Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology

Abstract

Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.

Keywords: Cancer; Circular RNA; Exosome; Extracellular vesicle; Long non-coding RNA; Micro RNA; Microvesicle; Premetastatic niche; Tumor microenvironment.

Fig. 1

Extracellular vesicle biogenesis and secretion in donor cells as well as its interaction with and intracellular fate in recipient cells. Microvesicles directly shed from the plasma membrane, where budding microdomains undergo phosphatidylserine translocation and remodeling of the actin cytoskeleton. By contrast, exosomes originate from endosomal pathway. Deriving from endocytosis, early sorting endosomes accumulate ILVs within the endosomal lumen and then mature into MVEs, where ESCRT components, ceramide, tetraspanins and syntenin could act in parallel or separately to recruit exosomal cargoes and generate ILVs. At this checkpoint, the MVEs can either enter into autophagy-lysosome pathway or exosomal secretion pathway. of note, amphisomes can either fuse with lysosomes or the plasm membrane. Upon secretion into extracellular space, exosomes and microvesicles can bind to the recipient cell surface via ligand-receptor or glycoprotein interactions and initiate signaling, uptake and fusion processes, contributing to transfer functional messages and cellular phenotypes. MVE (multivesicular endosome), EV (extracellular vesicle), PM (the plasma membrane), Ub (ubiquitin), ECM (extracellular matrix), ESCRT (endosomal sorting complex required for transport), SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)

Fig. 2

RNA incorporation into EVs. Various RBPs and membrane-associated proteins are required for the different steps of EV-RNA sorting. First, intracellular RNAs can interact with RBPs or motif-specific RBPs, which may prevent RNAs from degradation. Second, RNA-loaded RBPs undergoing post-translational modification can be recruited to the sites of EV budding via binding to membrane-associated proteins; otherwise, RNAs and RNA-loaded RBPs are incorporated passively into EVs. Third, upon reaching the budding membrane, the RBPs can be co-sorted with loaded RNAs into EVs or unload RNAs into EVs. In addition, 3′ end RNA tailing, such as adenylation and uridylation, controls RNA distribution between cells and EVs. MVE (multivesicular endosome), EV (extracellular vesicle), RBP (RNA binding protein).

Fig. 3

EV-RNA mediated crosstalk within tumors and between tumors and stroma modulating malignant behaviors of cancer cells. Cancer initiation, development and progression are attributed to sophisticated and multidirectional communication between various cells. Tumor-derived EV-RNAs can elicit oncogenic, prometastatic, proangiogenic and differentiated phenotypes of stromal cells in the tumor microenvironment or prometastatic niches. Tumor-derived EV-RNAs also drive normal and tumor cell subpopulations towards malignant phenotypes. EV-RNAs from cancer-reprogrammed stromal or normal cells also contribute to malignant behaviors of cancer cells, thereby affecting the growth, migration, invasion and survival of primary and metastatic cancer cells. Of note, EV-RNAs from normal cell can also restrain the malignant behaviors of cancer cells.

Fig. 4

EV-RNA mediated crosstalk between cancer cells and immune cells and within immune cells modulating malignant behaviors of cancer cells. Tumor-derived EV-RNAs can contribute to the immunosuppressive and decreased anti-tumoral activities of various immune cells and induce immunoinhibitory phenotype of CAFs and normal cells. EV-RNA-mediated communication between immunes also leads to cancer progression.