IL-6及其受体在乳腺癌治疗中的作用研究进展

doi:10.11904/j.issn.1002-3070.2023.02.010

摘要/Abstract

摘要： 白细胞介素-6(IL-6)是存在于肿瘤微环境中的一种多效的促炎细胞因子,通过自身及其受体IL-6R和糖蛋白130(IL-6/IL-6R/gp130)组成的六聚体复合物激活JAK/STAT3、PI3K-Akt等多种信号通路,从而导致肿瘤的发生发展。因此,IL-6可作为治疗恶性肿瘤的重要靶点。目前,在临床上有很多治疗乳腺癌的手段,但总体治疗效果仍不理想,归其原因主要是癌细胞对传统抗癌疗法的耐药性。肿瘤微环境中的炎症因子能够促进肿瘤生长,并诱导对放化疗的抵抗。所以,深入研究IL-6介导的细胞效应及其信号通路可为今后IL-6用于乳腺癌的治疗研究中提供思路,故本文基于IL-6及其受体结合其他有效的抗癌疗法的最新研究,对抑制IL-6及其信号通路在乳腺癌治疗中的作用展开综述,以期为乳腺癌的治疗提供有效的治疗方法。

关键词: 白细胞介素-6, 肿瘤微环境, 信号通路, 乳腺癌

Abstract: Interleukin-6(IL-6)is a pleiotropic potent proinflammatory cytokine presenting in the tumor microenvironment.The hexamer complex and its receptor IL-6R and glycoprotein 130(IL-6/IL-6R/gp130)activate JAK/STAT3,PI3K-Akt and other signal pathways,leading to the occurrence and development of tumors.Therefore,IL-6 can be used as an important target for the treatment of malignant tumors.At present,there are many methods for treating breast cancer clinically,but the overall treatment effect is still unsatisfactory,which is mainly due to the drug resistance of cancer cells to traditional anti-cancer therapies.Inflammatory factors in tumor microenvironment can promote tumor growth and induce resistance to chemoradiotherapy.Therefore,an in-depth study of IL-6 mediated cell effects and its signal pathways can provide ideas for the future research on the treatment of IL-6 in breast cancer.The latest research reviews the role of inhibiting IL-6 and its signal pathways in the treatment of breast cancer,in order to provide effective therapeutic methods for the treatment of breast cancer.

Key words: Interleukin-6, Tumor microenvironment, Signal pathway, Breast cancer

中图分类号:

R737.9

刘欣欣, 马西元, 缪美琪, 王语晴, 陈晶. IL-6及其受体在乳腺癌治疗中的作用研究进展[J]. 实用肿瘤学杂志, 2023, 37(2): 149-154.

LIU Xinxin, MA Xiyuan, MIU Meiqi, WANG Yuqing, CHEN Jing. Research progress on the role of IL-6 and its receptor in the treatment of breast cancer[J]. Journal of Practical Oncology, 2023, 37(2): 149-154.

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链接本文: http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/10.11904/j.issn.1002-3070.2023.02.010

http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/Y2023/V37/I2/149

参考文献

1 Sung H,Ferlay J,Siegel RL,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries[J].CA Cancer J Clin,2021,71(3):209-249.
2 Denk D,Greten FR.Inflammation:the incubator of the tumor microenvironment[J].Trends Cancer,2022,8(11):901-914.
3 Covarrubias AJ,Horng T.IL-6 strikes a balance in metabolic inflammation[J].Cell Metab,2014,19(6):898-899.
4 Gyamfi J,Lee YH,Eom M,et al.Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells[J].Sci Rep,2018,8(1):8859.
5 Zilberstein A,Ruggieri R,Korn JH,et al.Structure and expression of cDNA and genes for human interferon-beta-2,a distinct species inducible by growth-stimulatory cytokines[J].EMBO J,1986,5(10):2529–2537.
6 Ataie-Kachoie P,Pourgholami MH,Morris DL.Inhibition of the IL-6 signaling pathway:a strategy to combat chronic inflammatory diseases and cancer[J].Cytokine Growth Factor Rev,2013,24(2):163-173.
7 Su JL,Lai KP,Chen CA,et al.A novel peptide specifically binding to interleukin-6 receptor(gp80)inhibits angiogenesis and tumor growth[J].Cancer Res,2019,79(14):3791.
8 Rose-John S.Local and systemic effects of interleukin-6(IL-6)in inflammation and cancer[J].FEBS Lett,2022,596(5):557-566.
9 Xu YD,Cheng M,Shang PP,et al.Role of IL-6 in dendritic cell functions[J].Leukoc Biol,2022,111(3):695-709.
10 O′Brien BJ,Singer HA,Adam AP,et al.CaMKIIδ is upregulated by pro-inflammatory cytokine IL-6 in a JAK/STAT3-dependent manner to promote angiogenesis[J].FASEB J,2021,35(4):e21437.
11 Liu L,Lu H,Loor JJ,et al.Sirtuin 3 inhibits nuclear factor-κB signaling activated by a fatty acid challenge in bovine mammary epithelial cells[J].J Dairy Sci,2021,104(12):12871-12880.
12 Baran P,Hansen S,Waetzig GH,et al.The balance of interleukin(IL)-6,IL-6·soluble IL-6 receptor(sIL-6R),and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling[J].Biol Chem,2018,293(18):6762-6775.
13 Kang S,Tanaka T,Narazaki M,et al.Targeting interleukin-6 signaling in clinic[J].Immunity,2019,50(4):1007-1023.
14 Guo YJ,Pan WW,Liu SB,et al.ERK/MAPK signalling pathway and tumorigenesis[J].Exp Ther Med,2020,19(3):1997-2007.
15 Heppler LN,Frank DA.Targeting oncogenic transcription factors:therapeutic implications of endogenous STAT inhibitors[J].Trends Cancer,2017,3(12):816-827.
16 Lassoued W,Murphy D,Tsai J,et al.Effect of VEGF and VEGF trap on vascular endothelial cell signaling in tumors[J].Cancer Biol Ther,2010,10(12):1326-1333.
17 Xie Y,Wang L,Sun H,et al.A polysaccharide extracted from alfalfa activates splenic B cells by TLR4 and acts primarily via the MAPK/p38 pathway[J].Food Funct,2020,11(10):9035-9047.
18 Thapa N,Choi S,Tan X,et al.Phosphatidylinositol Phosphate 5-Kinase Iγ and Phosphoinositide 3-Kinase/Akt signaling couple to promote oncogenic growth[J].J Biol Chem,2015,290(30):18843-18854.
19 Noori S,Hassan ZM.Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis[J].Free Radic Biol Med,2012,52(9):1987-1999.
20 Ge Y,Li F,He Y,et al.L-arginine stimulates the proliferation of mouse mammary epithelial cells and the development of mammary gland in pubertal mice by activating the GPRC6A/PI3K/AKT/mTOR signalling pathway[J].Anim Physiol Anim Nutr(Berl),2022,106(6):1383-1395.
21 Zhao L,Yang XR,Han X.MicroRNA-146b induces the PI3K/Akt/NF-κB signaling pathway to reduce vascular inflammation and apoptosis in myocardial infarction by targeting PTEN[J].Exp Ther Med,2019,17(2):1171-1181.
22 Razmkhah M,Abtahi S,Ghaderi A.Mesenchymal stem cells,immune cells and tumor cells crosstalk:a sinister triangle in the tumor microenvironment[J].Curr Stem Cell Res Ther,2019,14(1):43-51.
23 Al-Jomah N,Al-Mohanna FH,Aboussekhra A.Tocilizumab suppresses the pro-carcinogenic effects of breast cancer-associated fibroblasts through inhibition of the STAT3/AUF1 pathway[J].Carcinogenesis,2021,42(12):1439-1448.
24 Wolfe AR,Trenton NJ,Debeb BG,et al.Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models[J].Oncotarget,2016,7(50):82482-82492.
25 Rattigan Y,Hsu JM,Mishra PJ,et al.Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu[J].Exp Cell Res,2010,316(20):3417-3424.
26 Kim SY,Kang JW,Song X,et al.Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells[J].Cell Signal,2013,25(4):961-969.
27 Huang ZJ,You J,Luo WY,et al.Reduced tumorigenicity and drug resistance through the downregulation of octamer-binding protein 4 and nanog transcriptional factor expression in human breast stem cells[J].Mol Med Rep,2015,11(3):1647-1654.
28 Won HY,Lee JY,Shin DH,et al.Loss of mel-18 enhances breast cancer stem cell activity and tumorigenicity through activating notch signaling mediated by the Wnt/TCF pathway[J].FASEB J,2012,26(12):5002-5013.
29 Zhang C,Su L,Huang L,Song ZY.GSK3β inhibits epithelial-mesenchymal transition via the Wnt/β-catenin and PI3K/Akt pathways[J].Int J Ophthalmol,2018,11(7):1120-1128.
30 Jiang C,Zhang Q,Shanti RM,et al.Mesenchymal stromal cell-derived interleukin-6 promotes epithelial-mesenchymal transition and acquisition of epithelial stem-like cell properties in ameloblastoma epithelial cells[J].Stem Cells,2017,35(9):2083-2094.
31 Colín-Val Z,González-Puertos VY,Mendoza-Milla C,et al.DHEA increases epithelial markers and decreases mesenchymal proteins in breast cancer cells and reduces xenograft growth[J].Toxicol Appl Pharmacol,2017,333:26-34.
32 Ashrafizadeh M,Ang HL,Moghadam ER,et al.MicroRNAs and their influence on the ZEB family:mechanistic aspects and therapeutic applications in cancer therapy[J].Biomolecules,2020,10(7):1040.
33 Zhang J,Jia J,Zhao L,et al.Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell[J].Mol Carcinog,2016,55(5):732-742.
34 Weng YS,Tseng HY,Chen YA,et al.MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression,cancer stemness and M2 macrophage polarization in triple-negative breast cancer[J].Mol Cancer,2019,18(1):42.
35 Ishii G,Ishii T.Review of cancer-associated fibroblasts and their microenvironment in post-chemotherapy recurrence[J].Hum Cell,2020,33(4):938-945.
36 Bharti R,Dey G,Mandal M.Cancer development,chemoresistance,epithelial to mesenchymal transition and stem cells:A snapshot of IL-6 mediated involvement[J].Cancer Lett,2016,375(1):51-61.
37 Wang J,Lv X,Guo X,et al.Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells[J].Oncogenesis,2021,10(1):8.
38 Mao Y,Zhang Y,Qu Q,et al.Cancer-associated fibroblasts induce trastuzumab resistance in HER2 positive breast cancer cells[J].Mol Biosyst,2015,11(4):1029-1040.
39 Yin Y,Wang X,Li T,et al.MicroRNA-221 promotes breast cancer resistance to adriamycin via modulation of PTEN/Akt/mTOR signaling[J].Cancer Med,2020,9(4):1544-1552.
40 Dong X,Sun R,Wang J,et al.Glutathione S-transferases P1-mediated interleukin-6 in tumor-associated macrophages augments drug-resistance in MCF-7 breast cancer[J].Biochem Pharmacol,2020,182:114289.
41 Topalian SL,Weiner GJ,Pardoll DM.Cancer immunotherapy comes of age[J].Clin Oncol,2011,29(36):4828-4836.
42 Zamarron BF,Chen W.Dual roles of immune cells and their factors in cancer development and progression[J].Int J Biol Sci,2011,7(5):651-658.
43 Lee J,Lee SA,Gu NY,et al.Canine natural killer cell-derived exosomes exhibit antitumor activity in a mouse model of canine mammary tumor[J].Biomed Res Int,2021,2021:6690704.
44 Zhang HG,Zhuang X,Sun D,et al.Exosomes and immune surveillance of neoplastic lesions:a review[J].Biotech Histochem,2012,87(3):161-168.
45 Sabol RA,Villela VA,Denys A,et al.Obesity-altered adipose stem cells promote radiation resistance of estrogen receptor positive breast cancer through paracrine signaling[J].Int J Mol Sci,2020,21(8):2722.
46 Kitajima S,Yoshida A,Kohno S,et al.The RB-IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity[J].Oncogene,2017,36(36):5145-5157.

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