Presentation Authors: ChiaHao Wu*, Christopher Silvers, Edward Messing, Yi-Fen Lee, Rochester, NY
Introduction: Many types of cancer undergo endoplasmic reticulum (ER) stress. It is a stress response when unfolded protein accumulates, that leads to the activation of a series of signaling cascade, including apoptosis and inflammation. Tumors secrete a higher number of extracellular vesicles (EVs) containing oncogenic cargo that can be taken up and disrupt homeostasis in normal cells. We hypothesize that EVs derived from bladder cancer (BC) cells, by causing ER stress, impose a selection force in normal recipient cells that lead to a higher malignant transformation frequency.
Methods: EVs from TCC-SUP, a BC line, and SV-HUC cells, a non-malignant immortalized urothelial line, were collected by serial centrifugation, counted by nanoparticle tracking analysis, and examined by mass spectrometry. SV-HUC cells were chronically treated with TCC-SUP EVs and were determined by an in vitro colony formation assay and an in vivo xenograft mouse model. Some cancer cell properties: loss of contact inhibition, genome instability, and invasion were investigated. EVs provoked ER stress responses were assayed by Western blot.
Results: BC cells secreted a higher number of EVs than normal urothelial cells. These BCEVs carried distinct proteins; some were oncogenic and could induce normal recipient cells&[prime] pro-apoptotic ER stress response. Prolonged activation of ER stress led cells to switch to a pro-survival branch of ER stress response, and eventually, those cells were transformed and gained several cancerous properties. More importantly, inhibition of ER stress response by docosahexaenoic acid reduced BCEV-induced tumorigenesis.
Conclusions: Our data provide a novel mechanism whereby prolonged ER stress induced by persistent exposure to tumor-derived EVs drives the malignant transformation of clinically indolent recipient cells. This study provides insight into bladder cancer&[prime]s multifocal and recurrent nature and suggests EVs as potential markers of disease recurrence and progression.
Source of Funding: RO1CA173986