Exploiting tumor-intrinsic signals to induce mesenchymal stem cell-mediated suicide gene therapy to fight malignant glioma

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.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1194-0) contains supplementary material, which is available to authorized users.

Adipose-Derived Stem Cells in Cancer Progression: New Perspectives and Opportunities

“…Exploiting the intrinsically higher TGF-β expression in glioblastoma than in normal brain tissue, some researchers have engineered human ASCs in order to increase the expression of TRAIL under the trigger of TGF-β signaling via a SMAD4-controlled minimal promoter [97]. The therapeutic efficacy was proven by in vitro and in vivo assays using primary patient-derived glioblastoma models, which decreased tumor volume and prolonged survival time, as well as limiting off-target cytotoxicity with the controlled expression of the suicide inductor TRAIL [97]. The same strategy has proven effective in a mouse model of brainstem glioma [98].…”

Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer

“…Mesenchymal stem cells can uptake the majority of anticancer drugs from the culture environment (Kalimuthu et al, 2018;Salehi et al, 2018;Li et al, 2019). Considering this ability, simple methods have been used to prime hBM-MSCs with drugs.…”

IL10-modified Human Mesenchymal Stem Cells inhibit Pancreatic Cancer growth through Angiogenesis Inhibition

“…MSCs (mesenchymal stem cells) that have been genetically modified are hypothesized to show potential therapeutic abilities in several human diseases, including cancer. MSCs expressing IFN -β (interferon-β) injected intravenously may impede the pulmonary metastasis expansion of breast cancer and melanoma in mice [9][10][11], and increase the survival of mice having glioma xenografts [12]. The intrinsic homing ability is a well-accepted and a vital property of MSCs in cellular therapies.…”