Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis

Qin, Guohui; Lian, Jingyao; Huang, Lan; Zhao, Qitai; Li, Shasha; Zhang, Zhen; Chen, Xinfeng; Yue, Dongli; Li, Lifeng; Li, Feng; Wang, Lidong; Umansky, Viktor; Zhang, Bin; Yang, Shengli; Zhang, Yi

doi:10.1080/2162402x.2018.1442167

Cited by 72 publications

(60 citation statements)

References 44 publications

(58 reference statements)

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“…219 Metformin inhibits mTOR activity by activating ATM (ataxia telangiectasia mutated) and LKB1 (liver kinase B1) and AMP-activated kinase (AMPK), thus preventing protein synthesis and cell growth, 219 as well as MDSC expansion. 220,221 Taken together, these findings provide a rationale for combining strategies reprogramming the metabolism of MDSCs with immunotherapeutic strategies in cancer treatment and prevention.…”

Section: Chemotherapy (Ct) and Mdscsmentioning

confidence: 92%

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

et al. 2020

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Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.

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Section: Chemotherapy (Ct) and Mdscsmentioning

confidence: 92%

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

et al. 2020

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“…Moreover, knockdown of DACH1 expression blocked the effect of metformin on myeloid-derived suppressor cells’ (MDSCs) chemotaxis ( Table 1 ). 57 However, it is hard to separate direct antitumor effect of DACH1 on tumor cell to indirect tumor inhibition from immune modification by this in vivo xenograft model.…”

Section: Cytokine Signaling Regulated By Rdgnmentioning

confidence: 99%

The regulation of cytokine signaling by retinal determination gene network pathway in cancer

Zheng¹,

Liu²,

Yi³

et al. 2018

OTT

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Tumor environment plays a pivotal role in determining cancer biology characteristics. Cytokine factors, as a critical component in tumor milieu, execute distinct functions in the process of tumorigenesis and progression via the autocrine or paracrine manner. The retinal determination gene network (RDGN), which mainly comprised DACH, SIX, and EYA family members, is required for the organ development in mammalian species. While the aberrant expression of RDGN is involved in the proliferation, apoptosis, angiogenesis, and metastasis of tumors via interacting with different cytokine-related signals, such as CXCL8, IL-6, TGF-β, FGF, and VEGF, in a cell- or tissue-dependent manner. Thus, joint detection of this pathway might be used as a potential biomarker for the stratification of target therapy and for the precision prediction of the prognosis of cancer patients.

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“…Metformin inhibits NF-κB expression by increasing AMPK phosphorylation and inducing Dachshund homologue 1 (DACH1) mRNA expression, thereby reducing MDSCs migration and inhibiting CXCL1 secretion in esophageal carcinoma cells and tumor xenografts. Therefore, metformin may play an anti-tumor role by reducing the accumulation of MDSCs in the TME through AMPK/DACH1/CXCL1 axis [ 44 ].…”

Section: Metabolism Of Mdscsmentioning

confidence: 99%

Connections between Metabolism and Epigenetic Modification in MDSCs

Dai

Wang

et al. 2020

IJMS

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Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells in the tumor microenvironment (TME). During the differentiation and development of MDSCs from myeloid progenitor cells, their functions are also affected by a series of regulatory factors in the TME, such as metabolic reprogramming, epigenetic modification, and cell signaling pathways. Additionally, there is a crosstalk between these regulatory factors. This review mainly introduces the metabolism (especially glucose metabolism) and significant epigenetic modification of MDSCs in the TME, and briefly introduces the connections between metabolism and epigenetic modification in MDSCs, in order to determine the further impact on the immunosuppressive effect of MDSCs, so as to serve as a more effective target for tumor therapy.

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Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis

Cited by 72 publications

References 44 publications

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

Implications of metabolism-driven myeloid dysfunctions in cancer therapy

The regulation of cytokine signaling by retinal determination gene network pathway in cancer

Connections between Metabolism and Epigenetic Modification in MDSCs

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