Cancer becomes wasteful: emerging roles of exosomes(†) in cell-fate determination

Abstract

Extracellular vesicles (EVs), including exosomes, have been widely recognized for their role in intercellular communication of the immune response system. In the past few years, significance has been given to exosomes in the induction and modulation of cell-fate-inducing signalling pathways, such as the Hedgehog (Hh), Wnts, Notch, transforming growth factor (TGF-β), epidermal growth factor (EGF) and fibroblast growth factor (FGF) pathways, placing them in the wider context of development and also of cancer. These protein families induce signalling cascades responsible for tissue specification, homeostasis and maintenance. Exosomes contribute to cell-fate signal secretion, and vice versa exosome secretion can be induced by these proteins. Interestingly, exosomes can also transfer their mRNA to host cells or modulate the signalling pathways directly by the removal of downstream effector molecules from the cell. Surprisingly, much of what we know about the function of exosomes in cell determination is gathered from pathological transformed cancer cells and wound healing while data about their biogenesis and biology in normal developing and adult tissue lag behind. In this report, we will summarize some of the published literature and point to current advances and questions in this fast-developing topic. In a brief foray, we will also update and shortly discuss their potential in diagnosis and targeted cancer treatment.

Keywords: cell-fate ligands; exosomes; extracellular vesicles; multivesicular body (MVB); secretion; signalling pathways.

Fig. 1

Hypothetical representation depicting putative cell-fate-determinant secretion pathways that could lead to exosome secretion. (A) After synthesis and putative modification a generic signalling ligand transits to the plasma membrane and from there becomes re-internalized either alone or through receptor-mediated endocytosis. After passage through the endosomal network, it eventually undergoes inclusion into MVBs. MVBs can then either fuse with the lysosome leading to signal degradation or become secretory MVBs that fuse with the plasma membrane and release exosome-bound signalling ligands. Such proteins, however could also be directly transported to the endosomal compartment after synthesis and included into endosomes. Alternatively, exosomes could be generated at the plasma membrane itself in endosome-like domains. Signalling ligands are represented as yellow circles. (B) Summarizing components found to carry out functions during exosome trafficking.

Fig. 2

Schematic representation of a hypothetical microenvironment summarizing cell communication through cell-fate signals carrying exosomes.