Cancer cell-dependent increase in senescence-like populations following exosome treatment from bone marrow and induced pluripotent stem cell-derived mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cell (MSC) extracellular vesicles, particularly exosomes (Exos), are gaining recognition as promising therapeutic tools for cancer due to their capacity to modulate tumor cell biology. Induced pluripotent stem cell-derived MSCs (iMSCs) revealed therapeutic characteristics compared with conventional MSCs due to their proliferative capacity and enhanced differentiation potential. AIM: To study the impact of Exos derived from iMSCs (iMSC-Exos) and bone marrow MSCs (BMSC-Exos) on PANC1 and MDA-MB-231 cancer cells. METHODS: The iMSCs and BMSCs were characterized based on the International Society for Cellular Therapy (2006) criteria by verifying the expression of MSC-specific markers and their differentiation potential. Exos were isolated from 48-hour conditioned media using sequential ultracentrifugation and characterized based on size, morphology, and expression of surface markers including CD9, CD81, and CD63. PANC1 and MDA-MB-231 cells were treated with the isolated Exos, and their effects on cell proliferation, apoptosis, senescence, and invasion were assessed. RESULTS: In PANC1 cells iMSC-Exos sustained antiproliferative activity for 48 hours (35% reduction, P < 0.01) while BMSC-Exos had a transient effect. In MDA-MB-231 cells, both Exos lowered proliferation significantly after 48 hours (~28% and ~22% reduction, P < 0.05). Notably, these antiproliferative effects were not associated with apoptosis, but an increase in senescence-like tumor cells was identified as the primary response with iMSC-Exos inducing approximately 2.3-fold higher number of senescence-associated β-galactosidase-positive cells compared with BMSC-Exos across both cancer cell lines. Tumor cell invasion was markedly inhibited in PANC1 and MDA-MB-231 cells in response to iMSC-Exos (~60% and ~45% reduction, respectively, P < 0.001), and only in PANC1 cells in response to BMSC-Exos. CONCLUSION: iMSC-Exos effectively inhibited tumor proliferation and invasion via a senescence-like mechanism. These results indicated that iMSC-Exos could serve as a cell-free cancer therapy and merit further animal model evaluation.