Regulation of cancer metastasis by cell-free miRNAs

Abstract

MicroRNAs (miRNAs) are integral molecules in the regulation of numerous physiological cellular processes that have emerged as critical players in cancer initiation and metastatic progression, both by promoting and suppressing metastasis. Recently, cell-free miRNAs shed from cancer cells into circulation have been reported in cancer patients, raising hope for development of novel biomarkers that can be routinely measured in easily accessible samples. In fact, establishing miRNA expression in the circulation likely has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA detection in oncological practice. In addition, secretion of miRNAs impacting distant cell signaling or promoting the formation of a niche that sustains a distant tumor microenvironment allows for new treatment approaches to thwart cancer progression.

Keywords: Biomarker; Body fluids; Cell-free microRNA; Exosomes; Metastasis.

Figure 1. Cell-free miRNA secretion pathways

Tumor-derived cell-free miRNAs can be released into the local microenvironment using multiple pathways from where they can potentially enter any body fluids. The most commonly used body fluids for miRNA detection of brain tumors, breast cancer and renal cell carcinoma (RCC) are illustrated. Exosome and microvesicle secretion are active processes whereby small membrane-enclosed vesicles containing a variety of molecules, including, proteins, DNA, and various RNA species, are released into the extracellular milieu. Cell death by apoptosis and necrosis passively leak cell-free miRNAs into the surrounding. Apoptotic bodies can also enclose miRNAs. Carrier-bound cell-free miRNAs can be bound by protein or lipid carriers; it is not understood how this release is mediated.

Figure 2. Cell-free miRNA involvement in regulating metastasis

Cell-free miRNA can influence each step of the metastatic cascade by either promoting (onocmirs, red) or inhibiting (tumor suppressive miRNAs, green) metastatic progression. Cancer cells disseminate from the primary sites after acquiring an invasive phenotype, in part through the EMT, and enter the blood and lymphatic systems. Once in circulation, circulating cancer cells extravasate into distant organs such as the lung and the bone, where they actively grow into metastatic tumors or stay dormant before resuming expansion into overt metastasis. While a number of tumor miRNAs which have been identified in circulation of metastasis patients have been implicated in influencing particular metastatic steps, their role as cell-fee miRNAs has not been validated (miRNAs in italics). Nevertheless, the function of several cell-free miRNAs has been studied during metastatic progression (miRNAs in bold).