Exosomal MicroRNAs as Mediators of Cellular Interactions Between Cancer Cells and Macrophages

Abstract

Tumor microenvironment consists of cancer cells and various stromal cells such as endothelial cells, cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), neutrophils, macrophages, and other innate and adaptive immune cells. Of these innate immune cells, macrophages are an extremely heterogeneous population, and display both pro-inflammatory and anti-inflammatory functions. While M1 macrophages (classically activated macrophages) display anti-tumoral and pro-inflammatory functions, M2 macrophages display pro-tumoral and anti-inflammatory functions. Cellular interactions and molecular factors in the tumor microenvironment affect the polarization of macrophages. We review molecules and immune cells that influence the polarization status of macrophages. Tumor-associated macrophages (TAMs) generally express M2 phenotype, and mediate many processes that include tumor initiation, angiogenesis, and metastasis. A high number of TAMs has been associated with the poor prognosis of cancers. MicroRNAs (miRNAs) have been known to regulate cellular interactions that involve cancer cells and macrophages. Tumor-derived exosomes play critical roles in inducing the M1 or M2-like polarization of macrophages. The roles of exosomal miRNAs from tumor cells in the polarization of macrophages are also discussed and the targets of these miRNAs are presented. We review the effects of exosomal miRNAs from TAMs on cancer cell invasion, growth, and anti-cancer drug resistance. The relevance of exosomal microRNAs (miRNAs) as targets for the development of anti-cancer drugs is discussed. We review recent progress in the development of miRNA therapeutics aimed at elevating or decreasing levels of miRNAs.

Keywords: anti-cancer drugs; cancer cells; cellular interactions; exosomes; macrophages; microRNAs.

Figure 1

Tumor-stroma interactions in the tumor microenvironment modulate cancer progression. The tumor microenvironment comprises cancer cells, various stromal cells, and extracellular matrix. These stromal cells include endothelial cells, fibroblasts, and innate and adaptive immune cells. These cells can enhance or inhibit cancer progression by secreting cytokines, growth factors, and various other molecules. Mesenchymal stem cells (MSCs) and mast cells can enhance and inhibit cancer progression.

Figure 2

Polarization of macrophages by T-helper cells. Tumor associated macrophages (TAMs) are composed of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. IFN-γ, TNF-α, LPS, and GM-CSF induce M1 macrophages polarization. Th2 cytokines induce M2 macrophages polarization. Mo macrophages are circulating monocytes. M1 macrophages display higher expression level of MHC class I than M2 macrophages. M1 macrophages display higher expression level of iNOS than M2 macrophages. M2 macrophages display higher expression level of CD163 than M1 macrophages. Molecules that mediate effects of M1 macrophages or M2 macrophages are shown. SR denotes scavenger receptor. MR denotes mannose receptor. Nitric oxide synthase NOS2 (iNOS) in M1 macrophages converts L-arginine into citrulline and NO. Arginase 1 in M2 macrophages converts L-arginine into polyamine and urea.

Figure 3

Cellular interactions involving macrophages in tumor microenvironment. Cancer cells secrete chemoattractants and growth factors (CCL2, CCL5, VEGF, M-CSF) to recruit blood monocytes. Tumor-derived M-CSF, PDGF, IL-6, IL-10, TGF-β, VEGF-A, CCL2, PGE2, and endothelin 1 induce the polarization into M2-like macrophages with pro-tumor functions (TAMs). TAMs-derived cytokines/growth factors (IL-1β, IL-6, IL-10, IL-35, TGF-β, VEGF, and EGF), cathepsin, and MMPs enhance tumor cell proliferation, invasion, anti-cancer drug-resistance, and remodeling of extracellular matrix. TAMs-derived chemokines (CCL17, CCL18, and CCL22) recruit naïve and Th2 lymphocytes, which results in ineffective anti-tumor immune response. miRNAs denote microRNAs. M1 macrophages are activated by Th1 cells. M1 macrophages display anti-tumoral functions through TNF-α, IL-1, IL-6, IL-12, ROS, and iNOS.

Figure 4

Tumor-derived miRNAs regulate polarization of macrophages. Tumor-derived miRNAs induce polarization of anti-tumoral and pro-inflammatory M1 macrophages or Pro-tumoral and anti-inflammatory M2 macrophages.

Figure 5

Exosomal miRNAs from TAMs exert pro-tumoral and anti-tumoral effects. The biogenesis of exosomes involves four different steps: (a) the membrane invagination; (b) endosome formation; (c) inward budding of endosomes to form multivesicular bodies (MVBs); and (d) the fusion of MVBs with the plasma membrane release the ILVs in the extracellular space by exocytosis and become exosomes. Exosomal miRNAs (miR-7 and miR-142-3p) that exert anti-tumoral effects are shown. Exosomal miRNAs (miR-21-5p and other miRNAs) that exert pro-tumoral effects are also shown. CD63 and TSG101 are surface markers of exosomes.