Extracellular Vesicles Derived From Human Embryonic Stem Cells Reduce the Stemness Properties of Cancer Cell Lines Publisher



Akhoundi M ; Rezaei Larijani M ; Azmakan R ; Saber M ; Safarpour A ; Sodeifi N ; Ebrahimi M ; Hassani SN
Source: Cell Journal Published:2025

Abstract

Objective: Aggressive cancer cells exhibit many phenotypic and functional similarities to embryonic stem cells (ESCs), including characteristics such as self-renewal, differentiation flexibility, and specific gene expression signatures. While the ESC microenvironment precisely regulates proliferation to balance self-renewal and differentiation, it remains unclear whether tumor cells can respond to these regulatory signals to suppress their tumorigenic phenotype. Extracellular vesicles (EVs) released by human ESCs (hESCs) are known to exert paracrine effects, making them prime candidates for carrying these regulatory signals. The aim of this study was to determine if hESC-EVs suppress the tumorigenic phenotype of aggressive cancer cells by affecting their proliferative, invasive, and stem cell properties. Materials and Methods: In this experimental study, EVs were isolated from hESC-conditioned medium (hESC-CM) and thoroughly characterized. Aggressive breast and melanoma cancer cell lines were treated with the isolated hESC derived EVs (hESC-EVs). The resulting effects on cell growth (proliferation), invasion, stem cell properties (stemness), and overall tumorigenesis were evaluated in vitro and in vivo. Expression levels of key pluripotency markers were also assessed in the treated cancer cells. Results: The treatment of the aggressive cancer cell lines with hESC-EVs resulted in a significant reduction in proliferation, invasion, stemness, and tumorigenesis across both in vitro and in vivo models. Mechanistically, exposure to hESC-EVs led to the clear downregulation of pluripotency markers within the recipient cancer cells. Conclusion: These findings suggest that hESC-EVs transmit powerful regulatory signals capable of inducing the loss of stem cell characteristics in aggressive cancer cells. This mechanism offers a potential pathway for reprogramming highly malignant tumor cells toward a more differentiated and less aggressive phenotype, suggesting a novel strategy for anti-cancer therapy.