Intraperitoneal transfer of microRNA‐29b‐containing small extracellular vesicles can suppress peritoneal metastases of gastric cancer

Abstract

Small extracellular vesicles (sEV) contain various microRNAs (miRNAs) and play crucial roles in the tumor metastatic process. Although miR‐29b levels in peritoneal exosomes were markedly reduced in patients with peritoneal metastases (PM), their role has not been fully clarified. In this study, we asked whether the replacement of miR‐29b can affect the development of PM in a murine model. UE6E7T‐12, human bone marrow‐derived mesenchymal stem cells (BMSCs), were transfected with miR‐29b‐integrating recombinant lentiviral vector and sEV were isolated from culture supernatants using ultracentrifugation. The sEV contained markedly increased amounts of miR‐29b compared with negative controls. Treatment with transforming growth factor‐β1 decreased the expression of E‐cadherin and calretinin with increased expression of vimentin and fibronectin on human omental tissue‐derived mesothelial cells (HPMCs). However, the effects were totally abrogated by adding miR‐29b‐rich sEV. The sEV inhibited proliferation and migration of HPMCs by 15% (p < 0.005, n = 6) and 70% (p < 0.005, n = 6), respectively, and inhibited adhesion of NUGC‐4 and MKN45 to HPMCs by 90% (p < 0.0001, n = 5) and 77% (p < 0.0001, n = 5), respectively. MicroRNA‐29b‐rich murine sEV were similarly obtained using mouse BMSCs and examined for in vivo effects with a syngeneic murine model using YTN16P, a highly metastatic clone of gastric cancer cell. Intraperitoneal (IP) transfer of the sEV every 3 days markedly reduced the number of PM from YTN16P in the mesentery (p < 0.05, n = 6) and the omentum (p < 0.05, n = 6). Bone marrow mesenchymal stem cell‐derived sEV are a useful carrier for IP administration of miR‐29b, which can suppress the development of PM of gastric cancer.

The biological role of extracellular vesicles in gastric cancer metastasis

“…The overexpression of miR-221 is significantly associated with advanced tumor lymphatic metastasis ( Liu et al, 2012 ), and a study reported that MSC-derived EVs delivered miR-221 to GC cells and promoted their metastasis ( Wang et al, 2014 ). Several studies have also reported that MSC-derived EVs can effectively influence the TME and tumor metastasis through the delivery of miRNAs ( Ma et al, 2017 ; Ji et al, 2023 ; Kimura et al, 2023 ). Gu et al found that MSC-derived EVs induced EMT through the AKT pathway, thereby enhancing the metastasis of GC, however, the key cargoes within these EVs still need to be identified ( Gu et al, 2016 ).…”

“…EMT is considered a driving force for tumor cells metastasis, and is a significant contributor to cancer recurrence and metastasis ( Zheng et al, 2020 ; Zhu et al, 2022b ). The loss of epithelial cell markers (such as E-cadherin) and the acquisition of mesenchymal cell markers (such as N-cadherin and vimentin) are two key steps in EMT ( Kimura et al, 2023 ). During EMT, tumor cells lose polarity of epithelial cells and acquire mesenchymal-like motility, which enhances their invasive and migratory abilities, which is considered as the initial stage of tumor metastasis ( Maharati and Moghbeli, 2023 ).…”

“…Additionally, EVs can serve as carriers for drug or small interfering RNA (siRNA) delivery, they can be engineered to possess specific targeting and drug delivery functions. By encapsulating drugs or siRNA within EVs, their stability and bioavailability can be enhanced, while reducing their side effects ( Kimura et al, 2023 ; Zeng et al, 2023 ). For example, Yu et al discovered that encapsulating VEGFR2 siRNA within EVs for the treatment of lung metastasis in mice with osteosarcoma is a more efficient and less toxic therapeutic approach ( Yu et al, 2023 ).…”