Gene therapy of gastric cancer using LIGHT-secreting human umbilical cord blood-derived mesenchymal stem cells

Abstract

Background Mesenchymal stem cells (MSCs) have the ability to migrate into tumors and therefore are potential vehicles for the therapy of malignant diseases. In this study, we investigated the use of umbilical cord blood mesenchymal stem cells (UCB-MSCs) as carriers for a constant source of transgenic LIGHT (TNFSF14) to target tumor cells in vivo.Methods Lentiviral vectors carrying LIGHT genes were constructed, producing viral particles with a titer of 2 9 10 8 TU/L. Fourteen days after UCB-MSCs transfected by LIGHT gene packaged lentivirus had been injected into mouse gastric cancer models, the expression levels of LIGHT mRNA and protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Then the tumors' approximate volumes were measured. Results The treatment with MSC-LIGHT demonstrated a strong suppressive effect on tumor growth compared to treatment with MSC and NaCl (p \ 0.001). Examination of pathological sections of the tumor tissues showed that the areas of tumor necrocis in the MSC-LIGHT group were larger than those in the MSC group. Moreover, we found that MSCs with LIGHT were able to significantly induce apoptosis of tumor cells. The expression levels of LIGHT mRNA and protein were significantly higher in the UCBMSCs with the LIGHT gene than the levels in UCB-MSCs (p \ 0.001). Conclusion These results suggest that UCB-MSCs carrying the LIGHT gene have the potential to be used as effective delivery vehicles in the treatment of gastric cancers.

Gastric cancer stem cells: A novel therapeutic target

“…In the gastric mucosa, quiescent and active stem cells have been reported, which suggests that there is dire need to design drugs that specifically target CSCs, including stem cell–targeting drugs, stemness-inhibitor drugs, stemness-promoting drugs, and microenvironment-modulating drugs [23, 62, 74–76, 147]. For targeting GCSCs, several novel strategies have been suggested, including a combination of chemotherapy-associated apoptosis, targeted imaging, and tumor stem cell differentiation induction; inducing apoptosis in the tumor; therapies targeting GCSC cell surface molecules; monoclonal antibody development; targeting the GCSC microenvironment; and inhibiting GCSC pathways [77,81,93,118,122,142,148–160]. Jiang et al [91] treated gastric tumor cells, which express CD90, with trastuzumab (humanized anti-ERBB2 antibody) and found that trastuzumab can reduce the CD90+ population in tumor size and growth when it is combined with traditional chemotherapy.…”

“…It is known that MSCs have the capacity to migrate into tumors; therefore, they can be utilized as potential vehicles cancer therapy. Zhu et al [160] engineered umblical cord blood mesenchymal stem cells (UCB-MSCs) to deliver a secretable form of LIGHT, a member of tumor necrosis factor (TNF) superfamily. They found that MSC-LIGHT had a strong suppressive effect on gastric cancer growth, which suggest that this system have the potential to be used as efficient delivery vehicles in the treatment of GCs Zhu et al [160].…”

“…Zhu et al [160] engineered umblical cord blood mesenchymal stem cells (UCB-MSCs) to deliver a secretable form of LIGHT, a member of tumor necrosis factor (TNF) superfamily. They found that MSC-LIGHT had a strong suppressive effect on gastric cancer growth, which suggest that this system have the potential to be used as efficient delivery vehicles in the treatment of GCs Zhu et al [160]. Zhan et al [157] demonstrated that the expression of orphan receptor TR3, a regulator of cell proliferation and apoptosis, is elevated in gastric tumorsphere cells, which display CSC properties.…”

Cells As Delivery Vehicles for Cancer Therapeutics

“…The LIGHT expressing MSCs homed effectively to tumors and organized a potent anti-tumor immune therapy by stimulating an influx of T cells. In another study umbilical cord blood derived MSCs were engineered to express a secretable form of LIGHT and attenuated subcutaneous tumors in a model of human gastric cancer [39].…”

VEGF Enhances the Migration of MSCs in Neural Differentiation by Regulating Focal Adhesion Turnover

“…Mesenchymal stem cells (MSCs) are of particular interest to stem cell‐based therapies for neuroregeneration not only due to their intrinsic neuronal potential and ability to differentiate into neural cell phenotypes both in vitro and in vivo (Tropel et al, ; Alexanian et al, ; Bae et al, ), but also because of their migration to sites of injury after intravenous infusion, and their ability to promote recovery of damaged tissues through secretion of a variety of cytokines and chemokines (Crigler et al, ; Pisati et al, ). Several studies reveal that implanted MSCs could incorporate into the injured spinal cord and display a tendency to migrate toward pathological insults which raises the hope for developing new therapeutic strategies for CNS injury repair (Shyu et al, ; Zhu et al, ). Furthermore, in case of injury, MSCs inhibit fibrotic remodeling and apoptosis, stimulate endogenous stem cell recruitment and proliferation, and reduce immune responses (Uccelli et al, ; Oh et al, ).…”