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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (01) : 36 -44. doi: 10.3877/cma.j.issn.2095-1221.2023.01.005

综述

肺癌干细胞对EGFR-TKI耐药影响的研究进展
甘开梅1, 黄剑1,†()   
  1. 1. 524000　湛江，广东省湛江市广东医科大学病理学系；524001　湛江，广东省湛江市广东医科大学附属医院病理诊断与研究中心
  • 收稿日期:2022-11-13 出版日期:2023-02-01
  • 通信作者: 黄剑
  • 基金资助:
    国家自然科学资金(81572610); 广东省"扬帆计划"引进紧缺拔尖人才(粤人才办（2016）6号)

Research progress in the effect of lung cancer stem cells on EGFR-TKI drug resistance

Kaimei Gan1, Jian Huang1,†()   

  1. 1. Department of Pathology, Guangdong Medical University, Zhanjiang 524000, China; the Center of Pathological Diagnosis and Research, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
  • Received:2022-11-13 Published:2023-02-01
  • Corresponding author: Jian Huang
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甘开梅, 黄剑. 肺癌干细胞对EGFR-TKI耐药影响的研究进展[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(01): 36-44.

Kaimei Gan, Jian Huang. Research progress in the effect of lung cancer stem cells on EGFR-TKI drug resistance[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(01): 36-44.

肺癌是导致全球癌症死亡最主要的原因之一，其中以非小细胞肺癌（NSCLC）占比最高。临床上，靶向治疗是肺癌常见的治疗方式，对于存在表皮生长因子受体（EGFR）突变的NSCLC患者，靶向药物EGFR-酪氨酸激酶抑制剂（EGFR-TKI）在治疗中取得较为理想的临床疗效，但仍有大部分患者在治疗后出现耐药现象。肺癌干细胞（LCSCs）指肺肿瘤内部具有无限增殖、自我更新及多向分化潜能的细胞亚群，对肿瘤的发生发展及靶向治疗耐药有显著影响。本文论述了LCSCs的特性及其相关标记物、信号转导通路及微环境与EGFR-TKI耐药的相关性，以期为肺癌EGFR-TKI耐药的患者提供新的治疗策略。

关键词: 肺癌, 肿瘤干细胞, 表皮生长因子受体-酪氨酸激酶抑制剂, 耐药

Lung cancer is a significant contributor to cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent form. Targeted therapy is commonly used in the clinical treatment of lung cancer, particularly in patients with NSCLC and epidermal growth factor receptor (EGFR) mutations. Although EGFR tyrosine kinase inhibitors (TKIs) have shown promising clinical results, most patients develop drug resistance after treatment. Lung cancer stem cells (LCSCs) are a subset of cells within lung tumors that possess unlimited proliferation, self-renewal, and multi-directional differentiation potential. They play a significant role in tumor development and targeted drug resistance. This article examines the characteristics of LCSCs, the correlation of LCSCs related markers, signal transduction pathways and the microenvironment with EGFR-TKI resistance.

Key words: Lung cancer, Cancer stem cells, Epidermal growth factor receptor-tyrosine kinase inhibitor, Drug resistance
图1 肿瘤干细胞特性及其标记物与EGFR-TKI耐药的关系注：a图为肺癌干细胞特性；b图为肺癌干细胞标记物与EGFR-TKI耐药敏感性的关系；EGFR-TKI为表皮生长因子受体-酪氨酸激酶抑制剂；ABCG2为ATP结合盒超家族G成员2；ALDH为乙醛脱氢酶；Non-LCSC为非肺癌干细胞；LCSC为肺癌干细胞；ALDH-high为ALDH高表达
图2 肺癌干细胞相关通路与EGFR-TKI耐药的关系注：EGFR-TKI为表皮生长因子受体-酪氨酸激酶抑制剂；NICD为细胞内结构域；EMT为上皮间质转化
图3 肿瘤干细胞微环境、EGFR-TKI敏感与耐药的肿瘤微环境特点注：a图为肿瘤干细胞微环境的特点；b图为EGFR-TKI敏感与EGFT-TKI耐药的肿瘤微环境差异；TGF-β为转化生长因子β；HIF1-α为缺氧诱导因子1；EGFR-TKI为表皮生长因子受体-酪氨酸激酶抑制剂
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
Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances[J]. Transl Lung Cancer Res, 2016, 5(3):288-300.
3
Gao J, Li HR, Jin C, et al. Strategies to overcome acquired resistance to EGFR TKI in the treatment of non-small cell lung cancer[J]. Clin Transl Oncol, 2019, 21(10):1287-1301.
4
Aramini B, Masciale V, Grisendi G, et al. Dissecting tumor growth: the role of cancer stem cells in drug resistance and recurrence[J]. Cancers (Basel), 2022, 14(4):976. doi:10.3390/cancers14040976.
5
Shien K, Toyooka S, Yamamoto H, et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells[J]. Cancer Res, 2013, 73(10):3051-3061.
6
Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells[J]. Nature, 2009, 458(7239):780-783.
7
Conde I, Ribeiro AS, Paredes J. Breast cancer stem cell membrane biomarkers: therapy targeting and clinical implications[J]. Cells, 2022, 11(6):934. doi: 10.3390/cells11060934.
8
Dianat-Moghadam H, Mahari A, Salahlou R, et al. Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy[J]. Stem Cell Res Ther, 2022, 13(1):150. doi: 10.1186/s13287-022-02829-9.
9
Clarke MF. Clinical and therapeutic implications of cancer stem cells. Reply[J]. N Engl J Med, 2019, 381(10):e19. doi: 10.1056/NEJMc1908886.
10
Dobson HE, Ruan S, Chang AE, et al. Targeting cancer stem cells via integrin beta4[J]. Oncotarget, 2021, 12(18):1850-1858.
11
Tsochantaridis I, Voulgaridou GP, Giatromanolaki A, et al. Profiling of aldehyde dehydrogenase isoforms in in vitro formed tumorspheres[J]. Anticancer Res, 2021, 41(11):5481-5488.
12
He J, Huang Z, Han L, et al. Mechanisms and management of 3rdgeneration EGFRTKI resistance in advanced nonsmall cell lung cancer (Review)[J]. Int J Oncol, 2021, 59(5):90. doi: 10.3892/ijo.2021.5270.
13
Reita D, Pabst L, Pencreach E, et al. Molecular mechanism of EGFR-TKI resistance in EGFR-mutated non-small cell lung cancer: application to biological diagnostic and monitoring[J]. Cancers (Basel), 2021, 13(19):4926. doi: 10.3390/cancers13194926.
14
Hu F, Li C, Zheng X, et al. Lung adenocarcinoma resistance to therapy with EGFRtyrosine kinase inhibitors is related to increased expression of cancer stem cell markers SOX2, OCT4 and NANOG[J]. Oncol Rep, 2020, 43(2):727-735.
15
Hsu LC, Chang WC, Hoffmann I, et al. Molecular analysis of two closely related mouse aldehyde dehydrogenase genes: identification of a role for Aldh1, but not Aldh-pb, in the biosynthesis of retinoic acid[J]. Biochem J, 1999, 339(Pt 2):387-395.
16
Orywal K, Jelski W, KozLowski MD, et al. Activity of alcohol dehydrogenase and aldehyde dehydrogenase in lung cancer cells[J]. Anticancer Res, 2020, 40(7):3857-3863.
17
Corominas-Faja B, Oliveras-Ferraros C, Cuyas E, et al. Stem cell-like ALDH(bright) cellular states in EGFR-mutant non-small cell lung cancer: a novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin[J]. Cell Cycle, 2013, 12(21):3390-3404.
18
Yiming R, Takeuchi Y, Nishimura T, et al. MUSASHI-2 confers resistance to third-generation EGFR-tyrosine kinase inhibitor osimertinib in lung adenocarcinoma[J]. Cancer Sci, 2021, 112(9):3810-3821.
19
WU L, YU Y, XU L, et al. TROY modulates cancer stem-like cell properties and gefitinib resistance through EMT signaling in non-small cell lung cancer[J]. Front Genet, 2022, 13:881875. doi: 10.3389/fgene.2022.881875.
20
Vora P, Venugopal C, Salim SK, et al. The rational development of CD133-targeting immunotherapies for glioblastoma[J]. Cell Stem Cell, 2020, 26(6):832-844.e6.
21
彭聪, 李盼, 杨明强, 等.干扰FOXC1逆转非小细胞肺癌吉非替尼耐药的作用[J]. 中国肺癌杂志, 2021, 24(8):538-547.
22
Yamashita N, So T, Miyata T, et al. Triple-negative expression (ALDH1A1-/CD133-/mutant p53-) cases in lung adenocarcinoma had a good prognosis[J]. Sci Rep, 2022, 12(1):1473. doi: 10.1038/s41598-022-05176-0.
23
Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells[J]. PLoS One, 2008, 3(7):e2637. doi:10.1371/journal.pone.0002637.
24
Wang J, Li W, Zheng X, et al. Research progress on the forkhead box C1[J]. Oncotarget, 2017, 9(15):12471-12478.
25
Glumac PM, LeBeau AM. The role of CD133 in cancer: a concise review[J]. Clin Transl Med, 2018, 7(1):18. doi: 10.1186/s40169-018-0198-1.
26
Goodell MA, Brose K, Paradis G, et al. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo[J]. J Exp Med, 1996, 183(4):1797-1806.
27
Bruckmueller H, Cascorbi I. ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?[J]. Expert Opin Drug Metab Toxicol, 2021, 17(4):369-396.
28
An Y, Ongkeko WM. ABCG2: the key to chemoresistance in cancer stem cells?[J]. Expert Opin Drug Metab Toxicol, 2009, 5(12):1529-1542.
29
Hu YP, Tao LY, Wang F, et al. Secalonic acid D reduced the percentage of side populations by down-regulating the expression of ABCG2[J]. Biochem Pharmacol, 2013, 85(11):1619-1625.
30
Zhang Y, Vagiannis D, Budagaga Y, et al. Sonidegib potentiates the cancer cells' sensitivity to cytostatic agents by functional inhibition of ABCB1 and ABCG2 in vitro and ex vivo[J]. Biochem Pharmacol, 2022, 199:115009. doi: 10.1016/j.bcp.2022.115009.
31
Ho MM, Ng AV, Lam S, et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells[J]. Cancer Res, 2007, 67(10):4827-4833.
32
Liao CH, Tzeng YT, Lai GM, et al. Omega-3 fatty acid-enriched fish oil and selenium combination modulates endoplasmic reticulum stress response elements and reverses acquired gefitinib resistance in HCC827 lung adenocarcinoma cells[J]. Mar Drugs, 2020, 18(8):399. doi: 10.3390/md18080399.
33
Wang CY, Huang CS, Yang YP, et al. The subpopulation of CD44-positive cells promoted tumorigenicity and metastatic ability in lung adenocarcinoma[J]. J Chin Med Assoc, 2019, 82(3):196-201.
34
Liu J, Xiao Z, Wong SK, et al. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells[J]. Oncotarget, 2013, 4(10):1698-1711.
35
Yaghobi Z, Movassaghpour A, Talebi M, et al. The role of CD44 in cancer chemoresistance: A concise review[J]. Eur J Pharmacol, 2021, 903:174147. doi: 10.1016/j.ejphar.2021.174147.
36
Sauzay C, Voutetakis K, Chatziioannou A, et al. CD90/Thy-1, a cancer-associated cell surface signaling molecule[J]. Front Cell Dev Biol, 2019, 7:66. doi: 10.3389/fcell.2019.00066.
37
Yang J, Zhan XZ, Malola J, et al. The multiple roles of Thy-1 in cell differentiation and regeneration[J]. Differentiation, 2020, 113:38-48.
38
Zhao M, Zhang Y, Zhang H, et al. Hypoxia-induced cell stemness leads to drug resistance and poor prognosis in lung adenocarcinoma[J]. Lung Cancer, 2015, 87(2):98-106.
39
Zhang H, Chen F, He Y, et al. Sensitivity of non-small cell lung cancer to erlotinib is regulated by the Notch/miR-223/FBXW7 pathway[J]. Biosci Rep, 2017, 37(3):BSR20160478. doi: 10.1042/BSR20160478.
40
Xie M, He CS, Wei SH, et al. Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo[J]. Eur J Cancer, 2013, 49(16):3559-3572.
41
Diluvio G, Del Gaudio F, Giuli MV, et al. NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest[J]. Oncogenesis, 2018, 7(5):42. doi: 10.1038/s41389-018-0051-9.
42
Zhang Y, Chen B, Wang Y, et al. NOTCH3 overexpression and posttranscriptional regulation by miR-150 were associated with EGFR-TKI resistance in lung adenocarcinoma[J]. Oncol Res, 2019, 27(7):751-761.
43
Leon G, MacDonagh L, Finn SP, et al. Cancer stem cells in drug resistant lung cancer: Targeting cell surface markers and signaling pathways[J]. Pharmacol Ther, 2016, 158:71-90.
44
Nusse R, Clevers H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities[J]. Cell, 2017, 169(6):985-999.
45
Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy[J]. J Cell Physiol, 2019, 234(6):8381-8395.
46
Lin S, Zhen Y, Guan Y, et al. Roles of Wnt/beta-catenin signaling pathway regulatory long non-coding RNAs in the pathogenesis of non-small cell lung cancer[J]. Cancer Manag Res, 2020, 12:4181-4191.
47
Yoo SB, Kim YJ, Kim H, et al. Alteration of the E-cadherin/beta-catenin complex predicts poor response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment[J]. Ann Surg Oncol, 2013, 3:S545-552.
48
Togashi Y, Hayashi H, Terashima M, et al. Inhibition of beta-catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation[J]. J Thorac Oncol, 2015, 10(1):93-101.
49
Wu J, He X, Xiong Z, et al. Bruceine H mediates EGFR-TKI drug persistence in NSCLC by Notch3-dependent beta-catenin activating FOXO3a signaling[J]. Front Oncol, 2022, 12:855603. doi: 10.3389/fonc.2022.855603.
50
Li K, Mo C, Gong D, et al. DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of beta-catenin[J]. Cancer Lett, 2017, 400:194-202.
51
Lee HJ, Min HY, Yong YS, et al. A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects[J]. Theranostics, 2022, 12(1):105-125.
52
Wang J, Zhou P, Wang X, et al. Rab25 promotes erlotinib resistance by activating the beta1 integrin/AKT/beta-catenin pathway in NSCLC[J]. Cell Prolif, 2019, 52(3):e12592. doi: 10.1111/cpr.12592.
53
Giroux-Leprieur E, Costantini A, Ding VW, et al. Hedgehog signaling in lung cancer: from oncogenesis to cancer treatment resistance[J]. Int J Mol Sci, 2018, 19(9):2835. doi: 10.3390/ijms19092835.
54
Moustafa EM, Abdel Salam HS, Mansour SZ. Withania somnifera modulates radiation-induced generation of lung cancer stem cells via restraining the hedgehog signaling factors[J]. Dose Response, 2022, 20(1):15593258221076711. doi: 10.1177/15593258221076711.
55
Ahmad A, Maitah MY, Ginnebaugh KR, et al. Inhibition of hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs[J]. J Hematol Oncol, 2013, 6(1):77. doi: 10.1186/1756-8722-6-77.
56
Chen H, Yang D, Wang Y, et al. Activation of the hedgehog pathway mediates resistance to epidermal growth factor receptor inhibitors in non-small cell lung cancer[J]. J Cancer, 2022, 13(3):987-997.
57
He X, Smith SE, Chen S, et al. Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche[J]. Cell Rep, 2021, 36(10):109674.doi: 10.1016/j.celrep.2021.109674.
58
Chen WJ, Ho CC, Chang YL, et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling[J]. Nat Commun, 2014, 5:3472. doi: 10.1038/ncomms4472.
59
Tsuyada A, Chow A, Wu J, et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells[J]. Cancer Res, 2012, 72(11):2768-2779.
60
Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress[J]. Mol Cell, 2010, 40(2):294-309.
61
Liu L, Salnikov AV, Bauer N, et al. Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-kappaB downregulation[J]. Int J Cancer, 2014, 134(10):2489-2503.
62
Vallee A, Lecarpentier Y, Vallee JN. The key role of the WNT/beta-catenin pathway in metabolic reprogramming in cancers under normoxic conditions[J]. Cancers (Basel), 2021, 13(21):5557.doi: 10.3390/cancers13215557.
63
Xu XX, Liu C, Liu Y, et al. Enrichment of cancer stem cell-like cells by culture in alginate gel beads[J]. J Biotechnol, 2014, 177:1-12.
64
Gkountakos A, Centonze G, Vita E, et al. Identification of targetable liabilities in the dynamic metabolic profile of EGFR-mutant lung adenocarcinoma: Thinking beyond genomics for overcoming EGFR TKI resistance[J]. Biomedicines, 2022, 10(2):277. doi: 10.3390/biomedicines10020277.
65
Liu L, Wang C, Li S, et al. Tumor immune microenvironment in epidermal growth factor receptor-mutated non-small cell lung cancer before and after epidermal growth factor receptor tyrosine kinase inhibitor treatment: a narrative review[J]. Transl Lung Cancer Res, 2021, 10(9):3823-3839.
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