Login to Access Video or Poster Abstract: MP65-02
Sources of Funding: NCI RO1CA173986

Introduction

Cancer field effect describes the predisposition of a field of tissue with histological anomalies or molecular alterations to a high incidence of tumor initiation and has been proposed to explain bladder cancer’s (BC’s) multifocal and recurrence nature, yet its mechanisms remain unknown. Extracellular vesicles (EVs) are small, membrane-bound vesicles with functions in cell-cell communication. We hypothesize that EVs derived from BC cells transfer bioactive cargo to reprogram recipient cells in the field and induce malignant transformation.

Methods

EVs from TCC-SUP, a BC line, were collected and purified. SV-HUC cells, a non-malignant immortalized urothelial line, were used as recipients. Tumorigenicity was determined by an in vitro anchorage-independent colony formation assay and an in vivo xenograft mouse model. Hallmarks of cancer such as loss of contact inhibition, genome instability, and invasion were studied. Molecular alterations in EV-transformed cells were assayed by qPCR and Western blot. Pro-inflammatory cytokines were compared by multiplex ELISA assays.

Results

Bladder cancer EVs induced malignant transformation of SV-HUC cells in vitro and in vivo. Molecular profiling revealed abnormal levels of endoplasmic reticulum (ER) stress sensors/effectors and pro-inflammatory cytokines in transformed cells. Moreover, the expression of ER chaperone protein Grp78 and two ER resident sensors, PERK and IRE1, was induced. Pro-apoptotic ER stress effector CHOP was absent, suggesting cancer EVs promote tumorigenesis by activating tumor-promoting signals while inhibiting pro-apoptotic signals.

Conclusions

Our data support a novel mechanism whereby cancer EVs and their cargo molecules play key roles in the malignant field of BC. Our study reveals that cancer EVs promote malignant transformation of predisposed cells by inhibiting pro-apoptotic signals and activating tumor-promoting ER stress induced unfolded protein response and inflammation. This study provides insight into mechanism of BC’s field effect and suggests EV as potential markers of disease recurrence and progression

Funding

NCI RO1CA173986