Toward brain tumor gene therapy using multipotent mesenchymal stromal cell vectors

Abstract

Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach.

Figure 1

Multipotent mesenchymal stromal cells (MSCs) in vitro and within gliomas. (a) Spindle-shaped morphology of rat bone marrow–derived MSCs in vitro. MSCs possess the capacity to differentiate into (b) osteoblasts and (c) adipocytes upon induction of differentiation. (d) Implantation of enhanced green fluorescent protein (eGFP)–expressing rat MSCs (green) into orthotopic rat gliomas (Hoechst, blue). MSCs spread extensively within the glioma but largely avoid adjacent normal brain parenchyma. (e) eGFP-MSCs migrate specifically along invasive DsRed-labeled glioma cells (red). a–c, Bar = 50 µm; d, bar = 200 µm; and e, bar = 100 µm. Figure 1a–c,e are reproduced from Bexell et al.²⁶ with permission from the publisher.

Figure 2

MSCs share pericyte characteristics. (a) Implanted rat eGFP⁺ MSCs (green) are attracted to perivascular niches within gliomas. Tumor blood vessels are delineated by the endothelial cell marker rat endothelial cell antigen (RECA, red). MSC expression of the pericyte markers (b) platelet-derived growth factor receptor-B (PDGFR-B) and (c) desmin in vitro. (d) Implanted eGFP-MSCs (green) express pericyte marker α-smooth muscle actin (red) within tumors. a, Bar = 100 µm; b,c, bar = 50 µm; d, bar = 20 µm.