Anti-tumorigenic effects of naive and TLR4-primed adipose-derived mesenchymal stem cells on pancreatic ductal adenocarcinoma cells

BackgroundOne of the main reasons for the unsuccessful treatment of pancreatic cancer is the intense desmoplastic pancreatic microenvironment. In the literature, the effects of mesenchymal stem cells (MSCs) and their inflammatory phenotypes on cancer cells have been a subject of controversy. Therefore, it is crucial to elucidate the underlying mechanisms of this interaction, especially in the context of pancreatic cancer. We aimed to investigate the effects of naive, TLR4-activated, and TLR4-inhibited phenotypes of adipose-derived MSCs (ADMSC) on pancreatic ductal cell line (Panc-1).Methods and MaterialsAdipose-derived MSCs were induced into a proinflammatory phenotype using a 0.5 mu g/mL dose of TLR4 agonist, while an anti-inflammatory phenotype was generated in ADMSCs using a 25 mu g/mL dose of TLR4 antagonist. We observed that the proliferation of Panc-1 cells was inhibited when naive ADMSCs:Panc-1(10:1) and proinflammatory ADMSCs:Panc-1(10:1) were directly cocultured.ResultsIn indirect coculture, both naive and proinflammatory ADMSCs exhibited a significant 10-fold increase in their inhibitory effect on the proliferation and colony forming capacity of Panc-1 cells, with the added benefit of inducing apoptosis. In our study, both naive and proinflammatory ADMSCs were found to regulate the expression of genes associated with metastasis (MMP2, KDR, MMP9, TIMP1, IGF2R, and COL1A1) and EMT (CDH1, VIM, ZEB1, and CLDN1) in Panc-1 cells. Remarkably, both naive and proinflammatory ADMSCs demonstrated antitumor effects on Panc-1 cells. However, it was observed that anti-inflammatory ADMSCs showed tumor-promoting effects instead. Furthermore, we observed a reciprocal influence between ADMSCs and Panc-1 cells on each other's proinflammatory cytokine expressions, suggesting a dynamic interplay within the tumor microenvironment.ConclusionsThese findings underscore the significance of both the naive state and different inflammatory phenotypes of MSCs in the microenvironment and represent a pivotal step toward the development of novel therapeutic approaches for pancreatic cancer. Understanding the intricate interactions between MSCs and cancer cells may open new avenues for targeted interventions in cancer therapy. In our study, we showed that the tumorigenic effects of ADMSCs on Panc-1 cells were altered when stimulated via TLR4 signaling, but this effect was altered when naive ADMSCs and ADMSCs with pro-inflammatory character stimulated by TLR4 agonist exerted anticarcinogenic effects on Panc-1 cells. Anti-inflammatory ADMSCs, on the other hand, showed tumor-promoting effects. Understanding the role of MSCs in the tumor microenvironment will be a guiding factor for the development of microenvironment-targeted therapeutic approaches in the future.image