Cell-to-cell miRNA transfer: From body homeostasis to therapy

Abstract

The role of non-protein coding RNAs (ncRNAs), microRNAs (miRNAs) in particular, as fine-tuners of both pathological and physiological processes is no longer a matter of debate. With the recent discovery of miRNAs in a wide variety of body fluids and considering them as tools employed in horizontal gene transfer between cells, a new horizon opens in the field of diagnosis and therapeutics. Circulating miRNAs not only enable the communication among cells, but also provide insight into the pathological and physiological state of the originating cells. In this review we summarize the recent advances made in this field, arguing for compelling translation of miRNAs into clinical practice. Moreover, we provide overview of their characteristics and how they impact the evolution of tumor microenvironment and cell-to-cell communication, advancing the idea that miRNAs may function as hormones.

Introduction

Victor Ambros's and Garry Ruvkun's discovery of miRNAs revolutionized research and changed the scientific world's perspective towards the traditional dogma: DNA → RNA → Protein. Most of the inquiries have been conducted in the cancer field, considering that miRNAs were first linked to this malignancy a decade ago (Calin et al., 2002). While their reputation as master regulators of almost all biological processes spread rapidly throughout the medical world, it has triggered the interest of scientists working in various fields and as our knowledge about diseases continuously expands, new roles of these small non-coding RNAs have been revealed.

Tumors are no longer being regarded as a collection of relatively homogeneous cancer cells, but rather as a complex assemble of distinct cell types (Hanahan & Weinberg, 2011) in which cell-to-cell communication is essential for the regulation of proliferation, angiogenesis and metastasis (Hu & Polyak, 2008). Furthermore, if one is to look at cancer through the lens of evolution and ecology, tumor microenvironment can be considered a dynamic ecosystem obeying Darwin's theory for the selection of the “fittest” cancer cells (Hede, 2009). In this context, horizontal gene transfer (HGT), a mechanism initially described in bacteria for passing of genetic material between organisms, that provides selective advantage in particular environments, emerges as extremely relevant, and various recent studies have advanced the idea that it may occur in multicellular organisms as well (Ratajczak et al., 2006, Valadi et al., 2007, Ahmed and Xiang, 2011). HGT through secreted miRNAs is a newly introduced concept aiding the elucidation of cell-to-cell interactions and the mechanisms of co-evolution of tumor cells and their microenvironment. Nevertheless, it is mandatory to point out that here we refer to HGT occurring without genomic integration. Moreover, analyzing miRNAs from this angle grants the means for regarding them as the last addition to the expanding world of hormones.

In this review, we will describe the known characteristics of secreted miRNAs and focus on their impact on the evolution of tumor microenvironment and cell-to-cell communication, highlighting the implications of secreted miRNAs in therapeutics and arguing for their relationship to hormones.