• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

M2 巨噬细胞通过激活 gefitinib 耐药细胞系 HCC827/GR 中的 AKT/mTOR 来降低 gefitinib 的疗效。

M2 macrophages reduce the effect of gefitinib by activating AKT/mTOR in gefitinib-resistant cell lines HCC827/GR.

机构信息

Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China.

出版信息

Thorac Cancer. 2020 Nov;11(11):3289-3298. doi: 10.1111/1759-7714.13670. Epub 2020 Sep 21.

DOI:10.1111/1759-7714.13670
PMID:32956565
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7606002/
Abstract

BACKGROUND

The biological behavior of cells change after they develop drug resistance, and the degree of resistance will be affected by the tumor microenvironment. Here, we aimed to explore the changes in the biological behavior of tumors and to observe the differences in the release of cytokines and chemokines which can influence the tumor microenvironment. We also aimed to study how TKIs-resistant cell lines recruit macrophages to reduce the sensitivity of the cells following gefitinib administration.

METHODS

We generated and maintained gefitinib-resistant cell lines to study the differences between gefitinib-sensitive cell lines according to clone formation, cell growth curve analysis, whole-exome sequencing, and qPCR ARRAY technology. We used the WNT/β-catenin inhibitor, WNT/β-catenin activator and overexpression β-catenin lentivirus to observe the changes in CCL2. M2 macrophages and gefitinib-resistant cell lines HCC827/GR were cocultured to detect the viability gefitinib for inducing cell death.

RESULTS

The proliferation and migratory activities were much more pronounced in HCC827/GR cells. CCL2 expression was also enhanced and regulated by β-catenin in HCC827/GR. CCL2 promoted the chemotactic ability of M2 macrophages. M2 macrophages reduced the antitumor effect of gefitinib treatment by activating AKT/mTOR.

CONCLUSIONS

Gefitinib-resistant cell lines have stronger proliferation and migration capabilities, and attract macrophages by releasing more CCL2 to reduce the sensitivity of cells to gefitinib.

摘要

背景

细胞产生耐药性后其生物学行为会发生改变，耐药程度会受到肿瘤微环境的影响。本研究旨在探讨肿瘤生物学行为的变化，并观察影响肿瘤微环境的细胞因子和趋化因子释放的差异。还研究了 TKI 耐药细胞系如何招募巨噬细胞，以减少吉非替尼给药后细胞的敏感性。

方法

我们生成并维持了吉非替尼耐药细胞系，根据克隆形成、细胞生长曲线分析、全外显子测序和 qPCR ARRAY 技术，研究了吉非替尼敏感细胞系之间的差异。我们使用 WNT/β-catenin 抑制剂、WNT/β-catenin 激活剂和过表达β-catenin 慢病毒观察 CCL2、M2 巨噬细胞和吉非替尼耐药细胞系 HCC827/GR 的变化。共培养检测诱导细胞死亡的吉非替尼对 HCC827/GR 细胞的活力。

结果

HCC827/GR 细胞的增殖和迁移活性明显增强。CCL2 的表达也增强，并受 HCC827/GR 中的β-catenin 调节。CCL2 促进了 M2 巨噬细胞的趋化能力。M2 巨噬细胞通过激活 AKT/mTOR 降低了吉非替尼治疗的抗肿瘤作用。

结论

吉非替尼耐药细胞系具有更强的增殖和迁移能力，通过释放更多的 CCL2 吸引巨噬细胞，从而降低细胞对吉非替尼的敏感性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/b5b3038d2af3/TCA-11-3289-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/35ddc551f2c0/TCA-11-3289-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/e8e02154474d/TCA-11-3289-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/68d6bf7d2427/TCA-11-3289-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/8c01971c3754/TCA-11-3289-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/b5b3038d2af3/TCA-11-3289-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/35ddc551f2c0/TCA-11-3289-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/e8e02154474d/TCA-11-3289-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/68d6bf7d2427/TCA-11-3289-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/8c01971c3754/TCA-11-3289-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a43b/7606002/b5b3038d2af3/TCA-11-3289-g005.jpg

相似文献

1
M2 macrophages reduce the effect of gefitinib by activating AKT/mTOR in gefitinib-resistant cell lines HCC827/GR.M2 巨噬细胞通过激活 gefitinib 耐药细胞系 HCC827/GR 中的 AKT/mTOR 来降低 gefitinib 的疗效。
Thorac Cancer. 2020 Nov;11(11):3289-3298. doi: 10.1111/1759-7714.13670. Epub 2020 Sep 21.
2
MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines.微小RNA-214通过PTEN/AKT途径调节表皮生长因子受体（EGFR）突变细胞系对吉非替尼的获得性耐药。
Asian Pac J Cancer Prev. 2012;13(1):255-60. doi: 10.7314/apjcp.2012.13.1.255.
3
Tumor-associated Macrophages Mediate Gefitinib Resistance in Lung Cancer through HGF/c-met Signaling Pathway.肿瘤相关巨噬细胞通过 HGF/c-met 信号通路介导肺癌对吉非替尼的耐药性。
Anticancer Agents Med Chem. 2024;24(1):30-38. doi: 10.2174/0118715206261966231103043418.
4
Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer.靶向腺嘌呤核苷酸转位酶-2（ANT2）以克服非小细胞肺癌对表皮生长因子受体酪氨酸激酶抑制剂的耐药性
Mol Cancer Ther. 2016 Jun;15(6):1387-96. doi: 10.1158/1535-7163.MCT-15-0089. Epub 2016 Feb 16.
5
Linc01014 regulates gefitinib resistance in oesophagus cancer via EGFR-PI3K-AKT-mTOR signalling pathway.Linc01014 通过 EGFR-PI3K-AKT-mTOR 信号通路调节食管癌对吉非替尼的耐药性。
J Cell Mol Med. 2020 Jan;24(2):1670-1675. doi: 10.1111/jcmm.14860. Epub 2019 Nov 30.
6
Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT.Cx26与PI3K/Akt信号通路之间的相互正向调节通过非间隙连接依赖的上皮-间质转化诱导赋予非小细胞肺癌细胞获得性吉非替尼耐药性。
Cell Death Dis. 2015 Jul 23;6(7):e1829. doi: 10.1038/cddis.2015.197.
7
Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation.利用微阵列对吉非替尼耐药的人肺腺癌中微小RNA表达进行全基因组分析以鉴定miR-149-5p的调控作用
Tumour Biol. 2017 Mar;39(3):1010428317691659. doi: 10.1177/1010428317691659.
8
An effective drug sensitizing agent increases gefitinib treatment by down regulating PI3K/Akt/mTOR pathway and up regulating autophagy in non-small cell lung cancer.一种有效的药物增敏剂通过下调非小细胞肺癌中的 PI3K/Akt/mTOR 通路和上调自噬来增加吉非替尼的治疗效果。
Biomed Pharmacother. 2019 Oct;118:109169. doi: 10.1016/j.biopha.2019.109169. Epub 2019 Jul 13.
9
Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro.肝脏X受体激动剂GW3965通过在体外抑制核因子κB使吉非替尼耐药的人非小细胞肺癌细胞对吉非替尼治疗重新敏感。
Oncotarget. 2017 Feb 28;8(9):15802-15814. doi: 10.18632/oncotarget.15007.
10
Tumor-associated macrophages secrete CC-chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer.肿瘤相关巨噬细胞通过激活乳腺癌中的 PI3K/Akt/mTOR 分泌 CC 趋化因子配体 2 并诱导他莫昔芬耐药。
Cancer Sci. 2020 Jan;111(1):47-58. doi: 10.1111/cas.14230. Epub 2019 Dec 19.

引用本文的文献

1
Fasting-mimicking diet enhances EGFR-TKI efficacy in oral cancer through dual mechanisms: direct cancer cell sensitization and tumor-associated macrophage crosstalk.模拟禁食饮食通过双重机制增强口腔癌中表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的疗效：直接使癌细胞致敏和肿瘤相关巨噬细胞相互作用。
Front Pharmacol. 2025 Jul 30;16:1641024. doi: 10.3389/fphar.2025.1641024. eCollection 2025.
2
The role of tumor-associated macrophages in lung cancer.肿瘤相关巨噬细胞在肺癌中的作用。
Front Immunol. 2025 Feb 26;16:1556209. doi: 10.3389/fimmu.2025.1556209. eCollection 2025.
3
Single-Cell RNA Sequencing in Unraveling Acquired Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: New Perspectives.

本文引用的文献

1
BRD4 promotes tumor progression and NF-κB/CCL2-dependent tumor-associated macrophage recruitment in GIST.BRD4 促进 GIST 中的肿瘤进展和 NF-κB/CCL2 依赖性肿瘤相关巨噬细胞募集。
Cell Death Dis. 2019 Dec 9;10(12):935. doi: 10.1038/s41419-019-2170-4.
2
IL-33 stimulates human mast cell release of CCL5 and CCL2 via MAPK and NF-κB, inhibited by methoxyluteolin.IL-33 通过 MAPK 和 NF-κB 刺激人肥大细胞释放 CCL5 和 CCL2，被 methoxyluteolin 抑制。
Eur J Pharmacol. 2019 Dec 15;865:172760. doi: 10.1016/j.ejphar.2019.172760. Epub 2019 Oct 26.
3
Human telomerase reverse transcriptase recruits the β-catenin/TCF-4 complex to transactivate chemokine (C-C motif) ligand 2 expression in colorectal cancer.
单细胞RNA测序在揭示非小细胞肺癌对EGFR-TKIs的获得性耐药中的应用：新视角
Int J Mol Sci. 2025 Feb 11;26(4):1483. doi: 10.3390/ijms26041483.
4
Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review.AKT信号通路在调节肿瘤相关巨噬细胞极化及肿瘤微环境中的作用：综述
Medicine (Baltimore). 2025 Jan 31;104(5):e41379. doi: 10.1097/MD.0000000000041379.
5
Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.酪氨酸激酶抑制剂靶向治疗的耐药机制及克服策略。
MedComm (2020). 2024 Aug 24;5(9):e694. doi: 10.1002/mco2.694. eCollection 2024 Sep.
6
CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway.CCL2 通过 AKT-EMT 通路促进非小细胞肺癌对 EGFR-TKIs 的耐药性。
Acta Biochim Biophys Sin (Shanghai). 2024 Jul 3;56(10):1549-1560. doi: 10.3724/abbs.2024106.
7
Establishment of a novel microfluidic co-culture system for simultaneous analysis of multiple indicators of gefitinib sensitivity in colorectal cancer cells.建立一种新型的微流控共培养系统，用于同时分析结直肠癌细胞中吉非替尼敏感性的多个指标。
Mikrochim Acta. 2024 Apr 22;191(5):279. doi: 10.1007/s00604-024-06362-9.
8
Tumor-associated macrophages mediate resistance of EGFR-TKIs in non-small cell lung cancer: mechanisms and prospects.肿瘤相关巨噬细胞介导非小细胞肺癌中 EGFR-TKIs 的耐药性：机制与展望。
Front Immunol. 2023 Aug 15;14:1209947. doi: 10.3389/fimmu.2023.1209947. eCollection 2023.
9
Long non-coding RNAs in non-small cell lung cancer: implications for EGFR-TKI resistance.非小细胞肺癌中的长链非编码RNA：对表皮生长因子受体酪氨酸激酶抑制剂耐药性的影响
Front Genet. 2023 Jun 30;14:1222059. doi: 10.3389/fgene.2023.1222059. eCollection 2023.
10
Identification of Master Regulators Driving Disease Progression, Relapse, and Drug Resistance in Lung Adenocarcinoma.驱动肺腺癌疾病进展、复发和耐药的主调控因子的鉴定
Front Bioinform. 2022 Jan 28;2:813960. doi: 10.3389/fbinf.2022.813960. eCollection 2022.
人端粒酶逆转录酶招募β-连环蛋白/TCF-4 复合物反式激活结直肠癌中趋化因子（C-C 基序）配体 2 的表达。
Biomed Pharmacother. 2019 Apr;112:108700. doi: 10.1016/j.biopha.2019.108700. Epub 2019 Feb 26.
4
Estrogen receptor β upregulates CCL2 via NF-κB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis.雌激素受体β通过 NF-κB 信号通路在上皮间质细胞中上调 CCL2，并招募巨噬细胞促进子宫内膜异位症的发病机制。
Hum Reprod. 2019 Apr 1;34(4):646-658. doi: 10.1093/humrep/dez019.
5
EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: Implications for combination therapies.表皮生长因子受体（EGFR）靶向治疗改变了 EGFR 驱动型肺部肿瘤的肿瘤微环境：对联合治疗的启示。
Int J Cancer. 2019 Sep 1;145(5):1432-1444. doi: 10.1002/ijc.32191. Epub 2019 Feb 19.
6
CD146-mediated acquisition of stemness phenotype enhances tumour invasion and metastasis after EGFR-TKI resistance in lung cancer.CD146介导的干性表型获得增强了肺癌表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药后的肿瘤侵袭和转移。
Clin Respir J. 2019 Jan;13(1):23-33. doi: 10.1111/crj.12976.
7
High expression of CCL2 in tumor cells and abundant infiltration with CD14 positive macrophages predict early relapse in breast cancer.肿瘤细胞中 CCL2 的高表达和大量浸润的 CD14 阳性巨噬细胞预示着乳腺癌的早期复发。
Virchows Arch. 2019 Jan;474(1):3-12. doi: 10.1007/s00428-018-2461-7. Epub 2018 Oct 27.
8
S100A8/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-κB signaling pathway.S100A8/A9 通过激活 NF-κB 信号通路诱导小胶质细胞活化，并促进少突胶质前体细胞的凋亡。
Brain Res Bull. 2018 Oct;143:234-245. doi: 10.1016/j.brainresbull.2018.09.014. Epub 2018 Sep 25.
9
Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC.Notch3 依赖性 β-连环蛋白信号通路介导 EGFR 突变型 NSCLC 对 EGFR-TKI 药物的耐药性。
Nat Commun. 2018 Aug 10;9(1):3198. doi: 10.1038/s41467-018-05626-2.
10
Estrogen promotes progression of hormone-dependent breast cancer through CCL2-CCR2 axis by upregulation of Twist via PI3K/AKT/NF-κB signaling.雌激素通过 PI3K/AKT/NF-κB 信号通路上调 Twist，通过 CCL2-CCR2 轴促进激素依赖性乳腺癌的进展。
Sci Rep. 2018 Jun 22;8(1):9575. doi: 10.1038/s41598-018-27810-6.