Metabolic reprogramming of macrophages during infections and cancer

Wang, Shiyao; Liu, Ruichen; Yu, Qing; Lin, Dong; Bi, Yujing; Liu, Guangwei

doi:10.1016/j.canlet.2019.03.015

Cited by 155 publications

(102 citation statements)

References 103 publications

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“…For instance, the polarization to M1-like macrophages results with the predominant activation of STAT1 pathway. On the contrary, the activation of STAT3 and STAT6 pathways leads to the polarization to M2-like macrophages 6,50 .…”

Section: Discussionmentioning

confidence: 99%

M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

Oshi

Tokumaru

Asaoka

et al. 2020

Sci Rep

135

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Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined “M1” macrophage and “M1”/“M2” ratio by transcriptomic signatures using xCell. We investigated the association between high level of “M1” macrophage or “M1”/“M2” ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that “M1” high tumors were not associated with prolonged survival compared with “M1” low tumors, or with the response to neoadjuvant chemotherapy. “M1” high tumors were associated with clinically aggressive features and “M1” high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, “M1” high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in “M1”/“M2” ratio high tumors. In conclusion, transcriptomically defined “M1” or “M1”/“M2” high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.

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Section: Discussionmentioning

confidence: 99%

M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

Oshi

Tokumaru

Asaoka

et al. 2020

Sci Rep

135

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show abstract

“…The cross‐talk between the cancer cells and their environment involves numerous oncogenic transcription factors. These factors are aberrantly reactivated and trigger a series of cellular events such as genome instability, reprogrammed metabolism, infinite proliferation, angiogenesis, invasion and metastasis, immune cell infiltration, and enhanced inflammation, all of which have been widely recognized as the characteristics of cancer …”

Section: Introductionmentioning

confidence: 99%

Role of telomerase in the tumour microenvironment

Liu

Guo

Liu

et al. 2019

Clin Exp Pharma Physio

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The tumour mass is an organ-like structure consisting of cancer cells and their directly associated microenvironment. The tumour microenvironment (TME) is the local environment where malignant cells strive and survive, and is composed of cancers cells and their surroundings such as blood vessels, extracellular matrix (ECM), infiltrating immune cells, fibroblasts, and signalling molecules. 1,2 In addition, cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress influence the properties of the TME to benefit tumour cell growth. 3,4 The cross-talk between the cancer cells and their environment involves numerous oncogenic transcription factors. These factors are aberrantly reactivated and trigger a series of cellular events such as genome instability, reprogrammed metabolism, infinite proliferation, angiogenesis, invasion and metastasis, immune cell infiltration, and enhanced inflammation, all of which have been widely recognized as the characteristics of cancer. Telomeres consist of a non-coding DNA tandem repeat of sequence 5′-TTAGGG-3′, located at the ends of the linear eukaryotic chromosomes. 26,27 Due to "the end replication problem", the telomeres shorten with each round of DNA replication. Once their lengths shorten to a certain level, the cells may undergo replicative senescence. 26,28 Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and maintains the telomere length, providing the immortal cells with the molecular basis for unlimited proliferation potential. Human telomerase essentially AbstractTelomeres are specialized genomic structures that protect chromosomal ends to maintain genomic stability. Telomeric length is primarily regulated by the telomerase complex, essentially consisting of an RNA template (TERC), an enzymatic subunit (telomerase reverse transcriptase, TERT). In humans, telomerase activity is repressed during embryonic differentiation and is absent in most somatic cells. However, it is upregulated or reactivated in 80%-90% of the primary tumours in humans. The human TERT (hTERT) plays a pivotal role in cellular immortality and tumourigenesis.However, the molecular mechanisms of telomerase functioning in cancer have not been fully understood beyond the telomere maintenance. Several research groups, including ours, have demonstrated that hTERT possesses vital functions independent of its telomere maintenance, including angiogenesis, inflammation, cancer cell stemness, and epithelial-mesenchymal transformation (EMT). All these telomereindependent activities of hTERT may contribute to the regulation of the dynamics and homeostasis of the tumour microenvironment (TME), thereby promoting tumour growth and development. Cancer progression and metastasis largely depend upon the interactions between cancer cells and their microenvironment. In this review, the involvement of TERT in the tumour microenvironment and the underlying implications in cancer therapeutics have been summarized. K E Y W O R D Sangiogenesis, inflammation, telomerase, TERT, tumour micro...

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“…Thus, the mitochondria of pro-in ammatory microglia would become consumers, rather than ATP generators, further increasing the energetic demand of these cells [39]. We have not found any essential role in the ANT reversal activity, which has also been described as key in the ΔΨm maintenance process in similar paradigms [29].Signalling events mediated by extracellular signals can regulate the metabolic pathways in immune cells, such as macrophages or microglia [40]. Accordingly, diverse cellular functions have been associated to metabolic reprogramming, including those related to mitochondrial function in general.…”

Section: Discussionmentioning

confidence: 61%

Role of mitochondrial dynamics in microglial activation and metabolic switch

Montilla

Ruiz

Matute

et al. 2020

Preprint

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Background Microglia are the endogenous immune cells of the central nervous system (CNS) and act as sensors of injury in the brain, favouring its homeostasis. Their activation and polarization towards a pro-inflammatory phenotype are associated to injury and disease. These processes are linked to a metabolic reprogramming of the cells, characterized by high rates of glycolytic function and suppressed levels of oxidative phosphorylation. This metabolic switch can be reproduced in vitro by stimulation with lipopolysaccharide (LPS) plus Interferon-γ (IFNγ). In an attempt to understand the mechanisms regulating mitochondrial respiration abolishment, we examined potential alterations in mitochondrial features during the metabolic switch. In addition, we studied the possible implication of mitochondrial dynamics in the metabolic switch using the mitochondrial division inhibitor-1 (Mdivi-1), which blocks Drp1-dependent mitochondrial fission. Methods Cultured microglia was treated with LPS + IFNγ to reproduce the metabolic switch under pro-inflammatory stimuli in the absence or in the presence of Mdivi-1 to block mitochondrial fission. Mitochondrial membrane potential and mitochondrial calcium were measured with living cell imaging, and microglial polarization was assessed by immunofluorescence and qRT-PCR. The metabolic profile of the cells was measured using the Seahorse XFe96 Extracellular Flux Analyzer. Results Under conditions of mitochondrial respiration abolishment, microglia did not show any change in mitochondria morphology, nor in mitochondrial membrane potential, indicative of a limited impact in its viability. We provided evidence that reverse operation of F0F1-ATP synthase contributes to mitochondrial membrane potential. On the other hand. mitochondrial fission blockage significantly reduced the expression of pro-inflammatory markers in LPS + IFNγ-treated microglia, such as the inducible nitric oxide synthase (iNOS). However, this inhibition did not lead to a recovery of the oxidative phosphorylation ablation by LPS + IFNγ or to a microglia repolarization. Conclusions Altogether, these results suggest that Drp1-dependent mitochondrial fission, although potentially involved in microglial activation, does not play an essential role in metabolic reprogramming and repolarization of microglia.

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Metabolic reprogramming of macrophages during infections and cancer

Cited by 155 publications

References 103 publications

M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

Role of telomerase in the tumour microenvironment

Role of mitochondrial dynamics in microglial activation and metabolic switch

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