Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

IL-33/ST2 Signaling and its Correlation with Macrophage Heterogeneity and Clinicopathologic Features in Human Intrahepatic Cholangiocarcinoma

Author(s): Aimaiti Yasen, ZhanDong Yang, Jun Feng, RunBin Liang, TianXing Dai, Kai Li, YuHong Cai and GuoYing Wang*

Volume 24, Issue 11, 2024

Published on: 30 January, 2024

Page: [1144 - 1156] Pages: 13

DOI: 10.2174/0115680096276605240108112135

Price: $65

Abstract

Background: IL-33/ST2 signaling plays crucial roles in the development and progression of various human malignancies. However, its significance in intrahepatic cholangiocarcinoma (ICC) still remains unclear.

Objective: This study aimed to investigate the expression of IL-33/ST2 signaling and its correlations with macrophage heterogeneity and ICC patients' clinicopathologic features.

Methods: The expression of different phenotype macrophage markers and IL-33/ST2 signalingrelated markers was detected. The correlation between L-33/ST2 signaling and different phenotype macrophage markers as well as ICC patients' clinicopathologic data was evaluated.

Results: Massive heterogeneous cancer cells and PAS-positive cells were observed in tumor tissues. CD68-positive cells accumulated in tumor tissues and expression of both M1 phenotype markers and M2 phenotype macrophage markers was higher in tumor samples than para-carcinoma samples. However, M2 phenotype macrophages represented the dominant macrophage population in ICC tissues. Plasma levels of IL-33, ST2, and MIF were evidently enhanced in ICC patients compared to healthy controls. IL-33/ST2 signaling-related markers exhibited a massive increase in tumor samples than para-carcinoma samples. IL-33 and ST2 expression in ICC tissues was positively associated with M1 and M2 phenotype macrophages. Plasma levels of IL-33, ST2, and MIF were correlated with the diameter of tumor lesions, lymph node metastasis, TNM stage, and tumor differentiation degree. Multivariate analysis demonstrated IL-33 expression to exhibit a correlation with the diameter of tumor lesions, lymph node metastasis, and TNM stage. Additionally, there was a relationship observed between ST2, MIF expression, and diameter of tumor lesions plus TNM stage.

Conclusion: IL-33/ST2 signaling exhibited a positive relationship with macrophage heterogeneity in ICC tissues, and upregulated levels of IL-33, ST2, and MIF were associated with aggressive clinicopathologic characteristics. These findings may provide promising diagnostic biomarkers and potential therapeutic strategies for ICC patients targeting IL-33/ST2 signaling.

Keywords: Intrahepatic cholangiocarcinoma, IL-33/ST2 signaling, macrophages, heterogeneity, correlation, clinicopathologic features.

« Previous Next »
Graphical Abstract

[1]
Huang, Y.H.; Zhang, C.Z.; Huang, Q.S.; Yeong, J.; Wang, F.; Yang, X.; He, Y.F.; Zhang, X.L.; Zhang, H.; Chen, S.L.; Zheng, Y.L.; Deng, R.; Lin, C.S.; Yang, M.M.; Li, Y.; Jiang, C.; Kin-Wah Lee, T.; Ma, S.; Zeng, M.S.; Yun, J.P. Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma. J. Hepatol., 2021, 74(4), 838-849.
[http://dx.doi.org/10.1016/j.jhep.2020.10.037] [PMID: 33212090]
[2]
Liu, B.; Yan, S.; Jia, Y.; Ma, J.; Wu, S.; Xu, Y.; Shang, M.; Mao, A. TLR 2 promotes human intrahepatic cholangiocarcinoma cell migration and invasion by modulating NF ‐κB pathway‐mediated inflammatory responses. FEBS J., 2016, 283(20), 3839-3850.
[http://dx.doi.org/10.1111/febs.13894] [PMID: 27616304]
[3]
Laurent, S.; Verhelst, X.; Geerts, A.; Geboes, K.; De Man, M.; Troisi, R.; Vanlander, A.; Rogiers, X.; Berrevoet, F.; Van Vlierberghe, H. Update on liver transplantation for cholangiocarcinoma: A review of the recent literature. Acta Gastroenterol. Belg., 2019, 82(3), 417-420.
[PMID: 31566330]
[4]
Tu, J.; Wu, F.; Chen, L.; Zheng, L.; Yang, Y.; Ying, X.; Song, J.; Chen, C.; Hu, X.; Zhao, Z.; Ji, J. Long non-coding RNA PCAT6 induces M2 polarization of macrophages in cholangiocarcinoma via modulating miR-326 and RhoA-ROCK signaling pathway. Front. Oncol., 2021, 10, 605877.
[http://dx.doi.org/10.3389/fonc.2020.605877] [PMID: 33552977]
[5]
Sedighzadeh, S.S.; Khoshbin, A.P.; Razi, S.; Keshavarz-Fathi, M.; Rezaei, N. A narrative review of tumor-associated macrophages in lung cancer: Regulation of macrophage polarization and therapeutic implications. Transl. Lung Cancer Res., 2021, 10(4), 1889-1916.
[http://dx.doi.org/10.21037/tlcr-20-1241] [PMID: 34012800]
[6]
Chanmee, T.; Ontong, P.; Konno, K.; Itano, N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers, 2014, 6(3), 1670-1690.
[http://dx.doi.org/10.3390/cancers6031670] [PMID: 25125485]
[7]
Atri, C.; Guerfali, F.; Laouini, D. Role of human macrophage polarization in inflammation during infectious diseases. Int. J. Mol. Sci., 2018, 19(6), 1801.
[http://dx.doi.org/10.3390/ijms19061801] [PMID: 29921749]
[8]
Petty, A.J.; Yang, Y. Tumor-associated macrophages: Implications in cancer immunotherapy. Immunotherapy, 2017, 9(3), 289-302.
[http://dx.doi.org/10.2217/imt-2016-0135] [PMID: 28231720]
[9]
Xiang, X.; Wang, J.; Lu, D.; Xu, X. Targeting tumor-associated macrophages to synergize tumor immunotherapy. Signal Transduct. Target. Ther., 2021, 6(1), 75.
[http://dx.doi.org/10.1038/s41392-021-00484-9] [PMID: 33619259]
[10]
Guilliams, M.; Scott, C.L. Liver macrophages in health and disease. Immunity, 2022, 55(9), 1515-1529.
[http://dx.doi.org/10.1016/j.immuni.2022.08.002] [PMID: 36103850]
[11]
Wu, K.; Lin, K.; Li, X.; Yuan, X.; Xu, P.; Ni, P.; Xu, D. Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment. Front. Immunol., 2020, 11, 1731.
[http://dx.doi.org/10.3389/fimmu.2020.01731] [PMID: 32849616]
[12]
Marvie, P.; Lisbonne, M.; L’Helgoualc’h, A.; Rauch, M.; Turlin, B.; Preisser, L.; Bourd-Boittin, K.; Théret, N.; Gascan, H.; Piquet-Pellorce, C.; Samson, M. Interleukin‐33 overexpression is associated with liver fibrosis in mice and humans. J. Cell. Mol. Med., 2010, 14(6b), 1726-1739.
[http://dx.doi.org/10.1111/j.1582-4934.2009.00801.x] [PMID: 19508382]
[13]
Schmieder, A.; Multhoff, G.; Radons, J. Interleukin-33 acts as a pro-inflammatory cytokine and modulates its receptor gene expression in highly metastatic human pancreatic carcinoma cells. Cytokine, 2012, 60(2), 514-521.
[http://dx.doi.org/10.1016/j.cyto.2012.06.286] [PMID: 22819319]
[14]
Qi, L.; Zhang, Q.; Miao, Y.; Kang, W.; Tian, Z.; Xu, D.; Xiao, W.; Fang, F. Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development. Int. J. Cancer, 2020, 146(5), 1421-1434.
[http://dx.doi.org/10.1002/ijc.32779] [PMID: 31709531]
[15]
Gao, X.; Wang, X.; Yang, Q.; Zhao, X.; Wen, W.; Li, G.; Lu, J.; Qin, W.; Qi, Y.; Xie, F.; Jiang, J.; Wu, C.; Zhang, X.; Chen, X.; Turnquist, H.; Zhu, Y.; Lu, B. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J. Immunol., 2015, 194(1), 438-445.
[http://dx.doi.org/10.4049/jimmunol.1401344] [PMID: 25429071]
[16]
Yamada, D.; Rizvi, S.; Razumilava, N.; Bronk, S.F.; Davila, J.I.; Champion, M.D.; Borad, M.J.; Bezerra, J.A.; Chen, X.; Gores, G.J. IL‐33 facilitates oncogene‐induced cholangiocarcinoma in mice by an interleukin‐6‐sensitive mechanism. Hepatology, 2015, 61(5), 1627-1642.
[http://dx.doi.org/10.1002/hep.27687] [PMID: 25580681]
[17]
Amôr, N.G.; de Oliveira, C.E.; Gasparoto, T.H.; Vilas Boas, V.G.; Perri, G.; Kaneno, R.; Lara, V.S.; Garlet, G.P.; da Silva, J.S.; Martins, G.A.; Hogaboam, C.; Cavassani, K.A.; Campanelli, A.P. ST2/IL-33 signaling promotes malignant development of experimental squamous cell carcinoma by decreasing NK cells cytotoxicity and modulating the intratumoral cell infiltrate. Oncotarget, 2018, 9(56), 30894-30904.
[http://dx.doi.org/10.18632/oncotarget.25768] [PMID: 30112116]
[18]
Xu, H.; Sun, L.; He, Y.; Yuan, X.; Niu, J.; Su, J.; Li, D. Deficiency in IL-33/ST2 axis reshapes mitochondrial metabolism in lipopolysac-charide-stimulated macrophages. Front. Immunol., 2019, 10, 127.
[http://dx.doi.org/10.3389/fimmu.2019.00127] [PMID: 30774633]
[19]
Xu, H.; Li, D.; Ma, J.; Zhao, Y.; Xu, L.; Tian, R.; Liu, Y.; Sun, L.; Su, J. The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization. Cancer Biol. Med., 2021, 18(1), 172-183.
[http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0211] [PMID: 33628592]
[20]
World medical association declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 2013, 310(20), 2191-2194.
[http://dx.doi.org/10.1001/jama.2013.281053] [PMID: 24141714]
[21]
Yasen, A.; Feng, J.; Xie, X.M.; Li, K.; Cai, Y.H.; Liao, Z.H.; Liang, R.B.; Dai, T.X.; Wang, G.Y. Exosomes derived from TGF-β1-pretreated mesenchymal stem cells alleviate biliary ischemia–reperfusion injury through Jagged1/Notch1/SOX9 pathway. Int. Immunopharmacol., 2023, 119, 110253.
[http://dx.doi.org/10.1016/j.intimp.2023.110253] [PMID: 37156030]
[22]
Yasen, A.; Li, W.; Ran, B.; Aini, A.; Wang, Z.; Jiang, T.; Shao, Y.; Aji, T.; Wen, H. Identification of infiltrating immune cell subsets and heterogeneous macrophages in the lesion microenvironment of hepatic cystic echinococcosis patients with different cyst viability. Acta Trop., 2021, 221, 106029.
[http://dx.doi.org/10.1016/j.actatropica.2021.106029] [PMID: 34216561]
[23]
Funes, S.C.; Rios, M.; Escobar-Vera, J.; Kalergis, A.M. Implications of macrophage polarization in autoimmunity. Immunology, 2018, 154(2), 186-195.
[http://dx.doi.org/10.1111/imm.12910] [PMID: 29455468]
[24]
Fernandez, A.; Vermeren, M.; Humphries, D.; Subiros-Funosas, R.; Barth, N.; Campana, L.; MacKinnon, A.; Feng, Y.; Vendrell, M. Chemical modulation of in vivo macrophage function with subpopulation-specific fluorescent prodrug conjugates. ACS Cent. Sci., 2017, 3(9), 995-1005.
[http://dx.doi.org/10.1021/acscentsci.7b00262] [PMID: 28979941]
[25]
Zhou, Z.; Wang, P.; Sun, R.; Li, J.; Hu, Z.; Xin, H.; Luo, C.; Zhou, J.; Fan, J.; Zhou, S. Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3. J. Immunother. Cancer, 2021, 9(3), e001946.
[http://dx.doi.org/10.1136/jitc-2020-001946] [PMID: 33692217]
[26]
Luo, C.; Xin, H.; Zhou, Z.; Hu, Z.; Sun, R.; Yao, N.; Sun, Q.; Borjigin, U.; Wu, X.; Fan, J.; Huang, X.; Zhou, S.; Zhou, J. Tumor‐derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression. Hepatology, 2022, 76(4), 982-999.
[http://dx.doi.org/10.1002/hep.32387] [PMID: 35106794]
[27]
Mertz, K.D.; Mager, L.F.; Wasmer, M.H.; Thiesler, T.; Koelzer, V.H.; Ruzzante, G.; Joller, S.; Murdoch, J.R.; Brümmendorf, T.; Genitsch, V.; Lugli, A.; Cathomas, G.; Moch, H.; Weber, A.; Zlobec, I.; Junt, T.; Krebs, P. The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice. OncoImmunology, 2016, 5(1), e1062966.
[http://dx.doi.org/10.1080/2162402X.2015.1062966] [PMID: 26942077]
[28]
Huang, N.; Cui, X.; Li, W.; Zhang, C.; Liu, L.; Li, J. IL 33/ST2 promotes the malignant progression of gastric cancer via the MAPK pathway. Mol. Med. Rep., 2021, 23(5), 361.
[http://dx.doi.org/10.3892/mmr.2021.12000] [PMID: 33760194]
[29]
Larsen, K.; Minaya, M.; Vaish, V.; Peña, M. The role of IL-33/ST2 pathway in tumorigenesis. Int. J. Mol. Sci., 2018, 19(9), 2676.
[http://dx.doi.org/10.3390/ijms19092676] [PMID: 30205617]
[30]
Samuchiwal, S.K.; Balestrieri, B.; Raff, H.; Boyce, J.A. Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J. Biol. Chem., 2017, 292(20), 8195-8206.
[http://dx.doi.org/10.1074/jbc.M116.769422] [PMID: 28341741]
[31]
Labrador, A.J.P.; Marin, N.R.G.; Valdez, L.H.M.; Valentina, M.P.; Sanchez, K.B.T.; Ibazetta, K.A.R.; Johan, B.; Cesar, A.V.; Wright, J.M. Clear cell odontogenic carcinoma a systematic review. Head Neck Pathol., 2021, 16(3), 838-848.
[http://dx.doi.org/10.1007/s12105-021-01383-9] [PMID: 34618301]
[32]
Guillot, A.; Tacke, F. Liver macrophages: Old dogmas and new insights. Hepatol. Commun., 2019, 3(6), 730-743.
[http://dx.doi.org/10.1002/hep4.1356] [PMID: 31168508]
[33]
Locati, M.; Curtale, G.; Mantovani, A. Diversity, mechanisms, and significance of macrophage plasticity. Annu. Rev. Pathol., 2020, 15(1), 123-147.
[http://dx.doi.org/10.1146/annurev-pathmechdis-012418-012718] [PMID: 31530089]
[34]
Hasita, H.; Komohara, Y.; Okabe, H.; Masuda, T.; Ohnishi, K.; Lei, X.F.; Beppu, T.; Baba, H.; Takeya, M. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci., 2010, 101(8), 1913-1919.
[http://dx.doi.org/10.1111/j.1349-7006.2010.01614.x] [PMID: 20545696]
[35]
Nobre, C.C.G.; de Araújo, J.M.G.; Fernandes, T.A.A.M.; Cobucci, R.N.O.; Lanza, D.C.F.; Andrade, V.S.; Fernandes, J.V. Macrophage migration inhibitory factor (MIF): Biological activities and relation with cancer. Pathol. Oncol. Res., 2017, 23(2), 235-244.
[http://dx.doi.org/10.1007/s12253-016-0138-6] [PMID: 27771887]
[36]
Fang, M.; Li, Y.; Huang, K.; Qi, S.; Zhang, J.; Zgodzinski, W.; Majewski, M.; Wallner, G.; Gozdz, S.; Macek, P.; Kowalik, A.; Pasiarski, M.; Grywalska, E.; Vatan, L.; Nagarsheth, N.; Li, W.; Zhao, L.; Kryczek, I.; Wang, G.; Wang, Z.; Zou, W.; Wang, L. IL33 promotes colon cancer cell stemness via JNK activation and macrophage recruitment. Cancer Res., 2017, 77(10), 2735-2745.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1602] [PMID: 28249897]
[37]
Lu, B.; Yang, M.; Wang, Q. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy. J. Mol. Med., 2016, 94(5), 535-543.
[http://dx.doi.org/10.1007/s00109-016-1397-0] [PMID: 26922618]
[38]
Cui, G.; Ren, J.; Xu, G.; Li, Z.; Zheng, W.; Yuan, A. Cellular and clinicopathological features of the IL-33/ST2 axis in human esophageal squamous cell carcinomas. Cancer Cell Int., 2018, 18(1), 203.
[http://dx.doi.org/10.1186/s12935-018-0700-2] [PMID: 30559604]
[39]
Jin, Z.; Lei, L.; Lin, D.; Liu, Y.; Song, Y.; Gong, H.; Zhu, Y.; Mei, Y.; Hu, B.; Wu, Y.; Zhang, G.; Liu, H. IL-33 released in the liver inhibits tumor growth via promotion of CD4+ and CD8+ T cell responses in hepatocellular carcinoma. J. Immunol., 2018, 201(12), 3770-3779.
[http://dx.doi.org/10.4049/jimmunol.1800627] [PMID: 30446569]
[40]
Dominguez, D.; Ye, C.; Geng, Z.; Chen, S.; Fan, J.; Qin, L.; Long, A.; Wang, L.; Zhang, Z.; Zhang, Y.; Fang, D.; Kuzel, T.M.; Zhang, B. Exogenous IL-33 restores dendritic cell activation and maturation in established cancer. J. Immunol., 2017, 198(3), 1365-1375.
[http://dx.doi.org/10.4049/jimmunol.1501399] [PMID: 28011934]
[41]
Yang, Y.; Andersson, P.; Hosaka, K.; Zhang, Y.; Cao, R.; Iwamoto, H.; Yang, X.; Nakamura, M.; Wang, J.; Zhuang, R.; Morikawa, H.; Xue, Y.; Braun, H.; Beyaert, R.; Samani, N.; Nakae, S.; Hams, E.; Dissing, S.; Fallon, P.G.; Langer, R.; Cao, Y. The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages. Nat. Commun., 2016, 7(1), 11385.
[http://dx.doi.org/10.1038/ncomms11385] [PMID: 27150562]
[42]
Chan, B.C.L.; Lam, C.W.K.; Tam, L.S.; Wong, C.K. IL33: roles in allergic inflammation and therapeutic perspectives. Front. Immunol., 2019, 10, 364.
[http://dx.doi.org/10.3389/fimmu.2019.00364] [PMID: 30886621]
[43]
Funamizu, N.; Hu, C.; Lacy, C.; Schetter, A.; Zhang, G.; He, P.; Gaedcke, J.; Ghadimi, M.B.; Ried, T.; Yfantis, H.G.; Lee, D.H.; Subleski, J.; Chan, T.; Weiss, J.M.; Back, T.C.; Yanaga, K.; Hanna, N.; Alexander, H.R.; Maitra, A.; Hussain, S.P. Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. Int. J. Cancer, 2013, 132(4), 785-794.
[http://dx.doi.org/10.1002/ijc.27736] [PMID: 22821831]
[44]
Babu, S.N.; Chetal, G.; Kumar, S. Macrophage migration inhibitory factor: A potential marker for cancer diagnosis and therapy. Asian Pac. J. Cancer Prev., 2012, 13(5), 1737-1744.
[http://dx.doi.org/10.7314/APJCP.2012.13.5.1737] [PMID: 22901113]
[45]
Hu, L.A.; Fu, Y.; Zhang, D.N.; Zhang, J. Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. Asian Pac. J. Cancer Prev., 2013, 14(4), 2563-2566.
[http://dx.doi.org/10.7314/APJCP.2013.14.4.2563] [PMID: 23725175]

Rights & Permissions Print Cite
Article Metrics
15
1
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy