MSC-Derived Extracellular Vesicle-Delivered L-PGDS Inhibit Gastric Cancer Progression by Suppressing Cancer Cell Stemness and STAT3 Phosphorylation

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.

Emerging roles of mesenchymal stem cell-derived exosomes in gastrointestinal cancers

“…The same could be demonstrated in another study where L-PGDS served as a potential drug to inhibit the proliferation of GC cells through the PPARγ signalling pathway ( Fukuoka et al, 2015 ). You ( You et al, 2022 ) and others found that MSC-derived extracellular vesicles overexpressing L-PGDS could inhibit GC progression by regulating GC cell stemness and inhibiting STAT3 phosphorylation. This suggests that MSC-derived exosomes could be an effective vehicle for GC therapy.…”

Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy

“…In addition to miRNAs, the piggybacking of endogenous proteins (enzymes [ 133 – 135 ], cytokines [ 136 ], and transcription factors [ 137 ]) has improved the therapeutic efficacy of MSC-exosomes in a variety of ischemic diseases. Wei et al used an adenoviral transfection system to transfect human antiprotease alpha-1 antitrypsin (hAAT) into MSCs (hAAT-MSCs) and found that hAAT-MSCs -exosomes exhibited more beneficial effects in immunoregulation [ 134 ].…”

The Dual Role of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Carcinogenesis

“…You et al used EVs from MSCs transfected with an adenoviral vector with a gene encoding lipocalin type prostaglandin D2 synthase (L-PGDS). EVs-L-PGDS inhibited gastric cancer growth, induced cell apoptosis, reduced the expression of stem cell markers including Oct4, Nanog, and Sox2, and inhibited STAT3 phosphorylation in SGC-7901 gastric cancer cells [ 177 ].…”