Gene Therapy Using TRAIL-Secreting Human Umbilical Cord Blood–Derived Mesenchymal Stem Cells against Intracranial Glioma

Abstract

Adenovirus-mediated gene therapies against brain tumors have been limited by the difficulty in tracking glioma cells infiltrating the brain parenchyma. Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSC) are particularly attractive cells for clinical use in cell-based therapies. In the present study, we evaluated the tumor targeting properties and antitumor effects of UCB-MSCs as gene delivery vehicles for glioma therapy. We efficiently engineered UCB-MSCs to deliver a secretable trimeric form of tumor necrosis factor-related apoptosis-inducing ligand (stTRAIL) via adenoviral transduction mediated by cellpermeable peptides. We then confirmed the migratory capacity of engineered UCB-MSCs toward tumor cells by an in vitro migration assay and by in vivo injection of UCB-MSCs into the tumor mass or the opposite hemisphere of established human glioma in nude mice. Moreover, in vitro coculture, experiments on Transwell plates, and in vivo survival experiments showed that MSC-based stTRAIL gene delivery has more therapeutic efficacy compared with direct injection of adenovirus encoding the stTRAIL gene into a tumor mass. In vivo efficacy experiments showed that intratumoral injection of engineered UCB-MSCs (MSCs-stTRAIL) significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with controls. These results suggest that human UCB-MSCs have potential use as effective delivery vehicles for therapeutic genes in the treatment of intracranial glioma. [Cancer Res 2008;68(23):9614-23]

Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

“…1 Although it is expressed in many tissues under physiological conditions, TRAIL is not toxic to resting parenchymal cells and selectively kills malignant cells, 2-4 a differential sensitivity of neoplastic cells to TRAIL-induced apoptosis that can be used for therapeutic purposes. [5][6][7] For example, induced expression of TRAIL in CD34 þ cells 8,9 and mesenchymal stromal cells 10,11 was successfully applied to target tumor cells and induced their selective death in vitro and in vivo. In both cases, overexpression of TRAIL did not significantly affect the differentiation capacity of mesenchymal stromal cells into multiple lineages in vitro, 11 and the hematopoietic function of progenitors was preserved in vivo.…”

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…Mesenchymal stem cells (MSC), subject for investigation of their therapeutic potential in various clinical studies are known to exhibit high tropism (2) toward sites of injury, inflammation, and neoplasms, including GBM cells (3,4) that is mediated by paracrine actions of secreted growth factors, chemokines, cytokines, other peptides, and macromolecules (5). Upon tumor infiltration, MSC become part of the heterogeneous tumor microenvironment and are believed to participate in tumor progression by augmenting stemness of tumor cells, enhancing migration and angiogenesis, and drug resistance, while suppressing immune response resistance (6).…”

Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth

“…28,29 Virus diffuse passively once they are administered into the tissue, and their inadequate distribution and propagation within the tumor diminish their therapeutic capacity. 30 Viral vectors are very large compared with chemotherapeutic agents (over 100-fold), causing their distribution within the tumor to be very limited, thus the penetration of these vectors from the site of injection or from the vasculature is severely restricted. 4,19 The extracellular matrix has an important role limiting the distribution of viral vectors within the tumor, and experimental approaches to modulate the matrix, and thus allowing a better distribution of the virus have been proposed.…”