Cancer cells can affect behaviour of neighbouring cells by transferring molecules through extracellular vesicles

Abstract

Most cells release into the extracellular space membrane-bound structures of different sizes, origin and composition, collectively called extracellular vesicles (EVs) [1]. Tumor cells are much more active than normal cells in producing EVs. Because of this property, they are able to transfer both nucleic acids and proteins to the surrounding normal cells, thus inducing in these latter at least some transformed behavior. We previously showed that EVs produced by G26/24 oligodendroglioma cells can horizontally transfer to their neighbours radioactive proteins [2]. In addition, EVs released by these cells contain pro-apoptotic proteins, such as TRAIL and Fas-Ligand, able to induce apoptosis in rat cortical neurons and astrocytes in culture [2]. Moreover these population of EVs also contain extracellular matrix remodelling proteases (such as ADAMTS) [3], as well as the H1.0 histone protein, and even H1.0 mRNA [4]. Another tumor cell line, with a different tissue origin (A375 melanoma cells), was then demonstrated to release into the medium EVs containing a sumoylated form of H1.0 histone [5]. By a T1 RNase-protection assay, using as target the H1.0 RNA, three main complexes were evidenced in these EVs, the most abundant of which had an apparent molecular mass of about 65 kDa. By affinity chromatography on a biotinylated H1.0 RNA, we isolated a group of proteins, among which we identified by mass spectrometry a protein of about 60 kDa: myelin expression factor-2 (MYEF2). Western blot analyses confirmed the presence of MYEF2 in EVs released from A375 melanoma cells [5]. MYEF2 was actually already known as a protein with putative RNA-binding domains and a demonstrated ability to function as a transcription factor. Our demonstration of its actual ability to bind RNA rises the interesting possibility that RNA can function as a carrier of factors that, once in the receiving cells, can change their transcriptional activity. Starting from this hypothesis, we are now analyzing cells of cerebral origin for the presence of MYEF2 and/or other transcription factors which are transferred among cells via EVs. [1] Schiera G, et al. 2015.Biomed Res Int. 2015:152926. [2] Lo Cicero A et al. 2011, Int J Oncol 39:1353-7 [3] Lo Cicero A et al. 2012, Matrix Biol 31:229-33 [4] Schiera G et al. 2013, Int J Oncol 43:1771-6 [5] Schiera G. et al. 2016. Int J Oncol. 49:1807-1814.