A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression
Tóm tắt
Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood. Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Flow Cytometers was applied to identify the source of cytokines. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites. The corresponding functions were verified in the complementation test and in vivo animal experiment. Our results revealed that hypoxia triggered macrophage secreted CXCL8, which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages and continued to increase the expression and secretion of CXCL8. It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient’s pessimistic outcome. Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.
Tài liệu tham khảo
Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
Yang L, Zheng R, Wang N, et al. Incidence and mortality of stomach cancer in China, 2014. Chin J Cancer Res. 2018;30(3):291–8. https://doi.org/10.21147/j.issn.1000-9604.2018.03.01 [published Online First: 2018/07/27].
Galletti G, Zhang C, Gjyrezi A, et al. Microtubule engagement with Taxane is altered in Taxane-resistant gastric Cancer. Clin Cancer Res. 2020;26(14):3771–83. https://doi.org/10.1158/1078-0432.Ccr-19-3018 [published Online First: 2020/04/24].
Zheng ZQ, Chen JT, Zheng MC, et al. Nestin +/CD31 + cells in the hypoxic perivascular niche regulate glioblastoma Chemoresistance by upregulating JAG1 and DLL4. Neuro-oncology. 2020. https://doi.org/10.1093/neuonc/noaa265 [published Online First: 2020/11/30].
Massara M, Bonavita O, Savino B, et al. ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity. Nat Commun. 2018;9(1):676. https://doi.org/10.1038/s41467-018-03080-8 [published Online First: 2018/02/16].
Lee KE, Spata M, Bayne LJ, et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. 2016;6(3):256–69. https://doi.org/10.1158/2159-8290.Cd-15-0822 [published Online First: 2015/12/31].
Zhang J, Wu Y, Lin YH, et al. Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer. World J Gastroenterol. 2018;24(22):2381–91. https://doi.org/10.3748/wjg.v24.i22.2381 [published Online First: 2018/06/16].
Piao H-y, Liu Y, Kang Y, et al. Hypoxia associated lncRNA HYPAL promotes proliferation of gastric cancer as ceRNA by sponging miR-431-5p to upregulate CDK14. Gastric Cancer. 2021;25:1–20.
Zhang J, Guo S, Wu Y, et al. P4HB, a novel hypoxia target gene related to gastric Cancer invasion and metastasis. Biomed Res Int. 2019;2019:9749751. https://doi.org/10.1155/2019/9749751 [published Online First: 2019/08/31].
Zhang J, Jin HY, Wu Y, et al. Hypoxia-induced LncRNA PCGEM1 promotes invasion and metastasis of gastric cancer through regulating SNAI1. Clin Transl Oncol. 2019;21(9):1142–51. https://doi.org/10.1007/s12094-019-02035-9 [published Online First: 2019/01/29].
Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541–66. https://doi.org/10.1146/annurev-physiol-022516-034339 [published Online First: 2016/11/05].
Okabe Y, Medzhitov R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014;157(4):832–44. https://doi.org/10.1016/j.cell.2014.04.016 [published Online First: 2014/05/06].
Hallowell RW, Collins SL, Craig JM, et al. mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis. Nat Commun. 2017;8:14208. https://doi.org/10.1038/ncomms14208 [published Online First: 2017/01/28].
Stein M, Keshav S, Harris N, et al. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med. 1992;176(1):287–92.
Mills CD, Kincaid K, Alt JM, et al. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164(12):6166–73.
Elinav E, Nowarski R, Thaiss CA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 2013;13(11):759–71. https://doi.org/10.1038/nrc3611 [published Online First: 2013/10/25].
Ramesh A, Brouillard A, Kumar S, et al. Dual inhibition of CSF1R and MAPK pathways using supramolecular nanoparticles enhances macrophage immunotherapy. Biomaterials. 2020;227:119559. https://doi.org/10.1016/j.biomaterials.2019.119559 [published Online First: 2019/11/02].
Lu SW, Pan HC, Hsu YH, et al. IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models. Nat Commun. 2020;11(1):4611. https://doi.org/10.1038/s41467-020-18244-8 [published Online First: 2020/09/16].
DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19(6):369–82. https://doi.org/10.1038/s41577-019-0127-6 [published Online First: 2019/02/06].
Cao Q, Yan X, Chen K, et al. Macrophages as a potential tumor-microenvironment target for noninvasive imaging of early response to anticancer therapy. Biomaterials. 2018;152:63–76. https://doi.org/10.1016/j.biomaterials.2017.10.036 [published Online First: 2017/11/08].
Yamaguchi T, Fushida S, Yamamoto Y, et al. Tumor-associated macrophages of the M2 phenotype contribute to progression in gastric cancer with peritoneal dissemination. Gastric Cancer. 2016;19(4):1052–65. https://doi.org/10.1007/s10120-015-0579-8 [published Online First: 2015/12/02].
Zhang Y, Meng W, Yue P, et al. M2 macrophage-derived extracellular vesicles promote gastric cancer progression via a microRNA-130b-3p/MLL3/GRHL2 signaling cascade. J Exp Clin Cancer Res. 2020;39(1):134. https://doi.org/10.1186/s13046-020-01626-7 [published Online First: 2020/07/15].
Wang X, Luo G, Zhang K, et al. Hypoxic tumor-derived Exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic Cancer metastasis. Cancer Res. 2018;78(16):4586–98. https://doi.org/10.1158/0008-5472.Can-17-3841 [published Online First: 2018/06/09].
Henze AT, Mazzone M. The impact of hypoxia on tumor-associated macrophages. J Clin Invest. 2016;126(10):3672–9. https://doi.org/10.1172/jci84427 [published Online First: 2016/08/03].
Okazaki S, Shintani S, Hirata Y, et al. Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells. Oncotarget. 2018;9(73):33832–43. https://doi.org/10.18632/oncotarget.26112 [published Online First: 2018/10/20].
Piao HY, Guo S, Wang Y, et al. Exosome-transmitted lncRNA PCGEM1 promotes invasive and metastasis in gastric cancer by maintaining the stability of SNAI1. Clin Transl Oncol. 2020. https://doi.org/10.1007/s12094-020-02412-9 [published Online First: 2020/06/11].
Piao H-y, Guo S, Jin H, et al. LINC00184 involved in the regulatory network of ANGPT2 via ceRNA mediated miR-145 inhibition in gastric cancer. J Cancer. 2021;12(8):2336.
Li HS, Watowich SS. Innate immune regulation by STAT-mediated transcriptional mechanisms. Immunol Rev. 2014;261(1):84–101. https://doi.org/10.1111/imr.12198 [published Online First: 2014/08/16].
Mellado M, Rodríguez-Frade JM, Mañes S, et al. Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Annu Rev Immunol. 2001;19:397–421. https://doi.org/10.1146/annurev.immunol.19.1.397 [published Online First: 2001/03/13].
Hu X, Li J, Fu M, et al. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. https://doi.org/10.1038/s41392-021-00791-1 [published Online First: 2021/11/27].
Lee JH, Lee GT, Woo SH, et al. BMP-6 in renal cell carcinoma promotes tumor proliferation through IL-10-dependent M2 polarization of tumor-associated macrophages. Cancer Res. 2013;73(12):3604–14. https://doi.org/10.1158/0008-5472.Can-12-4563 [published Online First: 2013/05/02].
Khalife J, Ghose J, Martella M, et al. MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages. JCI Insight. 2019;4(21). https://doi.org/10.1172/jci.insight.129348 [published Online First: 2019/10/09].
Zhang YM, Zheng T, Huang TT, et al. Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes. Phytomedicine. 2021;91:153686. https://doi.org/10.1016/j.phymed.2021.153686 [published Online First: 2021/08/02].
Peng J, Zhao K, Zhu J, et al. Sarsasapogenin suppresses RANKL-induced Osteoclastogenesis in vitro and prevents lipopolysaccharide-induced bone loss in vivo. Drug Des Devel Ther. 2020;14:3435–47. https://doi.org/10.2147/dddt.S256867 [published Online First: 2020/09/19].
Riera-Domingo C, Audigé A, Granja S, et al. Immunity, hypoxia, and metabolism-the Ménage à trois of Cancer: implications for immunotherapy. Physiol Rev. 2020;100(1):1–102. https://doi.org/10.1152/physrev.00018.2019 [published Online First: 2019/08/16].
Iriondo O, Liu Y, Lee G, et al. TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis. Nat Commun. 2018;9(1):1994. https://doi.org/10.1038/s41467-018-04460-w [published Online First: 2018/05/20].
Hamarsheh S, Osswald L, Saller BS, et al. Oncogenic Kras(G12D) causes myeloproliferation via NLRP3 inflammasome activation. Nat Commun. 2020;11(1):1659. https://doi.org/10.1038/s41467-020-15497-1 [published Online First: 2020/04/05].
Hakimi AA, Voss MH, Kuo F, et al. Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell Cancer: data from a randomized phase III trial. Cancer Discov. 2019;9(4):510–25. https://doi.org/10.1158/2159-8290.Cd-18-0957 [published Online First: 2019/01/10].
Peveri P, Walz A, Dewald B, et al. A novel neutrophil-activating factor produced by human mononuclear phagocytes. J Exp Med. 1988;167(5):1547–59. https://doi.org/10.1084/jem.167.5.1547 [published Online First: 1988/05/01].
Strieter RM, Kunkel SL, Showell HJ, et al. Monokine-induced gene expression of a human endothelial cell-derived neutrophil chemotactic factor. Biochem Biophys Res Commun. 1988;156(3):1340–5. https://doi.org/10.1016/s0006-291x(88)80779-4 [published Online First: 1988/11/15].
Wanninger J, Neumeier M, Weigert J, et al. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. Am J Physiol Gastrointest Liver Physiol. 2009;297(3):G611–8. https://doi.org/10.1152/ajpgi.90644.2008 [published Online First: 2009/07/18].
Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-Oncology. 2005;7(2):122–33. https://doi.org/10.1215/s1152851704001061 [published Online First: 2005/04/16].
Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential. Theranostics. 2013;3(1):26–33. https://doi.org/10.7150/thno.4922 [published Online First: 2013/02/06].
Podolin PL, Bolognese BJ, Foley JJ, et al. A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol. 2002;169(11):6435–44. https://doi.org/10.4049/jimmunol.169.11.6435 [published Online First: 2002/11/22].
Keane MP, Belperio JA, Xue YY, et al. Depletion of CXCR2 inhibits tumor growth and angiogenesis in a murine model of lung cancer. J Immunol. 2004;172(5):2853–60. https://doi.org/10.4049/jimmunol.172.5.2853 [published Online First: 2004/02/24].
Zhang M, Huang L, Ding G, et al. Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer. J Immunother Cancer. 2020;8(1). https://doi.org/10.1136/jitc-2019-000308 [published Online First: 2020/02/14].
Lin C, He H, Liu H, et al. Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut. 2019;68(10):1764–73. https://doi.org/10.1136/gutjnl-2018-316324 [published Online First: 2019/01/21].
Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. https://doi.org/10.1016/j.immuni.2014.06.008 [published Online First: 2014/07/19].
Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117(5):1155–66. https://doi.org/10.1172/jci31422 [published Online First: 2007/05/04].
Bu L, Baba H, Yoshida N, et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 2019;38(25):4887–901. https://doi.org/10.1038/s41388-019-0765-y [published Online First: 2019/03/01].
Casanova-Acebes M, Dalla E, Leader AM, et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. 2021;595(7868):578–84. https://doi.org/10.1038/s41586-021-03651-8 [published Online First: 2021/06/18].
Wang Q, Ni H, Lan L, et al. Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell Res. 2010;20(6):701–12. https://doi.org/10.1038/cr.2010.52 [published Online First: 2010/04/14].
Xu F, Wei Y, Tang Z, et al. Tumor-associated macrophages in lung cancer: friend or foe? (review). Mol Med Rep. 2020;22(5):4107–15. https://doi.org/10.3892/mmr.2020.11518 [published Online First: 2020/10/02].
Karakurum M, Shreeniwas R, Chen J, et al. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest. 1994;93(4):1564–70. https://doi.org/10.1172/jci117135 [published Online First: 1994/04/01].
Frey S, Derer A, Messbacher ME, et al. The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium. Ann Rheum Dis. 2013;72(9):1569–74. https://doi.org/10.1136/annrheumdis-2012-202264 [published Online First: 2012/12/27].