Bone Marrow–Derived Mesenchymal Stem Cell–Mediated Dual-Gene Therapy for Glioblastoma

Abstract

Bone-marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. However, the optimal treatment time post-BMSC implantation and the assessment of the long-term fate of therapeutic BMSCs post-tumor treatment are critical if such promising therapies are to be translated into clinical practice. An efficient BMSC-based therapeutic strategy has been developed that simultaneously allows killing of tumor cells, inhibiting of tumor angiogenesis, and assessment and eradication of implanted BMSCs after treatment of glioblastoma. BMSCs were engineered to co-express the angiogenesis inhibitor kringle 5 (K5) of human plasminogen, under the control of the cytomegalovirus promoter (CMV) and the human sodium-iodide symporter (NIS), involved in uptake of radioisotopes, under the control of early growth response factor 1 (Egr1), a radiation-activated promoter. A significant decrease in tumor growth and tumor angiogenesis and a subsequent increase in survival were observed when mice bearing glioblastoma were treated with Re post-therapeutic intravenous BMSC implantation. Furthermore, the systemic administration ofRe post-tumor treatment selectively eliminated therapeutic BMSCs expressing NIS, which was monitored in real time by I micro single photon emission computed tomography/computed tomography imaging. Meanwhile, the Egr1 promoter induced aRe radiation positive feedback effect absorbed by NIS. After intravenous BMSC implantation, BMSCs levels in the tumor and lung both peaked on day 10 and decreased to the lowest levels on days 24 and 17, respectively. These findings suggest that day 17 post-BMSC implantation could be an optimal time for Re treatment. These results provide a new adjuvant therapy mediated by BMSCs for glioblastoma treatment.

Kinins in Glioblastoma Microenvironment

“…Other studies, however, claimed that MSCs can be safely used as drug delivery vectors [64]. Lastly, after their engraftment to the tumour, MSCs can differentiate into tumour-associated fibroblasts, endothelial-, pericytes [59,65] and macrophage-like cells [64], possibly even to GSCs as hypothesized by Appaix [22]. In conclusion, MSCs in the tumour microenvironment interact with tumour cells and other stromal cells via a number of signalling molecules, forming a complex cellular cross-talk.…”

“…Another intrinsic characteristic of MSCs, worth researching, is the ability to home from bone marrow, adipose tissue or other tissues to glioma tumors [59]. MSCs affect GBM and GSCs directly and/or modulate other stromal components, such as immune cells.…”

“…Similar to their chemotactic response to the sites of injury, MSCs also exert, possibly by the same cues, tropism to brain tumours. Noteworthy, MSCs have the ability to cross the blood-brain barrier in particular in a loose intratumour vasculature in angiogenic GBM, where they have immunosuppressive effects [59]. Further, as GBM/GSC cells diffusely spread into the neighbouring parenchyma and interact with MSCs, immune cells, fibroblasts, endothelial cells, and astrocytes.…”

Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale

“…[16][17][18] Due to these desirable attributes, NIS has been used in many applications, such as tracking viral infection, replication, and spread in oncolytic virotherapy in animals and humans, tracking the intensity and durability of gene and cell therapies, and for treatment of NIS-expressing tumors with radioisotopes. 14,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Despite the growing utility of NIS as a reporter gene, there remain several challenges to NIS imaging and therapy. Endogenous NIS expression, efflux of radiotracer from NIS-expressing cells, and suboptimal NIS expression in target tissues decrease the efficacy of NIS imaging.…”

Enhanced Anticancer Property of Ad-MSC-TRAIL on Breast Cancer Cells When Combined with the Aqueous Extract of Berberis vulgaris

“…Thus, they open a window to improve clinical approaches like cancer gene therapy. One of the novel applications of MSCs is their use as expression vectors for anticancer proteins, and due to their native tumor homing property, they could be considered as a targeted cancer cell therapy (7). Among these anticancer agents, TNF-related apoptosisinducing ligand (TRAIL) has received more attention in the last decades (8).…”