Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis

Abstract

In the past several years, the importance of microRNA (miRNA) in cancer cells has been recognized. Proper control of miRNA expression is essential for maintaining a steady state of the cellular machinery. Recently, it was discovered that extracellular miRNAs circulate in the blood of both healthy and diseased patients, although ribonuclease is present in both plasma and serum. Most of the circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies, microvesicles, or exosomes, and are, therefore, highly stable. The existence of circulating miRNAs in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function, as well as the meaning of the existence of extracellular miRNAs, remain largely unclear. In this review, we summarize the usefulness of circulating miRNA for cancer diagnosis, prognosis, and therapeutics. Furthermore, we propose a mechanism for the secretion and incorporation of miRNA into the cells.

Figure 1

miRNAs in human body fluids are non‐invasive diagnostic markers for cancers. Many kinds of circulating miRNAs have been reported in various types of cancers. However, certain cancers cannot be diagnosed by known serum biomarkers. In such cases, circulating miRNAs in serum, saliva, and urine are good candidates for future use. AML, acute myeloid leukemia; DLBCL, diffuse large B‐cell lymphoma.

Figure 2

Secreted miRNAs contained in exosomes potentially influence microenvironmental cells, including immune cells, endothelial cells, and fibroblast cells. Soluble factors, such as cytokines and chemokines, have been shown to be intercellular communication tools between cancer and microenvironmental cells. In addition, recent observations have indicated that exosomes also function as an intercellular communication tool between them. For instance, exosomes, which are secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells, and dendritic cells then induce potent CD8+ T‐cell‐dependent antitumor effects on syngenic and allogeneic established mouse tumors. In addition, this transforming activity can possibly be transferred via exosome. Furthermore, miRNA, which regulates multiple target genes, can also be transferred from tumor cells to tumor cells or tumor cells to normal cells. When purified PKH67‐labeled exosomes from donor cancer cells were incubated with recipient cancer cells, they became fluorescent, indicating that an oncogene can be propagated horizontally through exosomes. CEA, carcinoembryonic antigen; HLA, human leukocyte antigen; HER2, human epidermal growth factor receptor 2; TGF; transforming growth factor; TNF, tumor necrosis factor.