Small extracellular vesicles in cancer

Abstract

Extracellular vesicles (EV) are lipid-bilayer enclosed vesicles in submicron size that are released from cells. A variety of molecules, including proteins, DNA fragments, RNAs, lipids, and metabolites can be selectively encapsulated into EVs and delivered to nearby and distant recipient cells. In tumors, through such intercellular communication, EVs can regulate initiation, growth, metastasis and invasion of tumors. Recent studies have found that EVs exhibit specific expression patterns which mimic the parental cell, providing a fingerprint for early cancer diagnosis and prognosis as well as monitoring responses to treatment. Accordingly, various EV isolation and detection technologies have been developed for research and diagnostic purposes. Moreover, natural and engineered EVs have also been used as drug delivery nanocarriers, cancer vaccines, cell surface modulators, therapeutic agents and therapeutic targets. Overall, EVs are under intense investigation as they hold promise for pathophysiological and translational discoveries. This comprehensive review examines the latest EV research trends over the last five years, encompassing their roles in cancer pathophysiology, diagnostics and therapeutics. This review aims to examine the full spectrum of tumor-EV studies and provide a comprehensive foundation to enhance the field. The topics which are discussed and scrutinized in this review encompass isolation techniques and how these issues need to be overcome for EV-based diagnostics, EVs and their roles in cancer biology, biomarkers for diagnosis and monitoring, EVs as vaccines, therapeutic targets, and EVs as drug delivery systems. We will also examine the challenges involved in EV research and promote a framework for catalyzing scientific discovery and innovation for tumor-EV-focused research.

Graphical abstract

Fig. 1

Biogenesis of extracellular vesicles. Extracellular vesicles form by mechanisms specific to the type of EV. (A) Exosomes form through a complex process that utilizes the ESCRT complex. (I) Exosomes first form by endocytosis, forming the (II) early endocytic vesicle also known as the endosome. (III) Upon construction of the ESCRT complex, the endosome invaginates to form the late endosome which incorporates endocytic vesicles. (IV) This forms the multivesicular body which fuses wit h the plasma membrane and releases the exosomes into extracellular space. Exosomes can also form independent of ESCRT complexes though this mechanism is not well understood. Macrovesicles, by contrast, form as an outward budding of the plasma membrane. (B) Apoptotic bodies form as a result of blebbing during apoptosis. All EVs harbor DNA, various RNA species, proteins, and other cellular constituents which are packaged into the vesicles. These vesicles can be taken up by neighboring or distant cells. When this happens, the contents of the vesicles are released into the new cell and can enact various biological and metabolic functions in the new cell.

Fig. 2

Role of sEVs Cargo in Cancer Biology. Transfer of tumor derived sEVs cargo molecules alter recipient cell phenotype and thus cancer biology.

Fig. 3

sEVs in cancer therapy. Naïve T-cells can be activated by sEVs from tumor and tumor-educated immune cells, thereby priming them against tumors. sEVs loaded with chemotherapeutics and toxic proteins can be used to deliver therapy directly to tumor cells, thereby avoiding the systemic toxicity that is common when patients undergo therapy. Drugs which interfere with sEV formation can also be delivered to tumor cells. This prevents tumor cells from creating sEVs and may result in inhibiting tumor progression.