Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL

Zhao, Zhiping; Zhang, Junfeng; Yin, Liangyu; Yang, Jiali; Zheng, Yao; Zhang, Mengjie; Ni, Bing; Wang, Huaizhi

doi:10.18632/aging.103830

Cited by 21 publications

(22 citation statements)

References 47 publications

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“… 32 , 33 However, these studies did not exclude direct mediation of a GDF15 effect by a pancreatic GFRAL, as has been reported in ductal pancreatic adenocarcinoma. 34 This indicates that GFRAL may not be restricted to the brain, although further investigations are warranted to confirm this point. In addition to the GFRAL receptor, GDF15 can also bind to Erb2 and CD44, 33 which may explain its peripheral effects.…”

Section: Genetic and Biochemical Characteristics Of Gdf15 ...mentioning

confidence: 93%

Overview of growth differentiation factor 15 in metabolic syndrome

Asrih

Wei

Nguyen

et al. 2023

J Cellular Molecular Medi

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Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor‐β (TGF‐β) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell‐derived neurotrophic factor family receptor alpha‐like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.

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Section: Genetic and Biochemical Characteristics Of Gdf15 ...mentioning

confidence: 93%

Overview of growth differentiation factor 15 in metabolic syndrome

Asrih

Wei

Nguyen

et al. 2023

J Cellular Molecular Medi

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“…Besides, some studies in other tumor types show that GDF15 achieves its tumor promotion effect through directly facilitates the growth of cancer cells. 48 49 However, according to our real-time cell impedance assay and orthotopic HCC model in Rag1 -/mice, we believe that GDF15 promotes carcinogenesis and the development of established tumors via immunosuppression, at least in HCC.…”

Section: Discussionmentioning

confidence: 88%

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma

Wang

et al. 2021

J Immunother Cancer

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BackgroundA better understanding of the molecular mechanisms that manifest in the immunosuppressive tumor microenvironment (TME) is crucial for developing more efficacious immunotherapies for hepatocellular carcinoma (HCC), which has a poor response to current immunotherapies. Regulatory T (Treg) cells are key mediators of HCC-associated immunosuppression. We investigated the selective mechanism exploited by HCC that lead to Treg cells expansion and to find more efficacious immunotherapies.MethodsWe used matched tumor tissues and blood samples from 150 patients with HCC to identify key factors of Treg cells expansion. We used mass cytometry (CyTOF) and orthotopic cancer mouse models to analyze overall immunological changes after growth differentiation factor 15 (GDF15) gene ablation in HCC. We used flow cytometry, coimmunoprecipitation, RNA sequencing, mass spectrum, chromatin immunoprecipitation and Gdf15–/–, OT-I and GFP transgenic mice to demonstrate the effects of GDF15 on Treg cells and related molecular mechanism. We used hybridoma technology to generate monoclonal antibody to block GDF15 and evaluate its effects on HCC-associated immunosuppression.ResultsGDF15 is positively associated with the elevation of Treg cell frequencies in patients wih HCC. Gene ablation of GDF15 in HCC can convert an immunosuppressive TME to an inflammatory state. GDF15 promotes the generation of peripherally derived inducible Treg (iTreg) cells and enhances the suppressive function of natural Treg (nTreg) cells by interacting with a previously unrecognized receptor CD48 on T cells and thus downregulates STUB1, an E3 ligase that mediates forkhead box P3 (FOXP3) protein degradation. GDF15 neutralizing antibody effectively eradicates HCC and augments the antitumor immunity in mouse.ConclusionsOur results reveal the generation and function enhancement of Treg cells induced by GDF15 is a new mechanism for HCC-related immunosuppression. CD48 is the first discovered receptor of GDF15 in the immune system which provide the possibility to solve the molecular mechanism of the immunomodulatory function of GDF15. The therapeutic GDF15 blockade achieves HCC clearance without obvious adverse events.

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“…HuCCT-1 cell proliferation was stimulated by 6.25–50 ng/ml MIC-1 but not by 100–200 ng/ml MIC-1. Previous studies have used several concentrations of MIC-1 in cell proliferation assays; one such report treated cells with 0–40 ng/ml MIC-1 and found that pancreatic cancer cell lines exposed to MIC-1 exhibited a greater increase in proliferation than control cells [ 23 ]. Another previous study used 200 ng/ml MIC-1 [ 32 ], and although MIC-1 was reported to contribute to the maintenance of breast cancer stem-like cells, a breast cancer cell line treated with this concentration of MIC-1 showed less proliferation than the control cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant human GDF15/MIC-1 (PeproTech, Cranbury, NJ, USA) was used in all cell culture experiments. In cell proliferation assays, MIC-1 was used at concentrations recommended by both the manufacturer and previous reports [ 32 , 33 ]. According to the manufacturer, MIC-1 was used at a concentration of 200 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, serum MIC-1 levels are markedly higher in patients with pancreatic cancer or BTC than in those with pancreaticobiliary inflammatory diseases or other cancers [15][16][17][18]. Although many reports on pancreatic cancer and MIC-1 have been published [19][20][21][22][23][24][25], few studies have investigated BTC and MIC-1. A previous study reported that biliary MIC-1 efficiently diagnosed early BTC [18].…”

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confidence: 99%

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Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis

Sugimoto

Suzuki

Nozawa³

et al. 2022

Cancer Cell Int

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Background Biliary tract cancer (BTC) has a poor prognosis; therefore, useful biomarkers and treatments are needed. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a member of the TGF-β superfamily, are elevated in patients with pancreaticobiliary cancers. However, the effect of MIC-1 on BTC is unknown. Therefore, we investigated the effect of MIC-1 on BTC and assessed whether MIC-1 is a biomarker of or therapeutic target for BTC. Methods MIC-1 expression in BTC cells was determined by performing histological immunostaining, tissue microarray (TMA), western blotting, and reverse transcription PCR (RT–PCR). Cell culture experiments were performed to investigate the effect of MIC-1 on BTC cell lines (HuCCT-1 and TFK-1). The relationships between serum MIC-1 levels and either the disease state or the serum level of the apoptosis marker M30 were retrospectively verified in 118 patients with pancreaticobiliary disease (individuals with benign disease served as a control group, n = 62; BTC, n = 56). The most efficient diagnostic marker for BTC was also investigated. Results MIC-1 expression was confirmed in BTC tissue specimens and was higher in BTC cells than in normal bile duct epithelial cells, as determined using TMA, western blotting and RT–PCR. In cell culture experiments, MIC-1 increased BTC cell proliferation and invasion by preventing apoptosis and inhibited the effect of gemcitabine. In serum analyses, serum MIC-1 levels showed a positive correlation with BTC progression and serum M30 levels. The ability to diagnose BTC at an early stage or at all stages was improved using the combination of MIC-1 and M30. The overall survival was significantly longer in BTC patients with serum MIC-1 < the median than in BTC patients with serum MIC-1 ≥ the median. Conclusions MIC-1 is a useful diagnostic and prognostic biomarker and might be a potential therapeutic target for BTC.

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Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL

Cited by 21 publications

References 47 publications

Overview of growth differentiation factor 15 in metabolic syndrome

Overview of growth differentiation factor 15 in metabolic syndrome

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma

Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis

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