Antitumor Activity of a Mesenchymal Stem Cell Line Stably Secreting a Tumor-Targeted TNF-Related Apoptosis-Inducing Ligand Fusion Protein

Abstract

Mesenchymal stem cells (MSCs) are currently exploited as gene delivery systems for transient in situ expression of cancer therapeutics. As an alternative to the prevailing viral expression, we here describe a murine MSC line stably expressing a therapeutic protein for up to 42 passages, yet fully maintaining MSC features. Because of superior antitumoral activity of hexavalent TNF-related apoptosis-inducing ligand (TRAIL) formats and the advantage of a tumor-targeted action, we choose expression of a dimeric EGFR-specific diabody single-chain TRAIL (Db-scTRAIL) as a model. The bioactivity of Db-scTRAIL produced from an isolated clone (MSC.TRAIL) was revealed from cell death induction in Colo205 cells treated with either culture supernatants from or cocultured with MSC.TRAIL. In vivo, therapeutic activity of MSC.TRAIL was shown upon peritumoral injection in a Colo205 xenograft tumor model. Best antitumor activity in vitro and in vivo was observed upon combined treatment of MSC.TRAIL with bortezomib. Importantly, in vivo combination treatment did not cause apparent hepatotoxicity, weight loss, or behavioral changes. The development of well characterized stocks of stable drug-producing human MSC lines has the potential to establish standardized protocols of cell-based therapy broadly applicable in cancer treatment.

Molecular definition of group 1 innate lymphoid cells in the mouse uterus

“…These pathways are important in the biology of DC and T cells 56 , 57 and future work will establish if uterine g1 ILCs require these pathways and whether their differentiation is modulated by metabolism. In a recent study, Srebp proteins and genes involved in fatty-acid and cholesterol synthesis appeared essential for the metabolic reprogramming of NK cells in response to cytokine stimulation 58 , 59 . Interestingly, our analysis reveals that uterine, not liver resident g1 ILCs upregulate Slc16a13 , which encodes lactate and pyruvate cell exporter MCT13 37 .…”

Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype

“…They may be genetically engineered to express anti-proliferative, anti-angiogenic, pro-apoptotic factors as well as cytokines and suicide genes. Recently, Marini et al reported the therapeutic activity of MSC stably transfected to express a TNF-Related Apoptosis-Inducing Ligand (TRAIL)-EGFR specific against Colo205 xenograft tumor model [ 116 ]. Similarly, when MSC expressing TRAIL were injected in pre-established Ewing's Sarcoma mouse model they caused significant tumor apoptosis and showed anti-angiogenic function respect to control group [ 117 ].…”

High expression of TRAIL by osteoblastic differentiated dental pulp stem cells affects myeloma cell viability

“…Furthermore, the localized action of TRAIL delivered by MSCs appeared to bypass the resistance of cancer cells, such as breast and colorectal, to soluble TRAIL (68,69). More recently, a stable MSC line expressing a highly bioactive form of TRAIL was generated and demonstrated a significant tumor regression in an in vivo Colo205 mouse xenograft tumor model (13). The advantage of our model is that DPSCs differentiated in osteogenic conditions, expressed high levels of endogenous TRAIL, thus this system did not require any transfection technology and the cells were resistant to TRAIL-mediated apoptosis.…”

“…Furthermore, two studies have reported the antitumor activity of human genetically modified MSCs expressing antibodies in a diabody format (22,23). Recently, a MSC line, stably producing TRAIL which is activated in a xenotransplantation tumor model, has been generated (13). Although the main known source of MSCs is the bone marrow, a wide variety of MSCs have been recognized in dental tissues such as pulp, periodontal ligament and apical papilla, exhibiting several multilineage potencies including osteogenic, adipogenic and neurogenic (24)(25)(26)(27)(28)(29)(30), besides the expected odontogenic (31).…”