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Circadian regulation of cancer cell and tumor microenvironment crosstalk - PubMed

Review

Circadian regulation of cancer cell and tumor microenvironment crosstalk

Wenjing Xuan et al. Trends Cell Biol. 2021 Nov.

Abstract

Circadian rhythms regulate a remarkable variety of physiologic functions in living organisms. Circadian disruption is associated with tumorigenesis and tumor progression through effects on cancer cell biological properties, including proliferation, DNA repair, apoptosis, metabolism, and stemness. Emerging evidence indicates that circadian clocks also play an influential role in the tumor microenvironment (TME). This review outlines recent discoveries on how cancer cell clock components (including circadian clock and clock genes/proteins) regulate TME biology and, reciprocally, how TME clock components affect tumor growth, metastasis, and therapeutic response. An improved understanding of how clock components regulate the symbiosis between cancer cells and the TME will inform the development of novel clock-oriented therapeutic strategies, including immunotherapy.

Keywords: CLOCK; circadian rhythms; crosstalk; symbiosis; tumor microenvironment.

Copyright © 2021 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Declaration of interests The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Clock components in cancer cells affect TME biology.

Clock components, including circadian clock and clock genes/proteins (e.g., CLOCK, ARNTL/BMAL1, PER, CRY, RORs, and REV-ERBα) in cancer cells or cancer stem cells regulate the expression and secretion of soluble factors (e.g., HIF1α, ARNT, VEGF, OLFML3, and other unidentified factors). Consequently, these secreted factors modulate TME biology, including endothelial cell (EC) biology (e.g., promoting angiogenesis and anti-angiogenic therapy resistance), infiltration of myeloid cells [e.g., macrophages (MΦ), microglia, neutrophils, and dendritic cells (DC)], as well as infiltration and activation/suppression of lymphocytes (e.g., CD8+ T cells, CD4+ T cells, and B cells). The dash arrows indicate that clock components are correlated with the infiltration of immune cells. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; BMAL1, brain and muscle ARNT-like protein-1; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; HIF-1α, hypoxia-inducible factor 1-alpha; OLFML3, olfactomedin-like 3; PER, period; ROR, retinoic acid receptor—related orphan receptor; and VEGF, vascular endothelial growth factor.

Figure 2.
Figure 2.. Impact of TME clock components on tumor growth, metastasis and stemness.

CLOCK and BMAL1 in the TME can induce the secretion of WNT10A, which, in turn, upregulates ALDH3A1 in cancer stem cells (CSCs) to promote stemness, tumor growth, and metastasis. In addition, PER1 and PER2 in the TME can induce a pre-metastatic niche to promote metastasis, and induce chemotherapy resistance and immunosuppression thus promoting tumor growth. Abbreviations: ALDH3A1, aldehyde dehydrogenase 3 family, member A1; BMAL1, brain and muscle ARNT-like protein-1; CLOCK, circadian locomotor output cycles kaput; PER, period; TME, tumor microenvironment; and WNT10A, wnt family member 10 A.

Figure 3.
Figure 3.. Clock components in specific TME that affect tumor growth.

BMAL1 in macrophages (MΦ) inhibits the production of ROS and HIF1α and affects tumor growth through regulating macrophage alternative polarization and CD8+ T cell-mediated immune response. BMAL1 in B cells and neutrophils can change their migration ability via modulating the expression of pro-migratory molecules (e.g., CD11A and PSGL-1). RORγ and RORα in T cells can modulate their differentiation (e.g., CD4+ Th17 cells, CD8+ Tc cells, and Tregs) and activation via regulation of indicated factors and pathways, which, affects tumor growth and anti-tumor immune response. Endothelial cell (EC) clocks (e.g., CLOCK, BMAL1, REV-ERBα, and CRY1) can influence adhesion and migration of white blood cells (WBC, as called leukocytes), macrophages and monocytes (Mo) via regulating the expression of pro-migratory molecules (e.g., VCAM-1, ICAM-1, and E-selectin) and/or cytokines (e.g., CCL2 and TNFα), and activating ERK and P38 pathways, thus affecting tumor growth. The dash lines indicate that further studies are needed to validate this conclusion. Abbreviations: BMAL1, brain and muscle ARNT-like protein-1; CCL2, CC chemokine ligand 2; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIF-1α, hypoxia-inducible factor 1-alpha; ICAM-1, intercellular adhesion molecule-1; IL-17A, interleukin 17A; NF-κB, nuclear factor kappa B; PSGL-1, P-selectin glycoprotein ligand-1; ROR, retinoic acid receptor—related orphan receptor; ROS, reactive oxygen species; TME, tumor microenvironment; TNFα, tumor necrosis factor alpha; and VCAM1, vascular cell adhesion molecule 1.

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