Exosomes as divine messengers: are they the Hermes of modern molecular oncology?

Abstract

Exosomes are cell-derived vesicles that convey key elements with the potential to modulate intercellular communication. They are known to be secreted from all types of cells, and are crucial messengers that can regulate cellular processes by 'trafficking' molecules from cells of one tissue to another. The exosomal content has been shown to be broad, composed of different types of cytokines, growth factors, proteins, or nucleic acids. Besides messenger RNA (mRNA) they can also contain noncoding transcripts such as microRNAs (miRNAs), which are small endogenous cellular regulators of protein expression. In diseases such as cancer, exosomes can facilitate tumor progression by altering their vesicular content and supplying the tumor niche with molecules that favor the progression of oncogenic processes such as proliferation, invasion and metastasis, or even drug resistance. The packaging of their molecular content is known to be tissue specific, a fact that makes them interesting tools in clinical diagnostics and ideal candidates for biomarkers. In the current report, we describe the main properties of exosomes and explain their involvement in processes such as cell differentiation and cell death. Furthermore, we emphasize the need of developing patient-targeted treatments by applying the conceptualization of exosomal-derived miRNA-based therapeutics.

Figure 1

Exosome structure and function. (a) Exosome biogenesis and function: once released, exosomes can travel through biological fluids (e.g. serum, lymph) and furthermore, they can be internalized by cells from nearby tissues, or more so, reach body sites very far from their tissue of origin. (b) Main classes of molecules included in the exosomal cargo. MT, mitochondria; MVB, multivesicular bodies

Figure 2

Immune surveillance of T cells and specific miRs of exosomes released from tumor cells

Figure 3

Exosome secretion by tumor cells. The released exosomes are uptaken by neighboring cells and are capable of inducing pathways involved in cancer initiation/progression (e.g. migration, invasion), or alternatively, they can modulate immunogenic responses. Their downstream effect is attributed to their molecular cargo, which can be rich in miRNAs

Figure 4

Tumor-derived exosomes are secreted via a constitutive/inducible pathway that can be activated by a p53-mediated response. Through this pathway (and possibly additional ones that remain unknown), exosomes can transport microRNAs into the vascular system and regulate important cellular processes such as immunosurveillance, apoptosis and angiogenesis. For example: (a) TP53 can induce the activity of TSAP6 proteins, thereby modulating key functions associated with tumor-derived exosome trafficking. Exosomes are generated by reverse budding of the membrane of multivesicular bodies (MVBs) that fuse with the plasma membrane, causing the release of these particles outside the cell. (b) From this moment on, exosomes enter the vascular or lymphatic system and circulate freely until they bind to their specific target. (c) The release from the cell is possible after the membrane is stimulated by calcium ionophores or phorbol esters. Inositol 3-kinase inhibitors can inhibit this process