Trends in Immunology
Volume 34, Issue 7, July 2013, Pages 350-359
Journal home page for Trends in Immunology

Review
MicroRNA-mediated control of macrophages and its implications for cancer

https://doi.org/10.1016/j.it.2013.02.003Get rights and content

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.

Highlights

► MicroRNAs (miRNAs) modulate macrophage activation. ► miRNAs modulate all stages of macrophage production and amplification. ► miRNAs control macrophage function in tumors. ► Altered miRNA expression in macrophages modulates tumor progression.

Section snippets

miRNAs in inflammation and cancer

miRNAs are noncoding RNAs that induce gene silencing by modulating gene expression at the post-transcriptional level. The miRNA processing machinery is expressed in most eukaryotic cells, ranging from plants to vertebrates, thereby indicating that miRNA regulation of gene expression is a highly conserved and widespread phenomenon. Indeed, miRNAs participate in virtually all biological processes, most notably cell proliferation, differentiation, and metabolism (Box 1). Furthermore, it is

miRNA-mediated regulation of macrophage production

TAMs are typically short-lived and unlikely to proliferate in tumor tissue 10, 12, therefore, they must be continuously replenished by newly produced precursors throughout cancer growth. Tumors frequently activate a macrophage progenitor response characterized by the sustained amplification of bone marrow (BM)-derived HSCs and myeloid progenitors, followed by the production of monocytes and the recruitment of these monocytes to tumors for local differentiation into macrophages [13]. Below, we

HSC maintenance

Microenvironmental niches in the BM harbor HSCs and regulate their maintenance and clonogenic activity. Several exogenous and endogenous cues guide the decision between HSC self-renewal or differentiation, and recent research has identified miRNAs as important endogenous regulators of HSC fate. Genetically ablating Dicer has revealed that the miRNA processing enzyme is necessary for maintaining long-term repopulation by HSCs in vivo [14]. A miRNA cluster containing miR-125a, miR-99b, and let-7e

HSC differentiation into monocytes

Several miRNAs appear to influence the commitment of HSCs and their progenitors. For instance, miR-146a, miR-155, miR-342, and miR-338 are upregulated by the transcription factor PU.1 16, 17, which controls myeloid cell development. Ectopic expression of miR-146a is sufficient to direct HSC differentiation to the mononuclear phagocyte lineage in mouse transplantation assays [16].

miR-21 and miR-196b have been shown to promote monocytopoiesis and to antagonize granulopoiesis, respectively [18].

Monocyte differentiation into macrophages

Monocytes consist of at least two functionally distinct subsets: mouse Ly-6Chi (human CD14hi) cells, which are inflammatory, and mouse Ly-6Clo (human CD14lo/CD16+) cells, which may facilitate the resolution of tissue inflammation [25]. At steady-state, Ly-6Clo monocytes constitutively express miR-146a, which may control their anti-inflammatory functions. Following inflammatory challenge, however, Ly-6Chi monocytes selectively induce miR-146a expression, and this process limits the magnitude of

miRNA-mediated control of macrophage activation

Macrophages residing in distinct tissue microenvironments can display divergent phenotypes and functions 7, 30, 31. Such heterogeneity is defined by the identity of the precursor from which the macrophage derives and by the ability of these cells to interact with, and respond to, factors to which they are exposed locally. When engaged, different macrophage receptors activate distinct intracellular molecular pathways and, consequently, activation states in macrophages. Mirroring T helper (Th)1

Exogenous miRNAs in cell-to-cell communication

miRNAs can act within the cells in which they are produced but may be also transferred to other cell types. Recent studies have suggested that macrophages and DCs produce miRNA-containing microvesicles (MVs) that can be conveyed to ‘acceptor’ cells upon fusing with their plasma membrane. For instance, DCs produce MV-shuttled miRNAs, which may downregulate the expression of target genes in acceptor DCs in vitro [67]. Other in vitro studies have suggested that alternatively activated macrophages

Significance of miRNA (de)regulation in macrophages for cancer

Our appreciation of the ability of miRNAs to control macrophage differentiation, activation, and function in cancer remains limited. This lack of information may reflect the current limited availability of genetic models that target individual miRNAs in (subsets of) TAMs. The majority of miRNAs that reportedly modulate macrophage activation in response to exogenous stimuli (e.g., miR-155 and miR-146) are indeed broadly expressed in multiple immune cell types, including T and B cells. Thus,

Concluding remarks

This review illustrates that miRNAs tightly regulate the macrophage response to microenvironmental cues and may modulate the pro- versus antitumoral functions of TAMs. It is also becoming clear that defined miRNAs regulate the biological properties of hematopoietic cells during the multiple stages of their development. However, it remains to be defined whether miRNAs operate differently as the cells progress along their maturation pathway. Several other considerations warrant investigation. For

Acknowledgments

We apologize to the authors whose work we could not cite because of the limit on the number of references. This work was supported in part by the European Research Council (ERC), the National Centres of Competence in Research (Oncology Program), Fonds National Suisse de la Recherche Scientifique (SNSF), and Anna Fuller fund (to M.D.P), and by US National Institutes of Health (NIH) grants R01-AI084880, P50-CA086355 and U54-CA126515 (to M.J.P.).

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    *

    Current address: Stem Cell Dynamics Research Unit, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

    These authors contributed equally.

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