Extracellular vesicles: emerging targets for cancer therapy

Abstract

Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are released by almost all cell types, including tumour cells. Through transfer of their molecular contents, EVs are capable of altering the function of recipient cells. Increasing evidence suggests a key role for EV mediated intercellular communication in a variety of cellular processes involved in tumour development and progression, including immune suppression, angiogenesis, and metastasis. Aspects of EV biogenesis or function are therefore increasingly being considered as targets for anticancer therapy. Here, we summarise the current knowledge on the contributions of EVs to cancer pathogenesis and discuss novel therapeutic strategies to target EVs to prevent tumour growth and spread.

Keywords: cancer therapy; exosomes; extracellular vesicles; metastasis; microvesicles; tumour microenvironment.

Figure 1. Types of EVs released by tumour cells

Exosomes and microvesicles are released constitutively and/or upon activation. Exosomes are formed from endosomes through inward budding to generate multivesicular bodies (MVBs) and are released upon fusion of MVBs with the plasma membrane. Exosomes are relatively homogeneous in size and, because of their endocytic origin, contain proteins involved in endosomal-lysosomal sorting which are used as exosomal markers. Microvesicles on the other hand are formed through direct outward budding of the plasma membrane. Tumour cells undergoing apoptosis release apoptotic bodies, which are formed by random blebbing of the plasma membrane. Apoptotic bodies are heterogeneous in size and may contain nuclear fragments as well as fragments of cytoplasmic organelles. Abbreviations: ER, endoplasmic reticulum; MVB, multivesicular body.

Figure 2. Schematic representation of processes affected by EV-mediated signalling in cancer

Tumour cells and stromal cells exchange EVs carrying proteins and nucleic acids that can affect the function of recipient cells. Tumour cell-derived EVs can contribute to spread of the transformed phenotype from transformed (light green) cells to surrounding non-transformed (dark green) cells (1) and contribute to tumours’ ability to escape from immune surveillance (2). EVs derived from stromal cells, such as fibroblast and immune cells, may influence tumour cell motility (3). Moreover, tumour-derived EVs stimulate endothelial angiogenic responses (4) and may enter the circulatory system and reach distant organs, where they promote thrombosis (5) and formation of pre-metastatic niches (6).

Figure 3. Therapeutic targeting of EV signalling in cancer

Different potential strategies to interfere with EV-mediated intercellular communication can be envisioned. (1) Inhibition of EV biogenesis or release through interference with components of pathways involved in EV formation (e.g. ESCRT, ceramide) or release (e.g. Rab27, ARF6, RhoA). (2) EV removal from the circulation by extracorporeal hemofiltration. (3) Inhibition of EV uptake in recipient cells by blocking EV ligands (e.g. PS, tetraspanins) or cell surface receptors involved in EV binding or internalization (e.g. HSPGs). Abbreviations: ARF6, ADP-ribosylation factor 6; Ca, calcium; ER, endoplasmic reticulum; ESCRT, Endosomal Sorting Complex Required for Transport; HSPG, heparan sulfate proteoglycans; MVB, multivesicular body; PS, phosphatidylserine; RhoA, Ras homolog family member A.