Intercellular Molecular Transfer Mediated by Extracellular Vesicles in Cancer.

Abstract

Among multiple pathways of intercellular communication operative in multicellular organisms, the trafficking of extracellular vesicles (EVs) and particles (EP) represents a unique mode of cellular information exchange with emerging roles in health and disease, including cancer. A distinctive feature of EV/EP-mediated cell-cell communication is that it involves simultaneous short- or long-range transfer of numerous molecular constituents (cargo) from donor to recipient cells. EV/EP uptake by donor cells elicits signalling or metabolic responses, or else leads to EV-re-emission or degradation. EVs are heterogeneous membranous structures released from cells via increasingly defined mechanisms involving either formation of multivesicular endosomes (exosomes) or budding from the plasma membrane (ectosomes). EPs (exomeres, supermeres) are membraneless complex particles, smaller than EVs and of less defined biogenesis and function. EVs/EPs carry complex assemblies of proteins, lipids and nucleic acids (RNA, DNA), which they shuttle into intercellular milieu, body fluids and recipient cells, via surface contact, fusion and different forms of internalization (endocytosis, micropinocytosis). While the physiological functions of EVs/EPs communication pathways continue to be investigated, their roles in cancer are increasingly well-defined. For example, EVs are involved in the transmission of cancer-specific molecular cargo, including mutant, oncogenic, transforming, or regulatory macromolecules to indolent, or normal cells, sometimes triggering their quasi-transformation-like states, or phenotypic alterations. Conversely, a reciprocal and avid uptake of stromal EVs by cancer cells may be responsible for modulating their oncogenic repertoire, as exemplified by the angiocrine effects of endothelial EVs influencing cancer cell stemness. EV exchanges during cancer progression have also been implicated in the formation of tumour stroma, angiogenesis and non-angiogenic neovascularization processes, immunosuppression, colonization of metastatic organ sites (premetastatic niche), paraneoplastic and systemic pathologies (thrombosis, diabetes, hepatotoxicity). Thus, an EV/EP-mediated horizontal transfer of cellular content emerges as a new dimension in cancer pathogenesis with functional, diagnostic, and therapeutic implications.