Therapeutic Targeting of MicroRNAs in the Tumor Microenvironment

Abstract

The tumor-microenvironment (TME) is an amalgamation of various factors derived from malignant cells and infiltrating host cells, including cells of the immune system. One of the important factors of the TME is microRNAs (miRs) that regulate target gene expression at a post transcriptional level. MiRs have been found to be dysregulated in tumor as well as in stromal cells and they emerged as important regulators of tumorigenesis. In fact, miRs regulate almost all hallmarks of cancer, thus making them attractive tools and targets for novel anti-tumoral treatment strategies. Tumor to stroma cell cross-propagation of miRs to regulate protumoral functions has been a salient feature of the TME. MiRs can either act as tumor suppressors or oncogenes (oncomiRs) and both miR mimics as well as miR inhibitors (antimiRs) have been used in preclinical trials to alter cancer and stromal cell phenotypes. Owing to their cascading ability to regulate upstream target genes and their chemical nature, which allows specific pharmacological targeting, miRs are attractive targets for anti-tumor therapy. In this review, we cover a recent update on our understanding of dysregulated miRs in the TME and provide an overview of how these miRs are involved in current cancer-therapeutic approaches from bench to bedside.

Keywords: RNA therapy; breast cancer; inflammation; macrophage; microRNA.

Figure 1

Examples of dysregulated microRNAs (miRs) in cells of the tumor microenvironment (TME) and their impact on tumor cells. MiRs can either act as tumor-suppressors by regulating molecules or pathways with anti-tumoral characteristics (red box; red T bar) or oncomiRs that directly or indirectly impact on tumor-promoting genes and protein networks (green box; green arrow). The differential expression of miRs in macrophages and tumor-associated macrophages (TAMs), or the uptake of exogenous miRs, modulate their polarization. Similarly, miRs expressed in cancer-associated fibroblasts (CAFs) regulate their migration, cytokine production, and trans-differentiation as well as tumor growth. CAF-derived miRs (e.g., miR-522) can also enhance drug resistance of tumor cells. In dendritic cells (DCs), miRs regulate Th17 differentiation, co-stimulatory molecule expression, and T cell activation. miRs expressed in cancer-associated endothelial cells (CAEs) regulate the microvascular invasion and angiogenesis activity to drive tumorigenesis. In myeloid-derived suppressor cell (MDSCs), miRs modulate the expansion/immune-suppressive functions. In natural killer (NK) cells, miRs modulate the production of effector molecules (e.g., IFN-γ) and the activating receptor encoded by killer cell lectin like receptor K1 (NKG2D). Furthermore, miRs regulate the expression of transcription factors and cytokine production of regulatory T cells (Tregs). ARG1, arginase 1; α-SMA, α-smooth muscle actin; CAE, cancer-associated endothelial cell; CAF, cancer-associated fibroblast; DC, dendritic cell; Fgf2, fibroblast growth factor 2; IFN, interferon; iNOS, inducible NO synthase; NF, normal fibroblast; NKG2D, encoded by killer cell lectin like receptor K1; ROS, reactive oxygen species; TAM, tumor-associated macrophage; Treg, regulatory T cell.

Figure 2

Therapeutic modulation of miR expression and miR carriers. Tumor suppressive miRs can be replenished by miR mimics (a), thereby suppressing translation of mRNAs encoding for oncogenes. On the other hand, oncogenic miRs can be inhibited by ASOs (b), miR-sponges (c), artificial ribonucleases (d), small molecules (e), or the CRISPR/Cas9 system (f). Small molecules have been shown to either suppress oncomiRs or globally enhance miR expression. To increase oligonucleotide stability, chemical modifications can be inserted. Several delivery systems have been established to further increase the stability of the miR therapeutic agent and improve tumor cell targeting, e.g., cationic dendrimers (g), lipoplexes (h), nanoparticles with tumor-specific ligands (i), inorganic nanoparticles (j), micelles (k), polymer nanoparticles (l), and exosomes/microvesicles (m). See text for more details. AGO, argonaute protein; ASOs, antisense-oligonucleotides; AuNPs, gold nanoparticles; DOPC, 1,2 dioleoyl-sn glycerol-3 phosphatidylcholine-lipid nanoparticles; EDVs, EnGeneIC Delivery Vehicle; LNA, locked nucleic acid; NLE, neutral lipid emulsions; PAMAM, poly(amidoamine); PEI, poly(ethyleneimine); pHLIP, pH low insertion peptide; PLGA, Poly(lactide-co-glycolide); Pol II, RNA-polymerase II; PPI, poly(propylenimine); RISC, RNA-induced silencing complex.