MicroRNA and extracellular vesicles in glioblastoma: small but powerful

Abstract

To promote the tumor growth, angiogenesis, metabolism, and invasion, glioblastoma (GBM) cells subvert the surrounding microenvironment by influencing the endogenous activity of other brain cells including endothelial cells, macrophages, astrocytes, and microglia. Large number of studies indicates that the intra-cellular communication between the different cell types of the GBM microenvironment occurs through the functional transfer of oncogenic components such as proteins, non-coding RNAs, DNA and lipids via the release and uptake of extracellular vesicles (EVs). Unlike the communication through the secretion of chemokines and cytokines, the transfer and gene silencing activity of microRNAs through EVs is more complex as the biogenesis and proper packaging of microRNAs is crucial for their uptake by recipient cells. Although the specific mechanism of EV-derived microRNA uptake and processing in recipient cells is largely unknown, the screening, identifying and finally targeting of the EV-associated pro-tumorigenic microRNAs are emerging as new therapeutic strategy to combat the GBM.

Keywords: Exosomes; Extracellular vesicles; Glioblastoma; microRNA.

Figure 1. Mechanism of microRNA action and secretion into the tumor microenvironment

Primary microRNAs are transcribed in the nucleus by DNA polymerase II and then cleaved to generate precursor microRNAs (pre-microRNAs). Pre-microRNAs are then transferred to the cytoplasm were they are further processed by Dicer to form the 17-23 nucleotide long mature microRNAs. Such mature microRNAs can bind the target mRNA to regulate their stability and translation, or they can be secreted through extracellular vesicles (EVs). EVs may generate directly from the cell plasma membrane, or they can be released by fusion of the multi-vesicular bodies (MVBs) with the plasma membrane. After secretion,GBM EV microRNAs are taken up by other tumor cells or normal cells in the microenvironment to change their phenotype and support tumor progression. GBM EV microRNAs are also released into the cerebrospinal fluid and into the bloodstream were they can be collected for detection of tumor biomarkers.