRAIL) which augment the expression of TRAIL under the trigger of TGF-β signaling. We validated our therapeutic technology in a series of functional in vitro and in vivo assays using primary patient-derived GBM models.ResultsOur current findings show that these biologic delivery vehicles have high tumor tropism efficacy and expression TRAIL gene under the trigger of TGF-β-secreting GBMs, as well as avoid unspecific TRAIL secretion into normal brain tissue. hAMSC-SBE4-TRAIL inhibited the proliferation and induced apoptosis in experimental GBMs both in vitro and in vivo. In addition, our improved platform of engineered MSCs significantly decreased the tumor volume and prolonged survival time in a murine model of GBM.ConclusionsOur results on the controlled release of suicide inductor TRAIL by exploiting an endogenous tumor signaling pathway demonstrate a significant improvement for the clinical utility of stem cell-mediated gene delivery to treat brain cancers. Harvesting immune-compatible MSCs from patients’ fat by minimally invasive procedures further highlights the clinical potential of this approach in the vision of applicability in a personalized manner. The hAMSC-SBE4-TRAIL exhibit great curative efficacy and are a promising cell-based treatment option for GBM to be validated in clinical exploration.

Highlights

  • Glioblastoma (GBM) is one of the most common and intractable primary malignant brain tumors, with an annual incidence of 5.26 per 100,000 population or 17,000 new diagnoses per year [1, 2]

  • Several studies reported that human adipose-derived mesenchymal stem cells exhibit remarkable tropism specificity toward glioblastoma including the tracking of hard-to-resect disseminated microscopic tumor foci [13,14,15]

  • Cell lines Following the approval by the Huazhong University of Science and Technology (HUST) Institutional Review Board, early passaged primary human adipose-derived mesenchymal stem cells and human glioblastoma (GBM025, GBM079, GBM106) were obtained from patients undergoing neurosurgical procedures as described in our previous studies [7, 15, 29]

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Summary

Introduction

Glioblastoma (GBM) is one of the most common and intractable primary malignant brain tumors, with an annual incidence of 5.26 per 100,000 population or 17,000 new diagnoses per year [1, 2]. Recent studies suggested that human stem cells can be used for the delivery of therapeutic genes to treat brain tumors [6,7,8]. Several studies reported that human adipose-derived mesenchymal stem cells (hAMSCs) exhibit remarkable tropism specificity toward glioblastoma including the tracking of hard-to-resect disseminated microscopic tumor foci [13,14,15]. Together with the possibility to genetically equip MSCs with therapeutic loads, hAMSCs are promising candidates for biological deliveries of therapies to fight a brain tumor. Human mesenchymal stem cell (MSC)-based tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene delivery is regarded as an effective treatment for glioblastoma (GBM). Adverse-free target site homing of the delivery vehicles to the tumor microsatellite nests is challenging, leading to erroneously sustained released of this suicide protein into the normal brain parenchyma; limiting off-target cytotoxicity and controlled expression of the suicide inductor is a prerequisite for the safe use of therapeutic stem cells

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