ONCOLOGY OF STEM CELL MARKERS' PROGNOSTIC FUNCTIONS IN ORAL SQUAMOUS CELL CARCINOMA PATIENTS RECEIVING CHEMOTHERAPY

Main Article Content

Zahid Manzoor Khanday
Sejuti Sarker Tinny
Usman Manzoor Warraich
Amna Rehman
Hijab Farid Khan
Samreen Malik
Rabia Zulfiqar
Muhammad Omair Khitab
Fozan Ahmad

Keywords

oncology, stem cell markers, prognostic functions, oral squamous cell carcinoma, chemotherapy

Abstract

Oral squamous cell carcinoma (OSCC) is a top-ranked cancer in the global population, and patient survival has remained unchanged at ∼50% for several decades. Recent advances have claimed that a subset of tumour cells, called cancer stem cells (CSCs), are responsible for tumour progression, treatment resistance, and metastasis, which leads to a poor prognosis. Anti-EGFR-based therapies have limited success in OSCC patients. Predictive biomarkers are needed to identify the patients most likely to benefit from these therapies. Here, we studied prognostic associations of different cancer stem cell markers in HPV-negative locally advanced (LA) OSCC patients. Pretreatment tumour tissues of 404 HPV-negative LA-OSCCs patients and a subset of study were comparing cisplatin-radiation (CRT) and nimotuzumab plus cisplatin-radiation(NCRT). The expression levels of CD44, CD44v6, CD98hc, ALDH1A1, SOX2 and OCT4A were evaluated using immunohistochemistry. Progression-free survival (PFS), loco-regional control(LRC),- and overall survival(OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models. NCRT showed significantly improved OS with low membrane expression of CD44 compared to CRT [HR (95% CI) = 0.69 (0.44–0.98)]. Patients with low CD44v6 also showed better outcomes with NCRT [LRC: HR (95% CI) = 0.25 (0.09–0.64); OS: HR (95% CI) = 0.39 (0.17–0.68)]. No similar benefit with NCRT observed in patients with high CD44 or CD44v6 expression. It was concluded that CD44 and CD44v6 are potential predictive biomarkers for NCRT response. CD98hc emerged as an independent negative prognostic biomarker.

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References

1. Byeon HK, Ku M, Yang J. Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer. Exp Mol Med. 2019;51:1–14. doi: 10.1038/s12276-018-0202-2.
2. Chen LF, Cohen EE, Grandis JR. New strategies in head and neck cancer: understanding resistance to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2010;16:2489–95. doi: 10.1158/1078-0432.CCR-09-2318.
3. Patel U, Pandey M, Kannan S, Samant TA, Gera P, Mittal N, et al. Prognostic and predictive significance of nuclear HIF1alpha expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab. Br J Cancer. 2020. 10.1038/s41416-020-01064-4.
4. Bossi P, Resteghini C, Paielli N, Licitra L, Pilotti S, Perrone F. Prognostic and predictive value of EGFR in head and neck squamous cell carcinoma. Oncotarget. 2016;7:74362–79. doi: 10.18632/oncotarget.11413.
5. Petrelli F, Borgonovo K, Barni S. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol. 2013;8:173–81. doi: 10.1007/s11523-013-0257-x.
6. Pinto C, Barone CA, Girolomoni G, Russi EG, Merlano MC, Ferrari D, et al. Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist. 2011;16:228–38. doi: 10.1634/theoncologist.2010-0298.
7. Allan DG. Nimotuzumab: evidence of clinical benefit without rash. Oncologist. 2005;10:760–1. doi: 10.1634/theoncologist.10-9-760.
8. Ramakrishnan MS, Eswaraiah A, Crombet T, Piedra P, Saurez G, Iyer H, et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs. 2009;1:41–doi: 10.4161/mabs.1.1.7509.
9. Patil VM, Noronha V, Joshi A, Agarwal J, Ghosh-Laskar S, Budrukkar A, et al. A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer. Cancer. 2019;125:3184–97. doi: 10.1002/cncr.32179.
10. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 2007;104:973–8. doi: 10.1073/pnas.0610117104.
11. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4:33–45. doi: 10.1038/nrm1004.
12. Fox SB, Fawcett J, Jackson DG, Collins I, Gatter KC, Harris AL, et al. Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. Cancer Res. 1994;54:4539–46.
13. Ioachim E, Assimakopoulos D, Goussia AC, Peschos D, Skevas A, Agnantis NJ. Glycoprotein CD44 expression in benign, premalignant and malignant epithelial lesions of the larynx: an immunohistochemical study including correlation with Rb, p53, Ki-67 and PCNA. Histol Histopathol. 1999;14:1113–8. doi: 10.14670/HH-14.1113.
14. Senbanjo LT, Chellaiah MA. CD44: A multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front Cell Dev Biol. 2017;5:18. doi: 10.3389/fcell.2017.00018.
15. Han S, Huang T, Li W, Wang X, Wu X, Liu S, et al. Prognostic value of CD44 and its isoforms in advanced cancer: a systematic meta-analysis with trial sequential analysis. Front Oncol. 2019;9:39. doi: 10.3389/fonc.2019.00039.
16. Martens-de Kemp SR, Brink A, Stigter-van Walsum M, Damen JM, Rustenburg F, Wu T, et al. CD98 marks a subpopulation of head and neck squamous cell carcinoma cells with stem cell properties. Stem Cell Res. 2013;10:477–88. doi: 10.1016/j.scr.2013.02.004.
17. Feral CC, Nishiya N, Fenczik CA, Stuhlmann H, Slepak M, Ginsberg MH. CD98hc (SLC3A2) mediates integrin signaling. Proc Natl Acad Sci USA. 2005;102:355–60. doi: 10.1073/pnas.0404852102.
18. Cantor JM, Ginsberg MH. CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci. 2012;125:1373–82. doi: 10.1242/jcs.096040.
19. Digomann D, Kurth I, Tyutyunnykova A, Chen O, Lock S, Gorodetska I, et al. The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity. Clin Cancer Res. 2019;25:3152–63. doi: 10.1158/1078-0432.CCR-18-2951.
20. Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385:307–13. doi: 10.1016/j.bbrc.2009.05.048.
21. Dong Y, Ochsenreither S, Cai C, Kaufmann AM, Albers AE, Qian X. Aldehyde dehydrogenase 1 isoenzyme expression as a marker of cancer stem cells correlates to histopathological features in head and neck cancer: a meta-analysis. PLoS ONE. 2017;12:e0187615. doi: 10.1371/journal.pone.0187615.
22. Sarkar A, Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell. 2013;12:15–30. doi: 10.1016/j.stem.2012.12.007.
23. Simandi Z, Horvath A, Wright LC, Cuaranta-Monroy I, De Luca I, Karolyi K, et al. OCT4 acts as an integrator of pluripotency and signal-induced differentiation. Mol Cell. 2016;63:647–61. doi: 10.1016/j.molcel.2016.06.039. [PubMed] [CrossRef] [Google Scholar]
24. Dong Z, Liu G, Huang B, Sun J, Wu D. Prognostic significance of SOX2 in head and neck cancer: a meta-analysis. Int J Clin Exp Med. 2014;7:5010–20.
25. Ge N, Lin HX, Xiao XS, Guo L, Xu HM, Wang X, et al. Prognostic significance of Oct4 and Sox2 expression in hypopharyngeal squamous cell carcinoma. J Transl Med. 2010;8:94. doi: 10.1186/1479-5876-8-94.
26. Diack, M., & Stewart, D. Development of Cardiovascular Abnormalities Because of Periodontitis in Nepali Population. Dinkum Journal of Medical Innovations, 1(01), 27-30.
27. Rijal, P. Advances of NGS in Understanding of Epilepsy Genetics and Recent Discoveries of Gene in Monogenic Epilepsies. Dinkum Journal of Medical Innovations, 2(05), 170-181.
28. Sharma, M., Aktar, H., & Akter, A. Literature Review on Contrast Sensitivity & Color Vision in Diabetics without Retinopathy. Dinkum Journal of Medical Innovations, 2(07), 249-255.
29. Zahra, D., & Chaudhary, P. R. Women’s Nutritional Variability and Domestic Food Safety in Rural and Semi-Urban Communities. Dinkum Journal of Medical Innovations, 2(05), 182-187.
30. Zulfiqar, N., & Hussain, I. A Comprehensive Review on Embolisation of Vertebral Metastasis Prior to Surgery. Dinkum Journal of Medical Innovations, 2(08), 296-301.
31. Younas, M., & Younas, M. Rehabilitation of Venous Ulcers in Individuals Undergoing the Trendelenburg Technique as Opposed to Trendelenburg with Stab Avulsion. Dinkum Journal of Medical Innovations, 2(03), 111-119.
32. Sana, R., & Rathore, A. Comparing Normal Saline Application with No Application During Minimally Invasive Pneumoperitoneum Cholecystectomy Using Laparoscopic Techniques. Dinkum Journal of Medical Innovations, 2(07), 261-270.
33. Akhter, M. N., Hussain, S. S., Riaz, N., & Zulfiqar, R. Using Technological Diagnostic Tools to Find Early Caries: A Systematic Review. Dinkum Journal of Medical Innovations, 2(07), 271-283.
34. Saeed, R. Academic Honesty in Undergraduate Students in Pakistan. Dinkum Journal of Medical Innovations, 2(03), 91-96.
35. Warda Anam, K. A., & Anas, M. Literature Review on Effectiveness of Mirror Therapy and Conventional Therapy in Patients with Stroke. Dinkum Journal of Medical Innovations, 2(07), 240-248.
36. Bayo P, Jou A, Stenzinger A, Shao C, Gross M, Jensen A, et al. Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma. Mol Oncol. 2015;9:1704–19. doi: 10.1016/j.molonc.2015.05.006.
37. Keysar SB, Le PN, Miller B, Jackson BC, Eagles JR, Nieto C, et al. Regulation of Head and Neck Squamous Cancer Stem Cells by PI3K and SOX2. J Natl Cancer Inst. 2017. 10.1093/jnci/djw189.
38. Koo BS, Lee SH, Kim JM, Huang S, Kim SH, Rho YS, et al. Oct4 is a critical regulator of stemness in head and neck squamous carcinoma cells. Oncogene. 2015;34:2317–24. doi: 10.1038/onc.2014.174.
39. Bhosale PG, Pandey M, Desai RS, Patil A, Kane S, Prabhash K, et al. Low prevalence of transcriptionally active human papilloma virus in Indian patients with HNSCC and leukoplakia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122:609–18. doi: 10.1016/j.oooo.2016.06.006.
40. Mukaka MM. Statistics corner: A guide to appropriate use of correlation coefficient in medical research. Malawi Med J. 2012;24:69–71.
41. Clark GM. Prognostic factors versus predictive factors: examples from a clinical trial of erlotinib. Mol Oncol. 2008;1:406–12. doi: 10.1016/j.molonc.2007.12.001.
42. Polley MY, Freidlin B, Korn EL, Conley BA, Abrams JS, McShane LM. Statistical and practical considerations for clinical evaluation of predictive biomarkers. J Natl Cancer Inst. 2013;105:1677–83. doi: 10.1093/jnci/djt282.
43. Sneath RJ, Mangham DC. The normal structure and function of CD44 and its role in neoplasia. Mol Pathol. 1998;51:191–200. doi: 10.1136/mp.51.4.191.
44. Toyoda M, Kaira K, Shino M, Sakakura K, Takahashi K, Takayasu Y, et al. CD98 as a novel prognostic indicator for patients with stage III/IV hypopharyngeal squamous cell carcinoma. Head Neck. 2015;37:1569–74. doi: 10.1002/hed.23797.

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