Прогностическая значимость исследований CD44 и CK19 при плоскоклеточном раке головы и шеи

Цель исследования. Анализ и обобщение современных научных сведений о роли экспрессии CD44 и CK19 в патогенезе плоскоклеточного рака головы и шеи (ПРГШ), их диагностической и прогностической значимости, а также возможностей клинического применения и перспективах.

Материалы и методы. Обзор основан на анализе публикаций в базах данных PubMed, Scopus, Web of Science и Embase, используя ключевые слова: «head and neck squamous cell carcinoma», «CD44», «CK19», «biomarker», «prognosis». Критерии включения: оригинальные исследования и метаанализы; исключались дублирующиеся и нерелевантные публикации. Сравнивались методы выявления CD44 и CK19, а также клинические и демографические характеристики изученных когорт в различных работах.

Результаты. Повышенная или аномальная экспрессия CD44 связана с большей агрессивностью, риском рецидива и метастазирования ПРГШ, а отдельные изоформы (CD44v4, CD44v6) могут указывать на резистентность и неблагоприятное течение. На экспрессию CD44 влияет ряд факторов (локализация, возраст, пол). Высокие уровни CK19 ассоциированы с низкой дифференцировкой, высокой злокачественностью и рисками рецидива; этот маркер часто выявляется при ВПЧ-ассоциированных опухолях. Иммуногистохимические и молекулярные тесты определения CK19 характеризуются высокой чувствительностью и специфичностью. Современные исследования подтверждают тот факт, что совместная оценка CD44 и CK19 повышает точность стратификации риска и клинического мониторинга ПРГШ.

Заключение. CD44 и CK19 – перспективные биомаркеры для персонализированного подхода к диагностике и ведению пациентов с ПРГШ. Их комбинация улучшает раннюю стратификацию риска прогрессирования и рецидива, а также выбор оптимальных лечебных методов. Необходимы дальнейшие масштабные исследования и унификация методик для внедрения этих маркеров в клиническую практику с целью повышения выживаемости пациентов и улучшения их качества жизни.

1. Guo K, Xiao W, Chen X, Zhao Z, Lin Y, Chen G. Epidemiological Trends of Head and Neck Cancer: A Population-Based Study. Biomed Res Int. 2021 Jul 14;2021:1738932. https://doi.org/10.1155/2021/1738932 Erratum in: Biomed Res Int. 2021 Nov 24;2021:9758328. https://doi.org/10.1155/2021/9758328

2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229–263. https://doi.org/10.3322/caac.21834

3. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020 Nov 26;6(1):92. https://doi.org/10.1038/s41572-020-00224-3 Erratum in: Nat Rev Dis Primers. 2023 Jan 19;9(1):4. https://doi.org/10.1038/s41572-023-00418-5

4. Bhat AA, Yousuf P, Wani NA, Rizwan A, Chauhan SS, Siddiqi MA, et al. Tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy. Signal Transduct Target Ther. 2021 Jan 12;6(1):12. https://doi.org/10.1038/s41392-020-00419-w Erratum in: Signal Transduct Target Ther. 2021 Feb 26;6(1):93. https://doi.org/10.1038/s41392-021-00503-9

5. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan 29;517(7536):576–582. https://doi.org/10.1038/nature14129

6. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011 Aug 26;333(6046):1157–1160. https://doi.org/10.1126/science.1208130

7. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24–35. https://doi.org/10.1056/nejmoa0912217

8. Oliveira-Silva RJ, Carolina de Carvalho A, de Souza Viana L, Carvalho AL, Reis RM. Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma. Recent Pat Anticancer Drug Discov. 2016;11(2):170–183. https://doi.org/10.2174/1574892811666160309121238

9. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856–1867. https://doi.org/10.1056/nejmoa1602252

10. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al.; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915–1928. https://doi.org/10.1016/s0140-6736(19)32591-7 Erratum in: Lancet. 2020 Jan 25;395(10220):272. https://doi.org/10.1016/s0140-6736(20)30116-1 Erratum in: Lancet. 2020 Feb 22;395(10224):564. https://doi.org/10.1016/s0140-6736(20)302543 Erratum in: Lancet. 2021 Jun 12;397(10291):2252. https://doi.org/10.1016/s0140-6736(21)01119-3

11. Zöller M. CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer. 2011 Apr;11(4):254– 267. https://doi.org/10.1038/nrc3023

12. Canning M, Guo G, Yu M, Myint C, Groves MW, Byrd JK, Cui Y. Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy. Front Cell Dev Biol. 2019 Apr 9;7:52. https://doi.org/10.3389/fcell.2019.00052

13. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020 Nov 26;6(1):92. https://doi.org/10.1038/s41572-020-00224-3 Erratum in: Nat Rev Dis Primers. 2023 Jan 19;9(1):4. https://doi.org/10.1038/s41572-023-00418-5

14. Loaiza B, Rojas E, Valverde M. The New Model of Carcinogenesis: The Cancer Stem Cell Hypothesis. In: Carcinogen. Edited by Pesheva M, Dimitrov M, Stefkova TS. InTechOpen, 2012. https://doi.org/10.5772/38324

15. Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020 Dec 10;9(1):36. https://doi.org/10.1186/s40164-020-00192-0

16. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003 Jan;4(1):33–45. https://doi.org/10.1038/nrm1004

17. Vuorio J, Škerlová J, Fábry M, Veverka V, Vattulainen I, Řezáčová P, Martinez-Seara H. N-Glycosylation can selectively block or foster different receptor-ligand binding modes. Sci Rep. 2021 Mar 4;11(1):5239. https://doi.org/10.1038/s41598-021-84569-z

18. Guo Q, Yang C, Gao F. The state of CD44 activation in cancer progression and therapeutic targeting. FEBS J. 2022 Dec;289(24):7970–7986. https://doi.org/10.1111/febs.16179

19. Judd NP, Winkler AE, Murillo-Sauca O, Brotman JJ, Law JH, Lewis JS Jr, et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res. 2012 Jan 1;72(1):365–374. https://doi.org/10.1158/0008-5472.can-11-1831

20. Gomez KE, Wu F, Keysar SB, Morton JJ, Miller B, Chimed TS, et al. Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells. Cancer Res. 2020 Oct 1;80(19):4185–4198. https://doi.org/10.1158/0008-5472.can-20-1079

21. Ortiz RC, Amôr NG, Saito LM, Santesso MR, Lopes NM, Buzo RF, et al. CSChighE-cadherinlow immunohistochemistry panel predicts poor prognosis in oral squamous cell carcinoma. Sci Rep. 2024 May 8;14(1):10583. https://doi.org/10.1038/s41598-024-55594-5

22. Hema K, Rao K, Devi HU, Priya N, Smitha T, Sheethal H. Immunohistochemical study of CD44s expression in oral squamous cell carcinoma-its correlation with prognostic parameters. J Oral Maxillofac Pathol. 2014 May;18(2):162–168. https://doi.org/10.4103/0973-029X.140722

23. Hier J, Vachon O, Bernstein A, Ibrahim I, Mlynarek A, Hier M, et al. Portrait of DNA methylated genes predictive of poor prognosis in head and neck cancer and the implication for targeted therapy. Sci Rep. 2021 May 11;11(1):10012. https://doi.org/10.1038/s41598-021-89476-x

24. Kashyap T, Pramanik KK, Nath N, Mishra P, Singh AK, Nagini S, et al. Crosstalk between Raf-MEK-ERK and PI3K-Akt-GSK3β signaling networks promotes chemoresistance, invasion/migration and stemness via expression of CD44 variants (v4 and v6) in oral cancer. Oral Oncol. 2018 Nov;86:234-243. https://doi.org/10.1016/j.oraloncology.2018.09.028

25. Singh B, Aggarwal S, Das P, Srivastava SK, Sharma SC, Das SN. Over Expression of Cancer Stem Cell Marker CD44 and Its Clinical Significance in Patients with Oral Squamous Cell Carcinoma. Indian J Otolaryngol Head Neck Surg. 2023 Mar;75(1):109-114. https://doi.org/10.1007/s12070-022-03200-3

26. Adnan Y, Ali SMA, Farooqui HA, Kayani HA, Idrees R, Awan MS. High CD44 Immunoexpression Correlates with Poor Overall Survival: Assessing the Role of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma Patients from the High-Risk Population of Pakistan. Int J Surg Oncol. 2022 Mar 7;2022:9990489. https://doi.org/10.1155/2022/9990489

27. Mohanta S, Siddappa G, Valiyaveedan SG, Dodda Thimmasandra Ramanjanappa R, Das D, Pandian R, et al. Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma. Tumour Biol. 2017 Jun;39(6): 1010428317703656. https://doi.org/10.1177/1010428317703656

28. Israelsson P, Oda H, Öfverman C, Stefansson K, Lindquist D. Immunoreactivity of LMO7 and other molecular markers as potential prognostic factors in oropharyngeal squamous cell carcinoma. BMC Oral Health. 2024 Jun 25;24(1):729. https://doi.org/10.1186/s12903-024-04510-4

29. Patel S, Shah K, Mirza S, Shah K, Rawal R. Circulating tumor stem like cells in oral squamous cell carcinoma: An unresolved paradox. Oral Oncol. 2016 Nov;62:139–146. https://doi.org/10.1016/j.oraloncology.2016.10.019

30. Kristensen MH, Sørensen MK, Tramm T, Alsner J, Sørensen BS, Maare C, et al. Tumor volume and cancer stem cell expression as prognostic markers for high-dose loco-regional failure in head and neck squamous cell carcinoma - A DAHANCA 19 study. Radiother Oncol. 2024 Apr;193:110149. https://doi.org/10.1016/j.radonc.2024.110149

31. Puzzo L, Bianco MR, Salvatorelli L, Tinnirello G, Occhiuzzi F, Latella D, Allegra E. CD44, PDL1, and ATG7 Expression in Laryngeal Squamous Cell Carcinomas with Tissue Microarray (TMA) Technique: Evaluation of the Potential Prognostic and Predictive Roles. Cancers (Basel). 2023 Apr 25;15(9):2461. https://doi.org/10.3390/cancers15092461

32. Öztürk Ç, Paşaoğlu HE, Emre F, Tetikkurt ÜS, Şentürk Ege T. Do immunohistochemical studies have a role in predicting prognosis of laryngeal squamous cell carcinomas? CD44 and Fascin experience. Acta Biomed. 2022 Jan 19;92(6):e2021309. https://doi.org/10.23750/abm.v92i6.10432

33. Kavitha L, Vijayashree Priyadharsini J, Kattula D, Rao UKM, Balaji Srikanth R, Kuzhalmozhi M, Ranganathan K. Expression of CD44 in Head and Neck Squamous Cell Carcinoma-An In-Silico Study. Glob Med Genet. 2023 Aug 16;10(3):221–228. https://doi.org/10.1055/s-0043-1772459

34. de Jong MC, Pramana J, van der Wal JE, Lacko M, Peutz-Kootstra CJ, de Jong JM, et al. CD44 expression predicts local recurrence after radiotherapy in larynx cancer. Clin Cancer Res. 2010 Nov 1;16(21):5329–5338. https://doi.org/10.1158/1078-0432.CCR-10-0799

35. Dubey P, Gupta R, Mishra A, Kumar V, Bhadauria S, Bhatt MLB. Evaluation of correlation between CD44, radiotherapy response, and survival rate in patients with advanced stage of head and neck squamous cell carcinoma (HNSCC). Cancer Med. 2022 May;11(9):1937–1947. https://doi.org/10.1002/cam4.4497

36. Jakob M, Sharaf K, Schirmer M, Leu M, Küffer S, Bertlich M, et al. Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC. Strahlenther Onkol. 2021 Mar;197(3):231–245. https://doi.org/10.1007/s00066-020-01653-5

37. Kuburich NA, den Hollander P, Pietz JT, Mani SA. Vimentin and cytokeratin: Good alone, bad together. Semin Cancer Biol. 2022 Nov;86(Pt 3):816–826. https://doi.org/10.1016/j.semcancer.2021.12.006

38. Bragulla HH, Homberger DG. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J Anat. 2009 Apr;214(4):516–559. https://doi.org/10.1111/j.1469-7580.2009.01066.x

39. Lu Q, Qu H, Lou T, Liu C, Zhang Z. CK19 Promotes Ovarian Cancer Development by Impacting on Wnt/β-Catenin Pathway. Onco Targets Ther. 2020 Mar 24;13:2421–2431. https://doi.org/10.2147/OTT.S242778

40. Rao Y, Li J, Shi L, Chen X, Hu Y, Mao Y, Zhang X, Liu X. Silencing CK19 regulates ferroptosis by affecting the expression of GPX4 and ACSL4 in oral squamous cell carcinoma in vivo and in vitro. Sci Rep. 2024 Jul 10;14(1):15968. https://doi.org/10.1038/s41598-024-65079-0

41. Tanaka S, Kawano S, Hattori T, Matsubaraet R, Sakamoto T, Hashiguchi Y, et al. Cytokeratin 19 as a biomarker of highly invasive oral squamous cell carcinoma with metastatic potential. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 2020;32(1):1–7. https://doi.org/10.1016/j.ajoms.2019.10.007

42. Santoro A, Pannone G, Ninivaggi R, Petruzzi M, Santarelli A, Russo GM, et al. Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma. Infect Agent Cancer. 2015 Dec 15;10:46. https://doi.org/10.1186/s13027-015-0041-x

43. Woods RSR, Callanan D, Jawad H, Molony P, Werner R, Heffron C, Feeley L, Sheahan P. Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma. Eur Arch Otorhinolaryngol. 2022 Mar;279(3):1435–1443. https://doi.org/10.1007/s00405-021-06894-3

44. Zhong LP, Chen WT, Zhang CP, Zhang ZY. Increased CK19 expression correlated with pathologic differentiation grade and prognosis in oral squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Sep;104(3):377– 384. https://doi.org/10.1016/j.tripleo.2006.07.019

45. Safadi RA, Abdullah NI, Alaaraj RF, Bader DH, Divakar DD, Hamasha AA, Sughayer MA. Clinical and histopathologic prognostic implications of the expression of cytokeratins 8, 10, 13, 14, 16, 18 and 19 in oral and oropharyngeal squamous cell carcinoma. Arch Oral Biol. 2019 Mar;99:1–8. https://doi.org/10.1016/j.archoralbio.2018.12.007

46. Rajeswari P, Janardhanan M, Suresh R, Savithri V, Aravind T, Raveendran GC. Expression of CK 19 as a biomarker in early detection of oral squamous cell carcinoma. J Oral Maxillofac Pathol. 2020 Sep-Dec;24(3):523–529. https://doi.org/10.4103/jomfp.JOMFP_302_19

47. Sharma P, Alsharif S, Fallatah A, Chung BM. Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin. Cells. 2019 May 23;8(5):497. https://doi.org/10.3390/cells8050497

48. Ernst J, Ikenberg K, Apel B, Schumann DM, Huber G, Studer G, et al. Expression of CK19 is an independent predictor of negative outcome for patients with squamous cell carcinoma of the tongue. Oncotarget. 2016 Nov 15;7(46):76151–76158. https://doi.org/10.18632/oncotarget.12691

49. Hsu YP, Hsieh CH, Chien HT, Lai CH, Tsao CK, Liao CT, et al. Serum markers of CYFRA 21-1 and C-reactive proteins in oral squamous cell carcinoma. World J Surg Oncol. 2015 Aug 21;13:253. https://doi.org/10.1186/s12957-015-0656-9

50. Rahadiani N, Sarwanti S, Handjari DR, Stephanie M, Krisnuhoni E. Clinical implications of Cytokeratin 19 expression in patients with oral squamous cell carcinoma. Pathologica. 2023 Jun;115(3):155–163. https://doi.org/10.32074/1591-951X-842

51. Shaw R, Christensen A, Java K, Maddani RE, Liloglou T, Asterios T, et al. Intraoperative Sentinel Lymph Node Evaluation: Implications of Cytokeratin 19 Expression for the Adoption of OSNA in Oral Squamous Cell Carcinoma. Ann Surg Oncol. 2016 Nov;23(12):4042–4048. https://doi.org/10.1245/s10434-016-5337-6

52. Chakraborty S, Suresh TN, Azeem Mohiyuddin SM. Expression of stem cell biomarker CD44 in oral squamous cell carcinoma and its association with lymph node metastasis and TNM staging. J Cancer Res Ther. 2024 Jul 1;20(5):1430–1434. https://doi.org/10.4103/jcrt.jcrt_178_23

53. Liu L, Xie W, Xue P, Wei Z, Liang X, Chen N. Diagnostic accuracy and prognostic applications of CYFRA 21-1 in head and neck cancer: A systematic review and meta-analysis. PLoS One. 2019 May 9;14(5):e0216561. https://doi.org/10.1371/journal.pone.0216561

54. Peigné L, Godey F, Le Gallo M, Le Gall F, Fautrel A, Morcet J, Jégoux F. One-step nucleic acid amplification for detecting lymph node metastasis of head and neck squamous cell carcinoma. Oral Oncol. 2020 Mar;102:104553. https://doi.org/10.1016/j.oraloncology.2019.104553

55. Aramini B, Masciale V, Arienti C, Dominici M, Stella F, Martinelli G, Fabbri F. Cancer Stem Cells (CSCs), Circulating Tumor Cells (CTCs) and Their Interplay with Cancer Associated Fibroblasts (CAFs): A New World of Targets and Treatments. Cancers (Basel). 2022 May 13;14(10):2408. https://doi.org/10.3390/cancers14102408

56. Zhou S, Xu H, Duan Y, Tang Q, Huang H, Bi F. Survival mechanisms of circulating tumor cells and their implications for cancer treatment. Cancer Metastasis Rev. 2024 Sep;43(3):941–957. https://doi.org/10.1007/s10555-024-10178-7

57. Chang PH, Wu MH, Liu SY, Wang HM, Huang WK, Liao CT, et al. The Prognostic Roles of Pretreatment Circulating Tumor Cells, Circulating Cancer Stem-Like Cells, and Programmed Cell Death-1 Expression on Peripheral Lymphocytes in Patients with Initially Unresectable, Recurrent or Metastatic Head and Neck Cancer: An Exploratory Study of Three Biomarkers in One-time Blood Drawing. Cancers (Basel). 2019 Apr 15;11(4):540. https://doi.org/10.3390/cancers11040540