Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages

de-Brito, Natália Mesquita; Duncan-Moretti, Julia; da-Costa, Hayandra C.; Saldanha-Gama, Roberta; Paula-Neto, Heitor A.; Dorighello, Gabriel G.; Simões, Rafael Loureiro; Barja‐Fidalgo, Christina

doi:10.1016/j.bbamcr.2019.118604

Cited by 60 publications

(45 citation statements)

References 31 publications

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“…In the TME, although TAMs have similar phenotypic characteristics to M2-type macrophages, there are differences in their selection of metabolic patterns. It has been demonstrated that TAMs are more inclined to select glycolysis as the main metabolic pattern [ 42 ] and inhibition of TAMs glycolysis can reverse the M2 phenotype [ 43 , 44 ]. However, the regulatory roles of Wnt signalling and glycolysis in TAMs have not been described.…”

Section: Discussionmentioning

confidence: 99%

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

Han

Zhao

et al. 2021

J Exp Clin Cancer Res

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Background Tumour-associated macrophages (TAMs) in the tumour microenvironment (TME) can promote the progression of hepatocellular carcinoma (HCC). Some tumours can be suppressed by targeting Wnt2b in tumour cells. However, the role of Wnt2b in HCC is still unknown. In particular, the role of Wnt2b-mediated signal activation in macrophage polarization in the HCC microenvironment, and the regulatory effect between Wnt and glycolysis in TAMs has not been described. Methods The expression of Wnt2b in TAMs was detected by qPCR and immunofluorescence. Wnt2b/β-catenin interference in HCC-TAMs was performed by lentivirus carrying targeted shRNA or TLR9 agonist. Markers related to macrophage polarization and the changes of key glycolytic enzymes expression were detected by flow cytometry and qPCR. ECAR was analysed by Seahorse analyser. MTT assay, wound healing assay, western blotting were used to evaluate the promoting effect of different HCC-TAMs on the proliferation, migration and EMT of HCC in vitro. Tumour cells and different HCC-TAMs were injected via subcutaneously into immunodeficient mice to assess the effects of CpG ODN, Wnt2b, or β-catenin on HCC-TAMs in tumour growth in vivo. Results Polarization-promoting factors derived from HCC cells upregulated the expression of Wnt2b in macrophages, which promoted the polarization of TAMs to M2-like macrophages by activating Wnt2b/β-catenin/c-Myc signalling. Furthermore, this process was associated with the activation of glycolysis in HCC-TAMs. These HCC-TAMs could promote the development of EMT, proliferation, and migration of HCC. In addition to silencing Wnt2b or β-catenin expression, TLR9 agonist CpG ODN downregulated the level of glycolysis and inhibited the M2 polarization of HCC-TAMs, reversing the tumour-promoting effects of TAMs in vitro and vivo. Conclusions As a potential target for HCC therapy, Wnt2b may play an important regulatory role for the functions of TAMs in the TME. Moreover, the TLR9 agonist CpG ODN might act as a Wnt2b signal inhibitor and can potentially be employed for HCC therapy by disturbing Wnt2b/β-catenin/c-Myc and inhibiting glycolysis in HCC-TAMs.

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Section: Discussionmentioning

confidence: 99%

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

Han

Zhao

et al. 2021

J Exp Clin Cancer Res

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“…TAMs polarization resulted in the increased GLUT1 and HK2 expression, increased glycolysis, and high amounts of lactate by Akt-mTOR-dependent pathway that was comparable with M1 macrophages. In parallel, TAMs were characterized by the supporting OXPHOS, presenting a high basal and maximal oxygen consumption rate (OCR), while showing low rates of FAO [247] (Table 4). This study showed that macrophages can produce lactate in response to soluble factors from condition medium of tumor cells, however the role of TAM-derived lactate in tumor progression remains to be identified.…”

Section: Role Of Lactate and Glycolysismentioning

confidence: 99%

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Larionova

Kazakova

Patysheva

et al. 2020

Cancers

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Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

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“…A recent report showed that human melanoma cell-educated TAMs are highly glycolytic, in turn, to maintain their M2-like polarization characterized by increased expression of the markers CD206, CD301, and CD163 [ 87 ]. Human PDAC cell-educated TAMs also exhibit a pronounced glycolytic signature, and 2-DG can disrupt the pro-metastatic phenotype of TAMs by reversing TAM-supported angiogenesis, extravasation, and epithelial-to-mesenchymal transition of tumor cells [ 88 ].…”

Section: Glucose Metabolismmentioning

confidence: 99%

Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Zhang

Chen

et al. 2021

Cells

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Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

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Aerobic glycolysis is a metabolic requirement to maintain the M2-like polarization of tumor-associated macrophages

Cited by 60 publications

References 31 publications

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

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