Akademik Veri Yönetim Sistemi
ISEV2025 Annual Meeting, Vienna, Avusturya, 24 - 27 Nisan 2025, ss.382, (Özet Bildiri)
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, fibrotic, immunosuppressive, and desmoplastic extracellular matrix. The dense microenvironment significantly impedes the effective delivery of conventional therapeutics to target tumor cells. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as a novel therapeutic strategy,in regards to their given capacity to be engineered with antitumor agents such as chemotherapeutic drugs and RNAs, making nanosized drug carriers a promising alternative. Nonetheless, the potential dual effects of MSC-EVs on tumor cells warrant careful consideration. This study aimed to evaluate the mechanistic effects of MSC-EVs on PDAC. Wharton's Jelly (WJ) MSC-derived small EVs were isolated using the differential ultracentrifugation method and analyzed through nanoparticle tracking analysis (NTA), Tunable Resistive Pulse Sensing (TRPS) and flow cytometry. EVs were added to Panc-1 cells at concentrations of 4.000, 8.000, and 12.000 EVs per cell. After 24 hours, apoptosis and cell cycle analyses were performed using flow cytometry. The expression of epithelial-mesenchymal transition (EMT)-related genes (CD44, CDH1, VIM, ZEB1, CLDN1, TIMP1 and MMP9) was assessed by quantitative Real-Time PCR (qRT-PCR). The expression of associated proteins (CD44, E-Cadherin, and Vimentin) were evaluated using immunohistochemistry. Additionally, the expression of immune-related genes (IL-6, IL-10, TNF-α, IFN-γ, IL-1α, IL-1β) was analyzed by qRT-PCR. NTA analysis indicated a mean small EV size of 104.6 nm and over 98% of the particles were positive for CD63,CD81 and CD9. Cell cycle analysis showed higher G1 phase percentage in the control group (31%) compared to MSC EV treated groups (35-36%). Apoptosis analysis revealed similar viable and necrotic cell percentages among the control (80% viable) and treated groups (approximately 78-79% viable). The CD44, VIM, MMP9, TIMP1 and ZEB1 genes were downregulated in treated groups compared to the control. Although CLDN1 and CDH1 genes were upregulated at the lowest EV concentration, they were downregulated at higher EV concentrations. Immune gene analysis showed downregulation of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-1α, IL-1β) and upregulation of the anti-inflammatory cytokine IL-10 in treated groups. This study revealed the dual role of WJ-MSC small EVs in PDAC. While they suppressed cell proliferation and modulated EMT markers, indicating their anti-tumor potential, they also exhibited an immunosuppressive profile, marked by increased IL-10 and reduced pro-inflammatory cytokines, which can hinder immune responses. These findings highlight both the promise and challenges of using WJ-MSC small EVs as therapeutic agents, necessitating further studies to optimize their application and balance their effects.
Keywords: Mesenchymal stem cells, PDAC, small EVs, pancreatic cancer, cancer therapy