# Pluripotent stem cell‐derived extracellular vesicles: Cell type‐dependent effect on tumorigenicity in cancer cell lines

## TL;DR

Extracellular vesicles from stem cells can either reduce or increase cancer cell tumorigenicity depending on the cancer cell type.

## Contribution

The study reveals that the effect of pluripotent stem cell-derived EVs on cancer cells is cell type-dependent, challenging the assumption of a universal anti-tumorigenic effect.

## Key findings

- EV treatment of MDA-MB-231 and DLD-1 cells reduced CD44 and C24 protein expression, markers of tumor-initiating cells.
- EV treatment of MCF7 and A431 cells increased CD44 and C24 expression, along with clonogenicity and drug resistance.
- EV-treated MCF7 cells formed larger tumors in mice compared to untreated cells.

## Abstract

Extracellular vesicles (EVs) derived from pluripotent stem cells have been reported to reprogram cancer cells to a more benign phenotype, due to its provision of an embryonic microenvironment. Here, we show that the effect of the EVs on the tumorigenicity of the cancer cell lines is cell type‐dependent. First, we characterized the complement of transcription factors contained in EVs derived from human embryonic and induced pluripotent stem cell lines and subsequently treated MCF7, A431, MDA‐MB‐231, and DLD‐1 cancer cell lines with the EVs derived from these pluripotent stem cell lines. For EV‐treated MDA‐MB‐231 and DLD‐1 cells, we found a decrease in the protein expression of CD44 and C24, which are accepted markers for cancer cell populations enriched with tumor‐initiating cells, a result that corresponds to the previous reports. However, for EV‐treated MCF7 and A431 cells, there was an increase in the protein expression of CD44 and C24 instead, with a corresponding increase in clonogenicity and resistance to a panel of anticancer drugs, when compared to non‐exosome‐treated cells. When subcutaneously implanted in nude mice, EV‐treated MCF7 cells gave rise to tumors of larger size than untreated cells. The cell type‐dependence of the effect of hPSC‐derived EV treatment was postulated to be due to occurrence of an EMT for cells located at different locations along the epithelial–mesenchymal spectrum, leading to either an increase or decrease in tumorigenicity. Therefore, exposure to EVs does not always reduce the tumorigenicity of cancer cells but is cell type‐dependent.