Exosome/microvesicle-mediated epigenetic reprogramming of cells

Abstract

Microvesicles (MVs) are released by different cell types and may remain in the extracellular space in proximity of the cell of origin or may enter the biological fluids. MVs released by tumor cells are detectable in patients with cancer and their number in the circulation correlates with poor prognosis. Recent studies demonstrated that MVs may act as mediator of cell-to-cell communication thus ensuring short- and long-range exchange of information. Due to their pleyotropic effects, MVs may play a role in the prothrombotic state associated with cancer as well as in cancer development and progression. It has been recently shown that MVs may induce epigenetic changes in target cells by transferring genetic information. This finding suggests that tumor and stromal cells may talk each other via MVs to establish a favorable tumor niche and to promote tumor growth, invasiveness and progression. Moreover, MVs contain genetic material under the form of mRNA and microRNA, that may allow an easy screening for cancer genetic markers and offer new diagnostic and prognostic information. This review presents an overview of the many biological actions of MVs and of the potential role of MV-mediated exchange of genetic information among cells in tumor biology.

Figure 1

Production and release of shedding vesicles and exosomes. (A) Schematic representation of production and release from the cell surface of the shedding vesicles. Shedding vesicles are produced by budding of cell plasmamembrane. (B) Schematic representation of exosome release. The exocytic multivesicular bodies may fuse with membrane and release exosomes.

Figure 2

Schematic representation of MV-mediated cell-to-cell interaction. (1) MVs may signal through surface expressed receptors leading stimulation of target cells. (2) MVs may transfer receptors from the cell of origin to the target cell. (3) MVs may transfer oncogene products, transcription factors or infectious particles to target cells. (4) MVs may mediate a horizontal transfer of mRNA and microRNA (miRNA) inducing epigenetic changes in the target cell.

Figure 3

Schematic representation of exchange of genetic information among tumor and stroma cells. Tumor and normal stroma cells talk each other to establish a favorable tumor niche and to promote tumor growth, invasiveness and progression via mutual shedding of MVs. This induces changes in the behaviour of normal cells and increases tumorigenic-ity. The MVs released from cancer cells may repro-gram the phenotype of cells present in the tumor microenvironment by delivering to cells the mRNA and/or microRNA (miRNA). This may induce epigenetic alterations in tumor endothelial cells promoting the angiogenic shift of the tumor. Moreover, tumor-derived MVs, by entering the circulation and biological fluids, may allow long distance cell-to-cell communication favoring the development of a pre-metastatic niche.