Macrophage Polarization in the Development and Progression of Ovarian Cancers: An Overview

Abstract

Ovarian cancer is the most lethal gynecological malignancy worldwide. Most patients are diagnosed at late stages because of atypical symptoms and the lack of effective early diagnostic measures. The mechanisms underlying the oncogenesis and development of ovarian cancer are not clear. Macrophages, immune cells derived from the innate immune system, have two states of polarization (M1 and M2) that develop in response to different stimuli. The polarization and differentiation of macrophages into the cancer-inhibiting M1 and cancer-promoting M2 types represent the two states of macrophages in the tumor microenvironment. The interaction of polarized macrophages with cancer cells plays a crucial role in a variety of cancers. However, the effects of macrophage M1/M2 polarization on ovarian cancer have not yet been systematically and fully discussed. In this review, we discuss not only the occurrence, development and influences of macrophage polarization but also the association between macrophage polarization and ovarian cancer. The polarization of macrophages into the M1 and M2 phenotypes plays a pivotal role in ovarian cancer initiation, progression, and metastasis, and provides targets for macrophage-centered treatment in the cancer microenvironment for ovarian cancer therapy. We also addressed the regulation of macrophage polarization in ovarian cancer via noncoding RNAs, exosomes, and epigenetics.

Keywords: M1/M2; TAMs; epigenetic; exosomes; macrophage polarization; microenvironment; ovarian cancer.

Figure 1

Activated factors and functions of M1 macrophages. Microbial stimuli, such as LPS, and Th1-related cytokines, such as IFN-γ, polarize macrophages into the M1 phenotype. M1 macrophages function in proinflammatory, microbicidal and tumor resistance processes under high production of IL-6 IL-12, and IL-23, high production of toxic intermediates, including NO and ROI, and expression of MMP12. LPS, lipopolysaccharide; IFN, interferon; IL, interleukin; NO, nitric oxide; ROI, reactive oxygen intermediates; MMP12, matrix metalloproteinase 12.

Figure 2

Activated factors and functions of M2 macrophages. The M2a type is induced by IL-4 or IL-13 (promotes tissue repair through the secretion of ECM); the M2b type is induced by exposure to ICs and agonists of TLRs or IL-1R (participates in anti-inflammatory responses and functions in immunoregulation); the M2c type is induced by glucocorticoid hormones and IL-10 (suppresses immune responses and tissue remodeling). M2d (TAMs) macrophages induced by adenosine, LIF and IL-6 are believed to induce angiogenesis to regulate tumor progression and enhance tumor survival. IL, interleukin; ECM, Extracellular matrix; ICs, immune complexes; TLRs, Toll-like receptors; IL-1R, interleukin-1 receptor; TAM, tumor-associated macrophage; LIF, leukemia inhibitory factor.

Figure 3

Signaling pathways of macrophage polarization associated with the M1 and M2 phenotypes.