Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy

Abstract

The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their ''stem-like'' properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.gliomas ͉ in vivo imaging ͉ TRAIL

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

“…TRAIL is important in the initiation of graft-versus-tumor reactivity, 36 and hematopoietic and mesenchymal progenitors can be used as vehicles that efficiently target neoplastic cells in vivo. [8][9][10][11] Thus, in addition to the selective sensitivity of neoplastic cells to TRAIL, 2-4 its engraftment-promoting attributes suggest its usefulness as an immunotherapeutic adjuvant to chemotherapy. 24,44 Furthermore, membrane-bound ligands of the TNF family, such as Fas-ligand, are effective in counterattacking graft rejection in addition to graft supportive functions.…”

“…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.…”

“…[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. 8 Although the intracellular signaling pathways associated with TRAIL receptor activation have been described in detail, [12][13][14][15][16] the role of TRAIL under physiological, pathological and stress conditions is not completely understood.…”

ATP promotes immunosuppressive capacities of mesenchymal stromal cells by enhancing the expression of indoleamine dioxygenase

“…It has been well demonstrated that MSCs are recruited to the site of tumor,9, 11, 12, 13, 14 playing a pivotal role by interfering with other immune cells present in the surrounding tumor tissue. For this reason, it is highly relevant to determine how MSCs exert their immunoregulatory functions.…”

Extended and stable gene expression via nucleofection of MIDGE construct into adult human marrow mesenchymal stromal cells

“…Genetic modifications of MSC with therapeutic genes make them more effective for therapeutic use (Reiser et al 2005). These cells have been manipulated for the delivery of various genes including cytotoxic T lymphocyte antigen-imunoglobulin (CTLA-Ig), factor VIII, interleukin-2 and tumor necrosis factor apoptosis ligand (TRAIL) to treat graft versus host disease (GvHD), hemophilia A, glioma and glioblastoma, respectively (Deng et al 2003;Doering 2008;Nakamura et al 2004;Sasportas et al 2009;Van Damme et al 2003).…”