Human Bone Marrow-Derived Mesenchymal Stromal Cells Expressing S-TRAIL as a Cellular Delivery Vehicle for Human Glioma Therapy

Abstract

Glioblastoma is among the most aggressive and treatment resistant of all human cancers. Conventional therapeutic approaches are unsuccessful because of diffuse infiltrative invasion of glioma tumor cells into normal brain parenchyma. Stem cell-based therapies provide a promising approach for the treatment of malignant gliomas because of their migratory ability to invasive tumor cells. Our therapeutic strategy was to use human bone marrowderived mesenchymal stromal cells (hMSCs) as a cellular vehicle for the targeted delivery and local production of the biologic agent tumor necrosis factor-related apoptosisinducing ligand (TRAIL) at the glioma tumor site. hMSCs were transduced with a lentivirus expressing secretable TRAIL (S-TRAIL) and mCherry (red fluorescent protein). Our results clearly demonstrate the retention of tumor tropic ability of hMSC S-TRAIL cells by in vitro and in vivo migration assays. In vitro assays confirmed the expression, release, and biological activity of S-TRAIL produced by hMSC S-TRAIL cells. For the in vivo assessment of therapeutic efficacy, hMSCs were injected ipsilateral to an established intracranial glioma tumor in a mouse xenograft model. Genetically engineered hMSC S-TRAIL cells were effective in inhibiting intracranial U87 glioma tumor growth (81.6%) in vivo and resulted in significantly longer animal survival. Immunohistochemical studies demonstrated significant, eight fold greater tumor cell apoptosis in the hMSC S-TRAIL-treated group than in controls. Our study demonstrates the therapeutic efficacy of hMSC S-TRAIL cells and confirms that hMSCs can serve as a powerful cell-based delivery vehicle for the site-specific release of therapeutic proteins. STEM CELLS

The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma

“…[29][30][31] MSCs expressing TRAIL exhibited short-and long-term therapeutic effects without significant complications in glioma. [32][33][34][35] But there was no report about TRAIL gene modified MSCs (TRAIL-MSCs) in the therapy of HCC. As mentioned above, HCC cells showed high resistance to TRAIL, so TRAIL-MSCs alone might be difficult to achieve desired effect.…”

“…The reconstructed Lentiviral Vectors (pLenti6.3-TNFSF10-IRES-hrGFP) was prepared, purified and their functional titers were determined as described previously. 35,49 For lentiviral transduction of MSCs, MSCs (1.5 × 10 6 cells) were plated on a T-25 culture flask and allowed to attach overnight. The medium was replaced with 5 ml fresh lentiviral supernatant with a multiplicity of infection (MOI) of 10 and 8 μg/ml polybrene (Sigma) to assist the uptake of viral particles.…”

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

“…[40][41][42] Thus, a potentially relevant form of application is the concept of injecting tGas1-producing cells into tumors. A possible source of the cells are cells from the same tumor, other somatic cells from the same patient, or from a different source, so the secreted protein could inhibit the growth of the tumor, and in the case of applied tumor cells would also kill the genetically modified cells and increase the safety of the system.…”

Mesenchymal Stem Cells: How Can we Realize their Therapeutic Potential in Cancer Therapy?

“…MSCs engineered to secrete interferon-β suppressed growth of breast, prostate, pancreatic and melanoma cancers in animal models [52][53][54][55], as did interleukin-12-expressing MSCs in renal cell cancer [56]. MSCs have also been transduced with interferon-γ [54], Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) [53,[57][58][59][60] and soluble decoy receptors such as type-I insulin-like growth factor receptor [61].…”