The forces driving cancer extracellular vesicle secretion

Abstract

The discovery that cancer cells discharge vast quantities of extracellular vesicles (EVs), underscored the explosion of the EV field. A large body of evidence now supports their onco-functionality in an array of contexts; stromal crosstalk, immune evasion, metastatic site priming, and drug resistance - justifying therapeutic intervention. The current bottleneck is a lack of clear understanding of why and how EV biogenesis ramps up in cancer cells, and hence where exactly avenues for intervention may reside. We know that EVs also play an array of physiological roles, therefore effective anticancer inhibition requires a target distinct enough from physiology to achieve efficacy. Taking the perspective that EV upregulation may be a consequence of the tumor landscape, we examine classic mutational events and tumor characteristics for EV regulators. All the while, aiming to illuminate topics worth further research in therapeutic development.

Keywords: Cancer cell signaling; Cancer therapy; Exosomes; Extracellular vesicles.

Fig. 1

Overview of the roles of oncogenes and tumor suppressors at various stages of cancer extracellular vesicle secretion and cargo loading. Where known, the links between the oncogene/tumor suppressor and the extracellular vesicle biogenesis machinery is highlighted. Created with BioRender.com.

Fig. 2

Overview of the influences of cell metabolism, autophagy and cell migration on cancer extracellular vesicle secretion. Cancer cells can release multiple subpopulations of exosomes from different compartments including early endosomes, multivesicular bodies and amphisomes. Upper right insert: Amoeboid migration and invadopodia-mediated invasion trigger the release of distinct extracellular vesicle subsets that help the migration of tumour cells through different types of extracellular matrix. Created with BioRender.com.