Роль опухолевых стволовых клеток и иммунного микроокружения в патогенезе рака легкого: механизмы взаимодействия и перспективы исследований

Несмотря на значительные успехи в лечении злокачественных новообразований, проблема резистентности к терапии, опосредованной опухолевыми стволовыми клетками (ОСК), диктует необходимость разработки новых стратегий лечения. Изучение роли ОСК и иммунного микроокружения в патогенезе рака, особенно немелкоклеточного рака легкого (НМРЛ), является актуальным вопросом современной онкологии. Настоящая работа основана на обширном анализе последних исследований и направлена на изучение механизмов, лежащих в основе развития НМРЛ. Рассматривается происхождение ОСК, их маркеры и основные сигнальные пути, участвующие в регуляции активности данного пула клеток. Особое внимание уделяется влиянию ОСК на прогрессирование рака легкого и механизмам, обусловливающим устойчивость к терапии. Освещаются различные подходы к лечению рака легкого, ориентированные на ОСК, с акцентом на таргетную терапию, направленную на специфические молекулярные мишени.

Отмечается важная роль иммунного микроокружения опухоли в патогенезе рака легкого и его влияния на ОСК. Обсуждаются механизмы регуляции иммунных реакций в опухоли и потенциал использования иммунотерапии для улучшения результатов лечения рака легкого. В статье также рассматриваются современные методы диагностики и лечения, включающие молекулярно-генетические и иммуногистохимические подходы. Работа представляет собой обзор современных знаний о механизмах развития рака легкого и имеет важное значение для понимания биологии опухолей и разработки новых методов лечения. Подчеркивается необходимость междисциплинарного подхода и комплексного использования современных диагностических и терапевтических методов для улучшения прогнозов и выживаемости пациентов с НМРЛ. Особое внимание уделено перспективам использования комбинированных терапевтических подходов, включающих таргетные препараты и иммунотерапию, направленные на подавление активности ОСК и модификацию опухолевого микроокружения.

В заключение, глубокое понимание молекулярных механизмов, регулирующих деятельность ОСК, и их взаимодействие с микроокружением опухоли открывает новые возможности для разработки эффективных стратегий лечения. Данный обзор подчеркивает необходимость дальнейших исследований в этой области, чтобы обеспечить более успешное лечение и повышение качества жизни пациентов с раком легкого.

1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol. 2015 Sep;10(9):1240–1242. https://doi.org/10.1097/JTO.0000000000000663

2. Travis WD, Brambilla E, Riely GJ. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol. 2013 Mar 10;31(8):992–1001. https://doi.org/10.1200/JCO.2012.46.9270

3. Dietel M, Bubendorf L, Dingemans AMC, Dooms C, Elmberger G, García RC, et al. Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group. Thorax. 2016 Feb;71(2):177–184. https://doi.org/10.1136/thoraxjnl-2014-206677

4. Kerr KM, Bibeau F, Thunnissen E, Botling J, Ryška A, Wolf J, et al. The evolving landscape of biomarker testing for non-small cell lung cancer in Europe. Lung Cancer. 2021 Apr;154:161–175. https://doi.org/10.1016/j.lungcan.2021.02.026

5. Giroux-Leprieur E, Costantini A, Ding VW, He B. Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance. Int J Mol Sci. 2018 Sep 19;19(9):2835. https://doi.org/10.3390/ijms19092835

6. Ahmad A, Maitah MY, Ginnebaugh KR, Li Y, Bao B, Gadgeel SM, et al. Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs. J Hematol Oncol. 2013 Oct 7;6(1):77. https://doi.org/10.1186/1756-8722-6-77

7. Li F, Zhou K, Gao L, Zhang B, Li W, Yan W, et al. Radiation induces the generation of cancer stem cells: A novel mechanism for cancer radioresistance. Oncol Lett. 2016 Nov;12(5):3059–3065. https://doi.org/10.3892/ol.2016.5124

8. Makena MR, Ranjan A, Thirumala V, Reddy AP. Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 1;1866(4):165339. https://doi.org/10.1016/j.bbadis.2018.11.015

9. Ahmed M, Chaudhari K, Babaei-Jadidi R, Dekker LV, Shams Nateri A. Concise Review: Emerging Drugs Targeting Epithelial Cancer Stem-Like Cells. Stem Cells. 2017 Apr;35(4):839–850. https://doi.org/10.1002/stem.2579

10. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019 Feb;20(2):69–84. https://doi.org/10.1038/s41580-018-0080-4

11. Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel). 2018 Jul 27;10(8):248. https://doi.org/10.3390/cancers10080248

12. Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O’Flaherty JD, et al. Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One. 2013;8(1):e54193. https://doi.org/10.1371/journal.pone.0054193

13. Kim WT, Ryu CJ. Cancer stem cell surface markers on normal stem cells. BMB Rep. 2017 Jun;50(6):285–298. https://doi.org/10.5483/bmbrep.2017.50.6.039

14. Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 2012 Jan 20;148(1–2):259–272. https://doi.org/10.1016/j.cell.2011.11.050

15. Herreros-Pomares A, de-Maya-Girones JD, Calabuig-Fariñas S, Lucas R, Martínez A, Pardo-Sánchez JM, et al. Lung tumor-spheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer. Cell Death Dis. 2019 Sep 10;10(9):660. https://doi.org/10.1038/s41419-019-1898-1

16. Ohnishi S, Maehara O, Nakagawa K, Kameya A, Otaki K, Fujita H, et al. hypoxia-inducible factors activate CD133 promoter through ETS family transcription factors. PLoS One. 2013;8(6):e66255. https://doi.org/10.1371/journal.pone.0066255

17. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008 Mar;15(3):504–514. https://doi.org/10.1038/sj.cdd.4402283

18. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology. 2013 Jul;18(5):757–764. https://doi.org/10.1111/resp.12094

19. Hou YC, Chao YJ, Hsieh MH, Tung HL, Wang HC, Shan YS. Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer. Cancers (Basel). 2019 Apr 15;11(4):541. https://doi.org/10.3390/cancers11040541

20. Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell. 2008 Jul 11;134(1):62–73. https://doi.org/10.1016/j.cell.2008.06.006

21. Leung ELH, Fiscus RR, Tung JW, Tin VPC, Cheng LC, Sihoe ADL, et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One. 2010 Nov 19;5(11):e14062. https://doi.org/10.1371/journal.pone.0014062

22. Roudi R, Madjd Z, Korourian A, Mehrazma M, Molanae S, Sabet MN, et al. Clinical significance of putative cancer stem cell marker CD44 in different histological subtypes of lung cancer. Cancer Biomark. 2014;14(6):457–467. https://doi.org/10.3233/cbm-140424

23. Bourguignon LYW. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol. 2008 Aug;18(4):251–259. https://doi.org/10.1016/j.semcancer.2008.03.007

24. Orian-Rousseau , Sleeman J. CD44 is a multidomain signaling platform that integrates extracellular matrix cues with growth factor and cytokine signals. Adv Cancer Res. 2014;123:231–254. https://doi.org/10.1016/B978-0-12-800092-2.00009-5

25. Ludwig N, Szczepanski MJ, Gluszko A, Szafarowski T, Azambuja JH, Dolg L, et al. CD44(+) tumor cells promote early angiogenesis in head and neck squamous cell carcinoma. Cancer Lett. 2019 Dec 28;467:85–95. https://doi.org/10.1016/j.canlet.2019.10.010

26. Kong T, Ahn R, Yang K, Zhu X, Fu Z, Morin G, et al. CD44 Promotes PD-L1 Expression and Its Tumor-Intrinsic Function in Breast and Lung Cancers. Cancer Res. 2020 Feb 1;80(3):444–457. https://doi.org/10.1158/0008-5472.CAN-19-1108

27. Masciale V, Grisendi G, Banchelli F, D’Amico R, Maiorana A, Sighinolfi P, et al. CD44+/EPCAM+ cells detect a subpopulation of ALDHhigh cells in human non-small cell lung cancer: A chance for targeting cancer stem cells? Oncotarget. 2020 Apr 28;11(17):1545–1555. https://doi.org/10.18632/oncotarget.27568

28. Hardavella G, George R, Sethi T. Lung cancer stem cells-characteristics, phenotype. Transl Lung Cancer Res. 2016 Jun;5(3):272–279. https://doi.org/10.21037/tlcr.2016.02.01

29. Eckert F, Schilbach K, Klumpp L, Bardoscia L, Sezgin EC, Schwab M, et al. Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer. Front Immunol. 2018;9:3018. https://doi.org/10.3389/fimmu.2018.03018

30. Trautmann F, Cojoc M, Kurth I, Melin N, Bouchez LC, Dubrovska A, et al. CXCR4 as biomarker for radioresistant cancer stem cells. Int J Radiat Biol. 2014 Aug;90(8):687–699. https://doi.org/10.3109/09553002.2014.906766

31. Gzil A, Zarębska I, Bursiewicz W, Antosik P, Grzanka D, Szylberg Ł. Markers of pancreatic cancer stem cells and their clinical and therapeutic implications. Mol Biol Rep. 2019 Dec;46(6):6629–6645. https://doi.org/10.1007/s11033-019-05058-1

32. Jung MJ, Rho JK, Kim YM, Jung JE, Jin YB, Ko YG, et al. Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. Oncogene. 2013 Jan 10;32(2):209–221. https://doi.org/10.1038/onc.2012.37

33. De Francesco EM, Sotgia F, Lisanti MP. Cancer stem cells (CSCs): metabolic strategies for their identification and eradication. Biochem J. 2018 May 9;475(9):1611–1634. https://doi.org/10.1042/BCJ20170164

34. Barkauskas CE, Chung MI, Fioret B, Gao X, Katsura H, Hogan BLM. Lung organoids: current uses and future promise. Development. 2017 Mar 15;144(6):986–997. https://doi.org/10.1242/dev.140103

35. Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, et al. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat Med. 2015 Mar;21(3):256–262. https://doi.org/10.1038/nm.3802

36. Nagle PW, Plukker JTM, Muijs CT, van Luijk P, Coppes RP. Patient-derived tumor organoids for prediction of cancer treatment response. Semin Cancer Biol. 2018 Dec;53:258–264. https://doi.org/10.1016/j.semcancer.2018.06.005

37. Shimono Y, Mukohyama J, Isobe T, Johnston DM, Dalerba P, Suzuki A. Organoid Culture of Human Cancer Stem Cells. Methods Mol Biol. 2019;1576:23–31. https://doi.org/10.1007/7651_2016_13

38. Kusumbe AP, Bapat SA. Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Res. 2009 Dec 15;69(24):9245–9453. https://doi.org/10.1158/0008-5472.CAN-09-2802

39. Arnold CR, Mangesius J, Skvortsova II, Ganswindt U. The Role of Cancer Stem Cells in Radiation Resistance. Front Oncol. 2020;10:164. https://doi.org/10.3389/fonc.2020.00164

40. Kumar V, Vashishta M, Kong L, Wu X, Lu JJ, Guha C, et al. The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies. Front Cell Dev Biol. 2021;9:650772. https://doi.org/10.3389/fcell.2021.650772

41. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020 Feb 7;5(1):8. https://doi.org/10.1038/s41392-020-0110-5

42. Васильева М. В., Хромова Н. В., Бойчук С. В., Копнин П. Б. Влияние подавления экспрессии NOTCH1 на формирование фенотипа опухолевых стволовых клеток рака легкого и толстой кишки человека. Успехи молекулярной онкологии. 2024;11(2):97–105. https://doi.org/10.17650/2313-805X-2024-11-2-97-105, EDN: RXXWTD

43. Yeh CT, Wu ATH, Chang PMH, Chen KY, Yang CN, Yang SC, et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. Am J Respir Crit Care Med. 2012 Dec 1;186(11):1180–1188. https://doi.org/10.1164/rccm.201207-1180OC

44. Arechaga-Ocampo E, Lopez-Camarillo C, Villegas-Sepulveda N, Gonzalez-De la Rosa CH, Perez-Añorve IX, Roldan-Perez R, et al. Tumor suppressor miR-29c regulates radioresistance in lung cancer cells. Tumour Biol. 2017 Mar;39(3):1010428317695010. https://doi.org/10.1177/1010428317695010

45. Yin H, Jing B, Xu D, Guo W, Sun B, Zhang J, et al. Identification of Active Bronchioalveolar Stem Cells as the Cell of Origin in Lung Adenocarcinoma. Cancer Res. 2022 Mar 15;82(6):1025–1037. https://doi.org/10.1158/0008-5472.CAN-21-2445

46. Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting Cancer Stemness in the Clinic: From Hype to Hope. Cell Stem Cell. 2019 Jan 3;24(1):25–40. https://doi.org/10.1016/j.stem.2018.11.017

47. Lang J, Zhao X, Wang X, Zhao Y, Li Y, Zhao R, et al. Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α In-hibitor Impairs Pancreatic Tumor Growth. ACS Nano. 2019 Feb 26;13(2):2176–2189. https://doi.org/10.1021/acsnano.8b08823

48. Dong L, Lyu X, Faleti OD, He ML. The special stemness functions of Tbx3 in stem cells and cancer development. Semin Cancer Biol. 2019 Aug;57:105–110. https://doi.org/10.1016/j.semcancer.2018.09.010

49. Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 2006 Feb;51(2):181–191. https://doi.org/10.1016/j.lungcan.2005.10.003

50. Zou W. Immune regulation in the tumor microenvironment and its relevance in cancer therapy. Cell Mol Immunol. 2022 Jan;19(1):1–2. https://doi.org/10.1038/s41423-021-00738-0

51. Oh SA, Wu DC, Cheung J, Navarro A, Xiong H, Cubas R, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nat Cancer. 2020 Jul;1(7):681–691. https://doi.org/10.1038/s43018-020-0075-x

52. Zhang D, Tang DG, Rycaj K. Cancer stem cells: Regulation programs, immunological properties and immunotherapy. Semin Cancer Biol. 2018 Oct;52(Pt 2):94–106. https://doi.org/10.1016/j.semcancer.2018.05.001

53. Wang C, Yu Q, Song T, Wang Z, Song L, Yang Y, et al. The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing. Signal Transduct Target Ther. 2022 Aug 26;7(1):289. https://doi.org/10.1038/s41392-022-01130-8

54. Shestopalov AV, Kit OI, Zabolotneva AA, Zlatnik EY, Maksimov AYu, Novikova IA и др. Alkylresorcinols as a New Type of Gut Microbiota Regulators Influencing Immune Therapy Efficiency in Lung Cancer Treatment. Advanced Gut & Microbiome Research. 2023. https://doi.org/10.1155/2023/2333767, EDN: ZIVEKT

55. Сагакянц А. Б., Теплякова М. А., Владимирова Л. Ю., Бондаренко Е. С., Златник Е. Ю., Новикова И. А. и др. Особенности популяционного состава иммунокомпетентных клеток периферической крови у пациентов с немелкоклеточным раком легкого на фоне проводимой иммунотерапии с различной ее эффективностью. Современные проблемы науки и образования. 2023;2:87. https://doi.org/10.17513/spno.32545, EDN: EWBINE

56. Karin M, Shalapour S. Regulation of antitumor immunity by inflammation-induced epigenetic alterations. Cell Mol Immunol. 2022 Jan;19(1):59–66. https://doi.org/10.1038/s41423-021-00756-y

57. Teplyakova MA, Vladimirova LYU, Popova IL, Lyanova AA, Abramova NA, Storozhakova AE и др. Cytokine profiles of peripheral blood in patients with non-small cell lung cancer receiving anti-PD1 therapy. Journal of Clinical Oncology. 2022;40(16). https://doi.org/10.1200/JCO.2022.40.16_suppl.e21068, EDN: RDAZOV

58. Ma F, Lei YY, Ding MG, Luo LH, Xie YC, Liu XL. LncRNA NEAT1 Interacted With DNMT1 to Regulate Malignant Phenotype of Cancer Cell and Cytotoxic T Cell Infiltration via Epigenetic Inhibition of p53, cGAS, and STING in Lung Cancer. Front Genet. 2020;11:250. https://doi.org/10.3389/fgene.2020.00250

59. Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J, et al. EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells. Cancer Res. 2019 Apr 15;79(8):2009–2020. https://doi.org/10.1158/0008-5472.CAN-18-2395

60. Zhu M, Huang Y, Bender ME, Girard L, Kollipara R, Eglenen-Polat B, et al. Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis. Cancer Res. 2021 Apr 1;81(7):1813–1826. https://doi.org/10.1158/0008-5472.CAN-20-2808