Abstract
Mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) serving as delivery system have attracted extensive research interest, especially in cancer therapy. In our previous study, lipocalin-type prostaglandin D2 synthase (L-PGDS) showed inhibitory effects on gastric cancer growth. In this study, we aimed to explore whether MSC-EV-delivered L-PGDS (EVs-L-PGDS) could inhibit gastric cancer progression. EVs-L-PGDS were generated from MSCs transfected with adenovirus encoding L-PGDS. Cell colony-forming, migration, invasion, and flow cytometry assays were used to show the inhibitory effects of EVs on tumor cells in vitro, and the nude mouse subcutaneous tumor model was performed to show the inhibitory effect of EVs on tumor progression in vivo. In vitro, EVs-L-PGDS could be internalized and inhibit the colony-forming, migration, and invasion ability of gastric cancer cell SGC-7901 and promote cell apoptosis. In vivo, EVs-L-PGDS inhibited the tumor growth in nude mouse subcutaneous tumor-bearing model. Compared with the PBS and EVs containing empty vector (EVs-Vector) group, more apoptotic cells and higher L-PGDS expression were detected in tumor tissue of the EVs-L-PGDS treatment group. And these differences are significant. Mechanistically, EVs-L-PGDS reduced the expression of stem cell markers including Oct4, Nanog, and Sox2 and inhibited STAT3 phosphorylation in gastric cancer cell SGC-7901. In conclusion, our results imply that MSC-derived EVs could be utilized as an effective nanovehicle to deliver L-PGDS for gastric cancer treatment, which provides a novel idea for the EV-based cancer therapy.
Highlights
The incidence of stomach cancer is generally declining, it has remained a heavy disease burden in developing countries over the past decades [1]
We have demonstrated that direct prostaglandin D2 (PGD2) stimulation or lipocalin-type prostaglandin D2 synthase (L-PGDS) overexpression is able to inhibit gastric cancer cell growth and migration
Fukuoka et al found that exogenous L-PGDS promoted PGD2 secretion of gastric cancer cells, thereby inhibiting the growth of gastric cancer cells by expressing peroxisome proliferator-activated receptor (PPAR γ) [35]
Summary
The incidence of stomach cancer is generally declining, it has remained a heavy disease burden in developing countries over the past decades [1]. Accumulating evidence has shown that mesenchymal stem cells (MSCs) hold promise for a wide range of applications in the treatment of many diseases including cancer [2, 3]. Huc-MSCconditioned medium containing extracellular vesicles (EVs) could effectively induce apoptosis and attenuate the migration of tumor cells, which has attracted increasing attention [5]. Tang et al found that human umbilical cord MSCs (huc-MSCs) inhibited the growth of HepG2 cells and promoted their apoptosis [4]. These findings point to the positive effects of MSCs in cancer therapy. EVs from various origins hold great potential in cell-free anticancer treatment [8].
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