Abstract

Oncogene Transmission by Extracellular Vesicles

Janusz Rak, Professor, McGill University

Oncogenic events occuring within the cancer cell genome and epigenome profoundly impact tumour cell secretory and interactive profiles. The resulting changes shape tumour microenvironment and exert systemic effects by altering the state of the vascular, coagulation and immune systems, and cellular homeostasis in distant organs. Mediators of these effects include both, the well established (paracrine, adhesive and enzymatic) signalling pathways, as well as some less studied (‘non-conventional’) mechanisms, such as the exchange of macromolecules via intercellular trafficking of extracellular vesicles (EVs). EVs are membrane structures heterogeneous and molecularly complex in nature known to be released from different subcellular compartments (membrane, endosomes) into the extracellular space, where they interact with diverse cellular targets (recipient cells). In this regard, oncogenic transformation impacts the EV release processes in several biologically consequential and diagnostically relevant ways. Thus, malignant transformation and altered differentiation pathways modulate the machinery involved in EV biogenesis (vesiculome) leading to changes in the emission profiles of different EV subpopulations (e.g. exosomes or ectosomes). Oncogenic events also influence molecular composition of the EV cargo by modulating cellular gene expression and molecular packaging processes involved in EV formation. Importantly, cancer-related EVs often carry bioactive and structurally altered (mutant) oncogenic proteins, transcripts, microRNA and DNA into extracellular space and biofluids. The latter property renders oncogene carrying EVs (oncosomes) molecularly and biologically unique. Notably, the uptake of EV-associated transforming molecules by various types of recipient cells often profoundly changes their biological properties, such as growth, survival, procoagulant and angiogenic activity. While some of these features are reminiscent of the cancer cell phenotype (e.g. foci for