TRAIL-secreting mesenchymal stem cells promote apoptosis in heat-shock-treated liver cancer cells and inhibit tumor growth in nude mice

Abstract

Liver cancer is one of the top six leading causes of cancer-related death. Radiofrequency ablation (RFA) is an important means of treating liver cancer. Residual cancer after RFA is the most frequent cause of recurrence in cases of liver cancer. The main difference between residual cancer cells and ordinary liver cancer cells is that residual cancer cells experience heat shock. The secretable form of trimeric human tumor necrosis factor-related apoptosis-inducing ligand (stTRAIL) induces apoptosis in a variety of human cancers but not in normal tissues. It has shown potent cancer-selective killing activity and has drawn considerable attention as a possible cancer therapy. In the present work, the therapeutic potential of this stTRAIL-based gene therapy was evaluated in hepatocellular carcinoma subjected to RFA. Rat bone marrow mesenchymal stem cells (BM-MSCs) were isolated and transduced with a lentiviral vector encoding stTRAIL (stTRAIL-MSCs, T-MSCs). Cells treated with heat treatment at 43 °C for 45 min served as simulated residual cancer cells. After treatment with T-MSCs, apoptosis in heat-shock-treated liver cancer cells increased significantly, and caspase-3 was upregulated. When T-MSCs were subcutaneously injected into nude mice, they localized to the tumors and inhibited tumor growth, significantly increasing survival. Collectively, the results of the present study indicate that BM-MSC can provide a steady source of stTRAIL and may be suitable for use in the prevention of the recurrence of hepatocellular carcinoma after RFA with secretable trimeric TRAIL.

Downregulation of SNAIL sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by regulating the NF-κB pathway

“…TRAIL (TNF-related apoptosis-inducing ligand), also known as Apo2 ligand (Apo2L), is a member of the TNF family, and has been shown to induce cell apoptosis in various types of tumor but not normal cells (7). Five receptors, including TRAIL-R1/DR4, TRAIL-R2/DR5, TRAIL-R3/DcR1, TRAIL-R4/DcR2 and TNFR-homologue osteoprotegerin (OPG) have been identified thus far (8).…”

Mesenchymal Stem Cell–Mediated, Tumor Stroma–Targeted Radioiodine Therapy of Metastatic Colon Cancer Using the Sodium Iodide Symporter as Theranostic Gene

“…Importantly, these cells also show a remarkable natural tropism for solid tumors (22,23). An array of therapy proteins has already been demonstrated to be successfully delivered to tumor environments using eMSC, including interferon-g, TNF-related apoptosis-inducing ligands, IL-12, the chemokine CX3CL1, and various suicide genes (4,5,24,25). Recent studies have shown that adoptively applied MSCs can also efficiently home to tumor metastases, opening the door to the potential use of eMSC for treatment of metastatic disease (26)(27)(28)(29).…”

Stem Cell Therapies for Treatment of Liver Disease

“…This same technique could be performed using iPSCs, which are able to provide an unlimited source of highly reactive antigen-specific cytotoxic T-lymphocytes that, when transferred into the patient, can target, infiltrate, and eradicate tumors [131]. Stem cells, in this case bone marrow-derived MSCs transduced with a lentiviral vector stTRAIL (trimeric human necrosis factor-related apoptosis-inducing ligand in its secretable form), have also been used to treat heat-shocked residual cancer cells after radio frequency ablation in rats, resulting in tumor growth inhibition and significantly increased survival [132]. …”