Abstract
Tumorigenesis is frequently accompanied by chronic inflammation, and the tumor microenvironment (TME) can be considered an ecosystem that consists of tumor cells, endotheliocytes, fibroblasts, immune cells and acellular components such as extracellular matrix. For tumor cells, their survival advantages are dependent on both genetic and epigenetic alterations, while other cells mainly present epigenetic modifications. Macrophages are the most plastic type of immune cells and undergo diverse epigenetic alterations in the TME. Some of these epigenetic modifications mitigate against cancer progression, and others accelerate this process. Due to the complex roles of macrophages in the TME, it is urgent to understand their epigenetic modifications associated with the TME. Here, we mainly summarize recent findings on TME-associated epigenetic alterations of tumor-associated macrophages (TAMs), including DNA methylation, posttranslational modifications of histone proteins, chromatin remodeling, and noncoding RNA-mediated epigenetic regulation. At the end of this review, we also discuss the translational potential of these epigenetic modifications for developing novel cancer therapies targeting TAMs.
Highlights
Reviewed by: Gurcan Gunaydin, Hacettepe University, Turkey Juan Ramon Tejedor, Nanomaterials and Nanotechnology Research Center (CSIC), Spain
Tumorigenesis is frequently accompanied by chronic inflammation, and the tumor microenvironment (TME) can be considered an ecosystem that consists of tumor cells, endotheliocytes, fibroblasts, immune cells and acellular components such as extracellular matrix
For the convenience of study, macrophages classically activated by proinflammatory signals such as interferons, granulocyte macrophage colony-stimulating factor (GM-CSF), and lipopolysaccharide (LPS) are defined as “M1 macrophages”, and macrophages alternatively activated by antiinflammatory factors such interleukin-4 (IL-4), interleukin-10 (IL10) and transforming growth factor-b (TGFb) are defined as “M2 macrophages”
Summary
Deoxyribonucleic acid (DNA) is the main substance controlling the inheritance of biological traits in every organism except prions and some viruses, but it is fascinating that embryonic cells harboring the same set of genes can produce all different types of cells with divergent phenotypes in a multicellular organism without alterations of DNA sequences. The methylation of DNA, the posttranslational modifications of histone proteins, chromatin remodeling, and the influences of noncoding RNAs on nucleosome structure all belong to the research field of epigenetics. These epigenetic modifications convert environmental signals into distinct portfolios of accessible genes, facilitating a limited number of transcription factors (TFs) to produce more divergent transcriptional profiles. The expression of PU., the master macrophage regulator, initiates epigenetic lineage determination during which PU. preferentially binds to tissue-specific TFs to produce tissuespecific macrophages [41] These TFs includes Sall, RUNX, GATA6, PPAR-г, and Spi-C for microglia, intestinal macrophages, peritoneal macrophages, alveolar macrophages and splenic macrophages, respectively [42]. We would mainly discuss experimental studies as well as the potential applications regarding the epigenetic modifications associated with TAMs, which might inspire more basic and translational researches to investigate the epigenetic modifications of macrophages in malignant transformation and cancer management
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