Associate Editor: Beverly TeicherCell-to-cell miRNA transfer: From body homeostasis to therapy
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.
Section snippets
What are microRNAs?
The role of non-protein coding RNAs (ncRNAs) as fine-tuners of both pathological and physiological processes is no longer a subject of debate. Findings over the past several years have linked this class of nucleic acids, once considered ‘background noise’, with a large panel of biological processes, such as homeostasis, development and carcinogenesis. MiRNAs are the members of this class that have seized all of the attention since their documented involvement in human diseases.
These small,
Circulating microRNAs
The recent detection of miRNAs in body fluids (e.g. blood, saliva, serum, milk) has led researchers to assign them the intriguing role of gene regulator molecules, in addition to their obvious role as biomarkers (Mitchell et al., 2008, Hu et al., 2010, Huang et al., 2010).
The secretory mechanism remains yet unclear, but three different possibilities have been suggested:
- i.
Passive leakage from cells due to injury, chronic inflammation, apoptosis or necrosis, or from cells with short half-lives,
Cell-derived membrane vesicle-mediated transfer
The first evidence of encapsulation of miRNAs into nanovesicles (erroneously called microvesicles, in view of their size) was reported by Valadi et al. (2007), who stated that mast cell exosomes containing RNA (mRNA and miRNA) from mouse, are transferred to both human and other murine cells. After this transferral, new murine proteins were found in the recipient cells, demonstrating that exosomal mRNA can be passed into other cells. Thus, it was established that the message delivered on from
MicroRNAs — Thinking outside the box
The process of cancer initiation and progression is a dynamic one involving a complex signaling network of tumor cells and their microenvironment. It was once pointed out that tumors are ecosystems in which cancer cells interact with normal host cells as well as growth factors, oxygen and other resources and factors in their environment (Hede, 2009). Combining these two concepts, we hypothesize that circulating miRNAs are among the essential players in the evolution of tumor microenvironment
Therapeutic implications of microRNAs as hormones
The diagnostic and therapeutic potentials of circulating miRNAs have long been acknowledged, with various studies vouching for their use as predictors of sensitivity to radiotherapy or anticancer agents, or as biomarkers for monitoring disease evolution during treatment (Weiss et al., 2008, Jung et al., 2012). Yet research has not found the means to transpose them into clinic, partly because of the conflicting data presented by most profiling studies. Some of the challenges encountered when
Conclusion
Our knowledge about extracellular miRNAs is at the germinal stage. We still have a great deal to learn about how miRNAs are sorted for secretion or recognized by different complexes for uptake, but most importantly what their function is. Answers to these questions will enable us to make full use of the complete potential of the “liquid biopsy” provided by the miRNAs, allowing physicians to observe changes in the physiological condition over time and tailor treatment modalities.
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
Dr. Calin is The Alan M. Gewirtz Leukemia & Lymphoma Society Scholar. He is supported also as a Fellow at The University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation. Work in Dr. Calin's laboratory is supported in part by the NIH/NCI, a Department of Defense Breast Cancer Idea Award, Developmental Research Awards in Breast Cancer, Ovarian Cancer, Brain Cancer, Prostate, Multiple Myeloma and Leukemia SPOREs
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