Skip to content
2000
Volume 32, Issue 32
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Background

Reprogramming of glutamine metabolism in Gastric Cancer (GC) can significantly affect the tumor immune microenvironment and immunotherapy. This study examines the role of glutamine metabolism in the microenvironment and prognosis of gastric cancer.

Methods

We obtained gene expression data and clinical information of patients from the TCGA database. The patients were divided into two metabolic subtypes based on consistent clustering. A prognostic risk model containing three glutamine metabolism-related genes (GMRGs) was developed using Lasso-Cox. It was validated by the GEO validation cohort. Additionally, the immune microenvironment composition of the high- and low-risk groups was assessed using ESTIMATE, CIBERSORT, and ssGSEA. Drug sensitivity analysis was conducted using the “oncoPredict” R package.

Results

We outlined the distinct clinical characteristics of two subtypes and developed a prognostic risk model. The high-risk group has a poorer prognosis due to an increased expression of immune checkpoints and immunosuppressive cellular infiltration. Our analysis, which included Cox risk regression, ROC curves, and nomogram, demonstrated that this risk model is an independent prognostic factor. The TIDE score was higher in the high-risk group than in the low-risk group. Additionally, the high-risk group did not respond well to chemotherapeutic drug treatment.

Conclusion

This study shows that modelling glutamine metabolism is a good predictor of prognosis and immunotherapy efficacy in gastric cancer. Thus, we can better understand the role of glutamine metabolism in the development of cancer and use these insights to develop more targeted and effective treatments.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673297812240811182813
2024-08-20
2025-10-26

  • From This Site

    /content/journals/cmc/10.2174/0109298673297812240811182813
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ChauI. Checkpoint inhibition: An attraction in advanced gastric cancer?Lancet2017390101112418241910.1016/S0140‑6736(17)32131‑128993053
     [Google Scholar]
  2. FuchsC.S. ÖzgüroğluM. BangY.J. Di BartolomeoM. MandalaM. RyuM.H. FornaroL. OlesinskiT. CaglevicC. ChungH.C. MuroK. Van CutsemE. ElmeA. Thuss-PatienceP. ChauI. OhtsuA. BhagiaP. WangA. ShihC.S. ShitaraK. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial.Gastric Cancer202225119720610.1007/s10120‑021‑01227‑z34468869
     [Google Scholar]
  3. LiR. ZhuangC. JiangS. DuN. ZhaoW. TuL. CaoH. ZhangZ. ChenX. ITGBL1 predicts a poor prognosis and correlates EMT phenotype in gastric cancer.J. Cancer20178183764377310.7150/jca.2090029151964
     [Google Scholar]
  4. LeeP. ChandelN.S. SimonM.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond.Nat. Rev. Mol. Cell Biol.202021526828310.1038/s41580‑020‑0227‑y32144406
     [Google Scholar]
  5. LibertiM.V. LocasaleJ.W. The warburg effect: How does it benefit cancer cells?Trends Biochem. Sci.201641321121810.1016/j.tibs.2015.12.00126778478
     [Google Scholar]
  6. StegenS. LaperreK. EelenG. RinaldiG. FraislP. TorrekensS. Van LooverenR. LoopmansS. BultynckG. VinckierS. MeersmanF. MaxwellP.H. RaiJ. WeisM. EyreD.R. GhesquièreB. FendtS.M. CarmelietP. CarmelietG. HIF-1α metabolically controls collagen synthesis and modification in chondrocytes.Nature2019565774051151510.1038/s41586‑019‑0874‑330651640
     [Google Scholar]
  7. AshyA.A. ArdawiM.S.M. ArdawiM. Glucose, glutamine, and ketone-body metabolism in human enterocytes.Metabolism198837660260910.1016/0026‑0495(88)90179‑53374327
     [Google Scholar]
  8. ReinfeldB.I. MaddenM.Z. WolfM.M. ChytilA. BaderJ.E. PattersonA.R. SugiuraA. CohenA.S. AliA. DoB.T. MuirA. LewisC.A. HongoR.A. YoungK.L. BrownR.E. ToddV.M. HuffstaterT. AbrahamA. O’NeilR.T. WilsonM.H. XinF. TantawyM.N. MerrymanW.D. JohnsonR.W. WilliamsC.S. MasonE.F. MasonF.M. BeckermannK.E. Vander HeidenM.G. ManningH.C. RathmellJ.C. RathmellW.K. Cell-programmed nutrient partitioning in the tumour microenvironment.Nature2021593785828228810.1038/s41586‑021‑03442‑133828302
     [Google Scholar]
  9. CruzatV. Macedo RogeroM. Noel KeaneK. CuriR. NewsholmeP. Glutamine: Metabolism and immune function, supplementation and clinical translation.Nutrients20181011156410.3390/nu1011156430360490
     [Google Scholar]
  10. MaG. ZhangZ. LiP. ZhangZ. ZengM. LiangZ. LiD. WangL. ChenY. LiangY. NiuH. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.Cell Commun. Signal.202220111410.1186/s12964‑022‑00909‑035897036
     [Google Scholar]
  11. CaoS. HungY.W. WangY.C. ChungY. QiY. OuyangC. ZhongX. HuW. CoblentzA. MaghamiE. SunZ. LinH.H. AnnD.K. Glutamine is essential for overcoming the immunosuppressive microenvironment in malignant salivary gland tumors.Theranostics202212136038605610.7150/thno.7389635966597
     [Google Scholar]
  12. LiuP.S. WangH. LiX. ChaoT. TeavT. ChristenS. Di ConzaG. ChengW.C. ChouC.H. VavakovaM. MuretC. DebackereK. MazzoneM. HuangH.D. FendtS.M. IvanisevicJ. HoP.C. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming.Nat. Immunol.201718998599410.1038/ni.379628714978
     [Google Scholar]
  13. YangL. VennetiS. NagrathD. Glutaminolysis: A hallmark of cancer metabolism.Annu. Rev. Biomed. Eng.201719116319410.1146/annurev‑bioeng‑071516‑04454628301735
     [Google Scholar]
  14. CuriR. LagranhaC.J. DoiS.Q. SellittiD.F. ProcopioJ. Pithon-CuriT.C. CorlessM. NewsholmeP. Molecular mechanisms of glutamine action.J. Cell. Physiol.2005204239240110.1002/jcp.2033915795900
     [Google Scholar]
  15. CuriR. LagranhaC.J. DoiS.Q. SellittiD.F. ProcopioJ. Pithon-CuriT.C. Glutamine-dependent changes in gene expression and protein activity.Cell Biochem. Funct.2005232778410.1002/cbf.116515386529
     [Google Scholar]
  16. HiscockN PetersenEW KrzywkowskiK BozaJ Halkjaer-KristensenJ PedersenBK. Glutamine supplementation further enhances exercise-induced plasma IL-6.J. Appl. Physiol.2003951145148
     [Google Scholar]
  17. LiL. ChaoZ. WaikeongU. XiaoJ. GeY. WangY. XiongZ. MaS. WangZ. HuZ. ZengX. Metabolic classifications of renal cell carcinoma reveal intrinsic connections with clinical and immune characteristics.J. Transl. Med.202321114610.1186/s12967‑023‑03978‑y36829161
     [Google Scholar]
  18. HeJ. ChenZ. XueQ. SunP. WangY. ZhuC. ShiW. Identification of molecular subtypes and a novel prognostic model of diffuse large B-cell lymphoma based on a metabolism-associated gene signature.J. Transl. Med.202220118610.1186/s12967‑022‑03393‑935468826
     [Google Scholar]
  19. LiuL. MoM. ChenX. ChaoD. ZhangY. ChenX. WangY. ZhangN. HeN. YuanX. ChenH. YangJ. Targeting inhibition of prognosis-related lipid metabolism genes including CYP19A1 enhances immunotherapeutic response in colon cancer.J. Exp. Clin. Cancer Res.20234218510.1186/s13046‑023‑02647‑837055842
     [Google Scholar]
  20. JohnsonMO WolfMM MaddenMZ. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism.Cell201817571780179510.1016/j.cell.2018.10.001
     [Google Scholar]
  21. XiaoM. YangH. XuW. MaS. LinH. ZhuH. LiuL. LiuY. YangC. XuY. ZhaoS. YeD. XiongY. GuanK.L. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.Genes Dev.201226121326133810.1101/gad.191056.11222677546
     [Google Scholar]
  22. KlyszD. TaiX. RobertP.A. CraveiroM. CretenetG. OburogluL. MongellazC. FloessS. FritzV. MatiasM.I. YongC. SurhN. MarieJ.C. HuehnJ. ZimmermannV. KinetS. DardalhonV. TaylorN. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation.Sci. Signal.20158396ra9710.1126/scisignal.aab261026420908
     [Google Scholar]
  23. ByunJ.K. ParkM. LeeS. YunJ.W. LeeJ. KimJ.S. ChoS.J. JeonH.J. LeeI.K. ChoiY.K. ParkK.G. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity.Mol. Cell2020804592606.e810.1016/j.molcel.2020.10.01533159855
     [Google Scholar]
  24. CaseyS.C. TongL. LiY. DoR. WalzS. FitzgeraldK.N. GouwA.M. BaylotV. GütgemannI. EilersM. FelsherD.W. MYC regulates the antitumor immune response through CD47 and PD-L1.Science2016352628222723110.1126/science.aac993526966191
     [Google Scholar]
  25. WangL. XuT. YangX. LiangZ. ZhangJ. LiD. ChenY. MaG. WangY. LiangY. NiuH. Immunosuppression induced by glutamine deprivation occurs via activating PD-L1 transcription in bladder cancer.Front. Mol. Biosci.2021868730510.3389/fmolb.2021.68730534805266
     [Google Scholar]
  26. JacobsS.R. HermanC.E. MacIverN.J. WoffordJ.A. WiemanH.L. HammenJ.J. RathmellJ.C. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.J. Immunol.200818074476448610.4049/jimmunol.180.7.447618354169
     [Google Scholar]
  27. Klein GeltinkR.I. O’SullivanD. CorradoM. BremserA. BuckM.D. BuescherJ.M. FiratE. ZhuX. NiedermannG. CaputaG. KellyB. WarthorstU. Rensing-EhlA. KyleR.L. VandersarrenL. CurtisJ.D. PattersonA.E. LawlessS. GrzesK. QiuJ. SaninD.E. KretzO. HuberT.B. JanssensS. LambrechtB.N. RamboldA.S. PearceE.J. PearceE.L. Mitochondrial priming by CD28.Cell20171712385397.e1110.1016/j.cell.2017.08.01828919076
     [Google Scholar]
  28. ChoiB.K. LeeD.Y. LeeD.G. KimY.H. KimS.H. OhH.S. HanC. KwonB.S. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation.Cell. Mol. Immunol.201714974875710.1038/cmi.2016.0226972770
     [Google Scholar]
  29. SabharwalS.S. RosenD.B. GreinJ. TedescoD. Joyce-ShaikhB. UedaR. SemanaM. BauerM. BangK. StevensonC. CuaD.J. ZúñigaL.A. GITR agonism enhances cellular metabolism to support CD8+ T-cell proliferation and effector cytokine production in a mouse tumor model.Cancer Immunol. Res.20186101199121110.1158/2326‑6066.CIR‑17‑063230154083
     [Google Scholar]
  30. Di GiacintoC. MarinaroM. SanchezM. StroberW. BoirivantM. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells.J. Immunol.200517463237324610.4049/jimmunol.174.6.323715749854
     [Google Scholar]
  31. MurrayP.J. AllenJ.E. BiswasS.K. FisherE.A. GilroyD.W. GoerdtS. GordonS. HamiltonJ.A. IvashkivL.B. LawrenceT. LocatiM. MantovaniA. MartinezF.O. MegeJ.L. MosserD.M. NatoliG. SaeijJ.P. SchultzeJ.L. ShireyK.A. SicaA. SuttlesJ. UdalovaI. van GinderachterJ.A. VogelS.N. WynnT.A. Macrophage activation and polarization: Nomenclature and experimental guidelines.Immunity2014411142010.1016/j.immuni.2014.06.00825035950
     [Google Scholar]
  32. XueJ. SchmidtS.V. SanderJ. DraffehnA. KrebsW. QuesterI. De NardoD. GohelT.D. EmdeM. SchmidleithnerL. GanesanH. Nino-CastroA. MallmannM.R. LabzinL. TheisH. KrautM. BeyerM. LatzE. FreemanT.C. UlasT. SchultzeJ.L. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.Immunity201440227428810.1016/j.immuni.2014.01.00624530056
     [Google Scholar]
  33. NewsholmeP. Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?J. Nutr.20011319Suppl.2515S2522S10.1093/jn/131.9.2515S11533304
     [Google Scholar]
  34. KimS. HuW. KellyD.R. HellmichM.R. EversB.M. ChungD.H. Gastrin-releasing peptide is a growth factor for human neuroblastomas.Ann. Surg.2002235562163010.1097/00000658‑200205000‑0000311981207
     [Google Scholar]
  35. QiaoJ. KangJ. IsholaT.A. RychahouP.G. EversB.M. ChungD.H. Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma.Proc. Natl. Acad. Sci. USA200810535128911289610.1073/pnas.071186110518753628
     [Google Scholar]
  36. LeeK.H. KohS.A. KimJ.R. Hepatocyte growth factor- mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells.Oncol. Res.201220939340210.3727/096504013X1365768938277023924923
     [Google Scholar]
  37. HaywardC.P. BaintonD.F. SmithJ.W. HorsewoodP. SteadR.H. PodorT.J. WarkentinT.E. KeltonJ.G. Multimerin is found in the alpha-granules of resting platelets and is synthesized by a megakaryocytic cell line.J. Clin. Invest.19939162630263910.1172/JCI1165028514871
     [Google Scholar]
  38. SainiA. KumarV. TomarA.K. SharmaA. YadavS. Multimerin 1 aids in the progression of ovarian cancer possibly via modulation of DNA damage response and repair pathways.Mol. Cell. Biochem.2023478102395240310.1007/s11010‑023‑04668‑536723821
     [Google Scholar]
  39. KopchickJ.J. AndryJ.M. Growth hormone (GH), GH receptor, and signal transduction.Mol. Genet. Metab.2000711-229331410.1006/mgme.2000.306811001823
     [Google Scholar]
  40. SubramaniR. NandyS.B. PedrozaD.A. LakshmanaswamyR. Role of growth hormone in breast cancer.Endocrinology201715861543155510.1210/en.2016‑192828379395
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673297812240811182813
Loading
Prediction of Prognosis and Immunotherapy Response of Gastric Cancer Based on Glutamine Metabolism-related Genes
Curr. Med. Chem. 32, 7062 (2025); https://doi.org/10.2174/0109298673297812240811182813
/content/journals/cmc/10.2174/0109298673297812240811182813
/content/journals/cmc/10.2174/0109298673297812240811182813
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): Gastric cancer; glutamine metabolism; immunotherapy; prognostic model; targeted drug; tumor microenvironment

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test