A recent article published by the journal Oncotarget (1), researchers at the Molecular Angiogenesis Laboratory in the GIGA-Cancer Unit at the University of Liege demonstrated the action of endothelial exosomes and the microRNAs they contain in relation to tumor growth. Their study shows that when the miR-503 microRNA is transferred into cancerous human breast cells it can bring about changes resulting in a reduction of the proliferative and invasive ability of these cells.

At the beginning of the 2,000s, biologists realized that the microRNAs, small non-coding RNAs, played a much more important role in mammals and humans that had previously been thought. While scientists were aware that these RNAs played a part in plant metabolism, about which very little is still known for that matter, they were nonetheless unaware that they were strongly expressed in humans, and that they varied greatly in many different pathologies.

Exosomes had already been identified in the 1980s as being small spherical-shaped membranous vesicles with a diameter varying between 40 to 100 nanometers. Initially, it was commonly accepted that they were secreted by the reticulocytes. They were believed to have the function of eliminating proteins that had become useless to the cell after being deposited in the extracellular medium. It later emerged that, not only could they be secreted by different types of cells and that their molecular composition and function depended on the type of cell they came from, but that they also enclosed microRNAs as well as other non-coding forms of RNA.

“Two theories were then put forward. According to the first of these, the cell got rid of an overflow of microRNAs. According to the second theory, these microRNAs played a part in communication between the cells”, explains Ingrid Struman, a research associate at the FNRS and head of the Laboratory of Molecular Biology and Genetic Engineering in the GIGA-Cancer unit of the University of Liege. For the moment, the debate is still open, at least from a semantic point of view, in so far as the notion of "communication" creates the idea of purpose which would imply a voluntary action, something that would not seem to be applicable to a cell.

Many unknowns

However, the idea came into being that microRNAs transferred by exosomes could have a function. It was, in fact, demonstrated that on contact with a recipient cell, they are capable of modifying the genetic response of these cells and therefore the phenotype.

Currently, the mechanisms by which the export of microRNAs into the exosomes is regulated is still not fully understood even though some work has demonstrated the intervention of a  specific RNA binding protein as being involved in some cases. “At GIGA-Cancer, we are trying to identify the proteins capable of transferring some determined microRNAs but not others to the exosomes”, says Ingrid Struman.

Another unanswered question that remains is: how does the exosome target the cell to which it will transfer its content? Some studies suggest that there is an interaction from protein to protein similar to that of the ligand-receptor type of interaction, between the exosome and the target cell, but this has not been proved to date. In practice, at the moment when it transfers its contents, the exosome is endocytosed by the target cell after fusion of the membranes. However, it remains unknown whether the exosomes produced by a cell are uniform and will always target the same type of cell. “We are not certain, but we think that the content of the exosomes can vary according to the moment they are produced”, explains Ingrid Struman.

The word “contents” must be used reservedly because some authors think that the microRNAs are not necessarily lodged inside the exosomes but can attach themselves to the exosome membrane by means of an electric charge.

The quantity of exosomes secreted depends first and foremost on the type of cell. For example, the endothelial cells produce a lot of exosomes and according to Ingrid Struman, are probably those that produce the most. The cancer cells are not at rest however. Through the work carried out at GIGA-Cancer by the Molecular Angiogenesis Laboratory, it seems that the quantity and content of exosomes are modulated by the conditions of the cells that produce them. The team of researchers from Liege established that endothelial cells placed in conditions of stress (hypoxia, presence of chemotherapeutic agents...) secreted an increased number of exosomes.