Abstract
Mesenchymal stem cells (MSCs) can exhibit either prooncogenic or antitumor properties depending on the context. Based on our previous study, we hypothesized that MSCs engineered to deliver IFN-γ would kill cancer cells through persistent activation of the TRAIL pathway. Human bone-marrow (BM-) derived MSCs were isolated, amplified, and transduced with a lentiviral vector encoding the IFN-γ gene under the control of the EF1α promoter. The IFN-γ-modified MSCs effectively secreted functional IFN-γ, which led to long-term expression of TRAIL. More importantly, the IFN-γ-modified MSCs selectively induced apoptosis in lung tumor cells through caspase-3 activation within the target cells. The percentage of activated-caspase-3-positive tumor cells in IFN-γ-modified MSCs cocultures was significantly higher than in control MSCs cocultures. Treatment with anti-TRAIL antibody dramatically suppressed the caspase-3 activation observed in H460 cells. After injection into nude mice, the IFN-γ-modified MSCs inhibited the growth and progression of lung carcinoma compared with control cells. Collectively, our results provide a new strategy for tumor therapy that utilizes IFN-γ-modified MSCs.
Highlights
Mesenchymal stem cells (MSCs) are derived from the mesodermal germ layer and can be isolated and cultured from many tissues, such as bone marrow, adipose tissue, and amniotic fluid [1,2,3]
We show that IFN-γ-modified MSCs continuously express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and induce apoptosis in lung cancer cells by activating caspase-3 within the target cells
Treatment with an anti-TRAIL antibody dramatically suppressed the observed caspase-3 activation in H460 cells (11.8±6% at 24 h and 27.9±5.7% at 48 h, P < 0.05). These results indicate that MSCs IFN-γ effectively induce apoptosis in tumor cells by activating caspase-3 within the target cells and reveal the TRAIL-mediated cytotoxic effect of MSCs IFN-γ
Summary
Mesenchymal stem cells (MSCs) are derived from the mesodermal germ layer and can be isolated and cultured from many tissues, such as bone marrow, adipose tissue, and amniotic fluid [1,2,3]. Other reports have indicated that MSCs exhibit tropism toward tumors [6]. In addition to isolation from normal tissue, MSCs have been found in tumor tissue and may be a key source of tumor-associated stromal cells [9, 10]. IFN-γ-primed MSCs were shown to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which causes apoptosis in tumor cells [12]. We evaluated whether IFN-γ-secreting mesenchymal stem cells could exert a persistent antitumor effect via the TRAIL pathway
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