Non-stem bladder cancer cell-derived extracellular vesicles promote cancer stem cell survival in response to chemotherapy

Abstract

Background Chemosenstive non-stem cancer cells (NSCCs) constitute the bulk of tumors and are considered as part of the cancer stem cell (CSC) niche in the tumor microenvironment (TME). Tumor-derived extracellular vesicles (EVs) mediate the communication between tumors and the TME. In this study, we sought to investigate the impacts of EVs released by NSCCs on the maintenance of CSC properties and chemoresistance. Methods We employed murine MB49 bladder cancer (BC) sub-lines representing CSCs and NSCCs as a model system. Chemotherapy drugs were used to treat NSCCs in order to collect conditioned EVs. The impacts of NSCC-derived EVs on CSC progression were evaluated through sphere formation, cytotoxicity, migration, and invasion assays, and by analyzing surface marker expression on these BC cells. Differential proteomic analyses were conducted to identify cargo protein candidates involved in the EV-mediated communication between NSCCs and CSCs. Results NSCC-derived EVs contained cargo proteins enriched in proteostasis-related functions, and significantly altered the development of CSCs such that they were more intrinsically chemoresistant, aggressive, and better able to undergo self-renewal. Conclusions We thus identified a novel communication mechanism whereby NSCC-EVs can alter the relative fitness of CSCs to promote disease progression and the acquisition of chemoresistance.

E-liquid exposure induces bladder cancer cells to release extracellular vesicles that promote non-malignant urothelial cell transformation

“…The proteins present within BCEVs were analyzed using a quantitative LC–MS/MS approach detailed in our recent study 68 . All pathway enrichment analyses of differentially abundant proteins in EV samples were performed using the DAVID bioinformatics database ( https://david.ncifcrf.gov/ ).…”

Role of the Pro-Inflammatory Tumor Microenvironment in Extracellular Vesicle-Mediated Transfer of Therapy Resistance

“…However, the use of cisplatin for the treatment of ovarian cancer (OC) promotes the release of EVs that induce drug resistance in bystander cells by modulating the p38 and JNK signaling pathways to increase cisplatin resistance ( 53 ). Furthermore, EVs released from chemosensitive bladder cancer cells, in particular the non-stem cancer cell (NSCCs) population, in response to cisplatin or gemcitabine, another chemotherapeutic agent, also promote therapy resistance and additionally favor cancer stem cell (CSC) survival in response to chemotherapy ( 54 ). A proteomic analysis of the EV cargo implicated the transfer from NSCCs to CSCs present in the TME of protein synthesis/degradation machinery components, which are critical for CSC survival, maintenance, and plasticity.…”

“…A proteomic analysis of the EV cargo implicated the transfer from NSCCs to CSCs present in the TME of protein synthesis/degradation machinery components, which are critical for CSC survival, maintenance, and plasticity. Even though, the large majority of NSCCs die in response to chemotherapy, they release EVs containing ribosomal proteins that are taken up by CSCs and induce protein synthesis, aiding CSCs in adapting to the post-therapy TME, ultimately resulting in resistance and disease ( 54 ).…”

The Role of Tumor Microenvironment in Regulating the Plasticity of Osteosarcoma Cells

“…EVs derived from chemosensitive non-stem bladder cancer cells were found to be enriched with cargo proteins that can mediate proteo-static functions to significantly alter the development of CSCs [130]. As a result, they became more intrinsically chemo-resistant and aggressive with enhanced self-renewal capabilities [134]. Furthermore, EVs derived from human liver stem cells or MSCs have been found to reduce CSC proliferation and invasion whilst increasing CSC apoptosis, but had no effect on non-CSCs [135].…”