Tumor-derived extracellular vesicles and microRNAs: Functional roles, diagnostic, prognostic and therapeutic options

Highlights

• Tumor cells transfer oncogenic activity by exosome release.

• MiRNAs are loaded into exosomes by selective mechanisms.

• Exosomal miRNAs communicate with cells of the tumor microenvironment.

• This interaction influence tumor progression and metastatization.

Abstract

In the last few years cancer research more and more highlighted the importance of cell to cell communication in tumor progression. Among many other functional mechanisms, results evidenced the importance of miRNAs loaded into exosomes and their actions as mediators in intercellular communication, either in the tumor microenvironment or at distant sites. Deregulation of miRNA levels is a prerogative of cancer cells and is reflected in the miRNA cargo of tumor derived exosomes. Thus, learning of circulating miRNA activities add the missing piece we need to understand some unclear aspects of cancer biology.

Here we summarized the current knowledge on exosome transfer capabilities between cancer cells and all the cells constituting tumor microenvironment with a particular focus on their miRNA cargos and regulatory functions. The clinical relevance of these molecular aspects is emphasized by numerous cell interactions that ultimately result in normal cell function defeat, relevant to increase tumor malignancy. The quantitative and qualitative evaluation of circulating miRNAs offers new perspective for better diagnosis and prognosis of cancer patients, eventually improving their management.

Introduction

Growing evidence shows that microvesicles, including exosomes, play an important role in transmitting biological information to proximal and distant sites by carrying and releasing their cargos. Many studies have demonstrated that exosomes can be secreted by all cellular types being able to transfer their specific properties via horizontal propagation, thus EXOs secreted by tumor cells are shown to transfer oncogenic activity, whereas those released by normal cells can be involved in the maintenance of physiological homeostasis.

Among many other transported molecules, miRNAs seem to play a fundamental role possibly because of their small size and direct action. Actually, mature miRNAs are less than 25 nucleotides long and, differently from mRNAs, do not require further maturative steps to exert their biological effects. In addition, each miRNA can regulate the expression of hundreds of mRNAs, and each mRNA can be targeted by several miRNAs, thus producing a complex and powerful regulatory network.

It is important to note that free or EXO-loaded miRNAs secreted in extracellular compartments, as blood and other body fluids, result representative of their producing cells, thus allowing frequent noninvasive analyses. Indeed the endogenously produced and the engineered exosomes will represent important tools with diagnostic and prognostic values as well as therapeutic effectiveness, respectively. Also, the fundamental role acquired by the tumor microenvironment in cancer progression suggests exosomes, in view of their involvement in the intercellular crosstalk, as a promising field whose development would offer novel insights and therapeutic opportunities.