Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model

Abstract

The prognosis of patients with malignant glioma is extremely poor, despite the extensive surgical treatment that they receive and recent improvements in adjuvant radio-and chemotherapy. In the present study, we propose the use of gene-modified mesenchymal stem cells (MSCs) as a new tool for gene therapy of malignant brain neoplasms. Primary MSCs isolated from Fischer 344 rats possessed excellent migratory ability and exerted inhibitory effects on the proliferation of 9L glioma cell in vitro. We also confirmed the migratory capacity of MSCs in vivo and showed that when they were inoculated into the contralateral hemisphere, they migrated towards 9L glioma cells through the corpus callosum. MSCs implanted directly into the tumor localized mainly at the border between the 9L tumor cells and normal brain parenchyma, and also infiltrated into the tumor bed. Intratumoral injection of MSCs caused significant inhibition of 9L tumor growth and increased the survival of 9L glioma-bearing rats. Gene-modification of MSCs by infection with an adenoviral vector encoding human interleukin-2 (IL-2) clearly augmented the antitumor effect and further prolonged the survival of tumor-bearing rats. Thus, gene therapy employing MSCs as a targeting vehicle would be promising as a new therapeutic approach for refractory brain tumor.

Therapeutic potential of genetically modified mesenchymal stem cells

“…37,38 Several studies with transplantable tumors in mice have shown homing of MSC to many different cancers. [39][40][41][42] As better understanding of the biology of MSC and cancer cell interaction is growing, many studies have successfully employed bone marrow-derived MSC as therapeutic agents to treat a wide range of cancers.…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…In addition, gene-modification of MSCs by infection with an adenoviral vectorencoding human interleukin-2 enhanced the antitumor effect and further prolonged survival. 83 Combination of suppression of miR-21 via locked nucleic acid (LNA)-antimiR-21 oligonucleotides and NSCs expressing a secretable variant of the cytotoxic agent tumor necrosis factor-related apoptosis-inducing ligand (S-TRAIL), led to a synergistic increase in caspase activity and decreased cell viability in human glioma cells in vitro and in vivo. 84 Although TRAIL selectively kills tumor cells, its short half-life, poor delivery and TRAIL-resistant tumor cells have diminished its clinical efficacy.…”

HSV-1 amplicon viral vector-mediated gene transfer to human bone marrow-derived mesenchymal stem cells

“…16,25 To investigate whether the transduction with pHGCX HSV-1 amplicon viral vector will alter the tumor tropism of BM-hMSCs, in vitro migration chamber assays were performed. In the presence of either conditioned medium from NHAs or medium alone, both the naı¨ve and pHGCX-transduced BM-hMSCs did not migrate toward the underside of the membrane.…”

“…HSV-1 vectors have been widely used for gene delivery, especially to the brain due to its neurotrophic properties. 25 The recombinant HSV-1, either replication conditional or defective, contains the full viral genome with mutations in one or more viral genes. The replication-conditional recombinant HSV-1 viral vectors have been used to efficiently transduce neural precursor cells.…”