Functional role of cancer stem cell like exosomes on survival and drug resistance behaviors of colorectal cancer cells

TL;DR

This study shows that exosomes from colorectal cancer stem cells increase drug resistance and survival of cancer cells.

Contribution

The novel contribution is identifying how cancer stem cell exosomes enhance drug resistance in colorectal cancer cells.

Findings

Cancer stem cell exosomes significantly increase drug resistance gene expression in treated cells.

Exosome-treated cells show reduced viability when combined with 5-fluorouracil compared to drug alone.

Colorectal cancer stem cells exhibit higher stemness gene expression and marker levels than parental cells.

Abstract

This study aimed to evaluate the potential impact of colorectal cancer stem cell exosomes (CRC CSCs-enriched exosomes/CSCs-EXOs) on drug resistance and cell proliferation of CRC tumor cells.

CSCs were enriched from HT-29 cells and characterized by sequential sphere formation, real-time PCR analysis of key stemness genes, and CRC-CSCs markers. The gene expression related to ABC transporters was analyzed in HT-29, HT-29 CSCs, and Caco-2 cells. CSCs-EXOs and parental-EXOs were isolated and characterized from HT-29 cells. The gene expression related to ABC transporters was investigated in Caco-2 cells treated with CSCs-EXOs and parental-EXOs of HT-29 cells by real-time PCR. The survival rate of exosome-treated Caco-2 cells was also studied in the presence of 5-fluorouracil (5-FU) at the IC50 concentration using MTT assay.

Colonospheres were found to have the ability to form serial spheres, along with the upregulatation of the key stemness genes (p-value ≤ 0.05). The expression of CRC-CSCs markers significantly increased relative to their parental counterparts (p-value ≤ 0.05). Treatment of Caco2 cells with CSCs-EXOs and their parental-EXOs revealed a substantial elevation in expression of drug resistance genes relative to those treated with their parental-EXOs (p-value ≤ 0.0001). The combination treatment of cells with exosomes and 5-FU at the IC50 concentration led to a more pronounced decrease in cell viability in all groups compared to applying 5-FU at the same concentration.

Our findings underscore the significance of targeting the CSCs-exosome axis as a prospective therapeutic strategy to overcome drug resistance. Upcoming studies ought to concentrate on exploring the molecular machinery of CSCs and tumor cells plasticity through the exosome-mediated functions.

The online version contains supplementary material available at 10.1007/s12672-025-04295-0.

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