Extracellular Vesicles and the Inflammasome: An Intricate Network Sustaining Chemoresistance

Abstract

Extracellular vesicles (EVs) are membrane enclosed spherical particles devoted to intercellular communication. Cancer-derived EVs (Ca-EVs) are deeply involved in tumor microenvironment remodeling, modifying the inflammatory phenotype of cancerous and non-cancerous residing cells. Inflammation plays a pivotal role in initiation, development, and progression of many types of malignancies. The key feature of cancer-related inflammation is the production of cytokines that incessantly modify of the surrounding environment. Interleukin-1β (IL-1β) is one of the most powerful cytokines, influencing all the initiation-to-progression stages of many types of cancers and represents an emerging critical contributor to chemoresistance. IL-1β production strictly depends on the activation of inflammasome, a cytoplasmic molecular platform sensing exogenous and endogenous danger signals. It has been recently shown that Ca-EVs can activate the inflammasome cascade and IL-1β production in tumor microenvironment-residing cells. Since inflammasome dysregulation has been established as crucial regulator in inflammation-associated tumorigenesis and chemoresistance, it is conceivable that the use of inflammasome-inhibiting drugs may be employed as adjuvant chemotherapy to counteract chemoresistance. This review focuses on the role of cancer-derived EVs in tuning tumor microenvironment unveiling the intricate network between inflammasome and chemoresistance.

Keywords: IL-1β; chemoresistance; extracellular vesicles; inflammasome; tumor microenvironment.

Figure 1

EVs and inflammasome. Schematic representation of EVs-induced effect on inflammasome activation. Ca-EVs (light blue) are up-taken by non-cancerous cells and, via the induction of intracellular signaling pathways, including ERK1/2 MAPK, induce inflammasome platform assembly and the maturation of IL-1β which release affects the microenvironment in a tumor-promoting fashion. EVs released by non-cancerous cells violet may produce soluble factor (Adenosine) that, via receptor (adenosine A2a receptor) engagement on the target cell, activates protein kinases (PKA) which impedes inflammasome platform assembly through NLRP3 phosphorylation (P).