MicroRNA-mediated control of macrophages and its implications for cancer

Abstract

Deregulation of microRNAs (miRNAs) can drive oncogenesis, tumor progression, and metastasis by acting cell-autonomously in cancer cells. However, solid tumors are also infiltrated by large amounts of non-neoplastic stromal cells, including macrophages, which express several active miRNAs. Tumor-associated macrophages (TAMs) enhance angiogenic, immunosuppressive, invasive, and metastatic programming of neoplastic tissue and reduce host survival. Here, we review the role of miRNAs (including miR-155, miR-146, and miR-511) in the control of macrophage production and activation, and examine whether reprogramming miRNA activity in TAMs and/or their precursors might be effective for controlling tumor progression.

Figure 1. Overview of miRNAs implicated in macrophage development and activation

Defined miRNAs control HSC maintenance, whereas others guide hematopoietic cell commitment toward the mononuclear phagocyte lineage (at steady-state), and/or control macrophage activation. The induction of miRNAs is context-dependent and is triggered and controlled by cell exogenous and endogenous cues (see also Figure 2).

Figure 2. Regulation of classical and alternative macrophage activation by miRNAs

The schematic illustrates prototypical ligand/receptor pairs that stimulate either the alternative (or M2; left, blue) or the classical (or M1; right, pink) activation of macrophages. Several miRNAs are induced upon either type of macrophage activation. These include miRNAs that primarily sustain classical activation (pink-shaded contours) either by enhancing proinflammatory signaling (e.g., miR-155, miR-125a/b) or by attenuating alternative activation (e.g., miR-511-3p, miR-378 and miR-155). Other miRNAs conversely attenuate classical activation (blue-shaded contours) by repressing several positive regulators of proinflammatory signaling (e.g., miR-146a, miR187 and Let-7e). Note that miR-155 may also function as a negative regulator of proinflammatory signaling (not depicted; see main text). Signaling molecules implicated in classical versus alternative activation of macrophages, and related to miRNAs, are discussed in the main text.

Figure 3. miR-511-3p modulates TAM's phenotype

Alternatively activated TAMs express the macrophages mannose receptor, MRC1, and upregulate a number of genes that underlie their protumoral functions (yellow box on the bottom left). Together with the coding sequence for MRC1, the Mrc1 gene promoter transcribes the primary miR-511, which is processed by the miRNA machinery to generate the mature miR-511-3p sequence. miR-511-3p directly targets a number of genes, including Rock2, which promotes alternative activation of macrophages by phosphorylating the transcription factor IRF4. miR-511-3p also modulates the expression of several indirect targets, which influence biological processes in the TAMs (yellow box on the bottom right). As a result, miR-511-3p may attenuate the protumoral functions of alternatively activated TAMs [63].