PROGNOSTIC SIGNIFICANCE OF THE EPITHELIAL-MESENCHYMAL TRANSITION MARKERS AND MORPHOLOGICAL CHARACTERISTICS OF HEAD AND NECK SQUAMOUS CELL CARCINOMAS IN THE DEVELOPMENT OF LYMPHOGENOUS METASTASES

Previous studies of the morphological features of head and neck squamous cell carcinomas revealed a significant association of the presence of discrete tumor cells and a low level of inflammatory infiltrate with lymphogenous metastasis. The aim of the study was to evaluate the quantity of tumor cells undergoing epithelial-mesenchymal transition (EMt) in tumor cell structures of different degrees of differentiation and to assess the prognostic model of lymphogenous metastasis based on the studied parameters. Material and methods. the main clinical tumor characteristics and morphological patterns of the tumor were assessed in 92 patients. the expressions of snail and Vimentin proteins were studied in 16 patients using confocal microscopy. Results. the expression of the EMt marker in cell structures of different degrees of differentiation was evaluated; the maximum number of snail- and Vimentin-positive cells (20 % each) was observed in discrete tumor cells. No difference in the proportion of cells undergoing epithelial-mesenchymal transition between patients with and without lymphogenous metastasis was found. thus, the prognostic model of lymphogenous metastasis included: the presence of single tumor cells and low level of inflammation. the sensitivity of the model was 54.5 %, and specificity was 89 %.

epithelial-mesenchymal transition, intratumoral heterogeneity, inflammation, lymphogenous metastasis

1. Amin M.B., Greene F.L., Edge S.B., Compton C.C., Gershenwald J.E., Brookland R.K., Meyer L., Gress D.M., Byrd D.R., Winchester D.P. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more «personalized» approach to cancer staging. CA Cancer J Clin. 2017 Mar; 67(2): 93–99. doi: 10.3322/caac.21388.

2. Philip J., James R. Maxillary squamous cell carcinoma: An 11-year retrospective study of one regional cancer centre. Int J Oral Maxillofac Surg. 2014 Oct; 43(10): 1195–8. doi: 10.1016/j.ijom.2014.05.020.

3. Montes D.M., Carlson E.R., Fernandes R., Ghali G.E., Lubek J., Ord R., Bell B., Dierks E., Schmidt B.L. Oral maxillary squamous carcinoma: An indication for neck dissection in the clinically negative neck. Head Neck. 2011 Nov; 33(11): 1581–5. doi: 10.1002/hed.21631.

4. Yang X., Song X., Chu W., Li L., Ma L., Wu Y. Clinicopathological characteristics and outcome predictors in squamous cell carcinoma of the maxillary gingiva and hard palate. J Oral Maxillofac Surg. 2015 Jul; 73(7): 1429–36. doi: 10.1016/j.joms.2014.12.034.

5. Boxberg M., Jesinghaus M., Dorfner C., Mogler C., Drecoll E., Warth A., Steiger K., Bollwein C., Meyer P., Wolff K.D., Kolk A., Weichert W. Tumour budding activity and cell nest size determine patient outcome in oral squamous cell carcinoma: proposal for an adjusted grading system. Histopathology. 2017 Jun; 70(7): 1125–1137. doi: 10.1111/his.13173.

6. Savenkova О.V., Zavyalova M.V., Bychkov V.A., Choinzonov Е.L., Perelmuter V.M. Relationship between expression of matrix metalloproteinases and morphological heterogeneity, tumor differentiation and lymphogenous metastasis of squamous cell laryngeal carcinoma. Siberian Journal of Oncology. 2015; 1(1): 51–58. (in Russian).

7. deRuiter E.J., Ooft M.L., Devriese L.A., Willems S.M. The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oncoimmunology. 2017 Aug 9; 6(11): e1356148. doi: 10.1080/2162402X.2017.1356148.

8. Bychkov V.A., Bondar L.N., Choynzonov E.L., Perelmuter V.M. Head and neck squamous cell carcinoma depending on the morphological characteristics of the primary tumor. Siberian Journal of Oncology. 2017; 16(2): 20–26. (in Russian). doi: 10.21294/1814-4861-2017-16-2-20-26.

9. Salgado R., Denkert C., Demaria S., Sirtaine N., Klauschen F., Pruneri G., Wienert S., Van den Eynden G., Baehner F.L., Penault-Llorca F., Perez E.A., Thompson E.A., Symmans W.F., Richardson A.L., Brock J., Criscitiello C., Bailey H., Ignatiadis M., Floris G., Sparano J., Kos Z., Nielsen T., Rimm D.L., Allison K.H., Reis-Filho J.S., Loibl S., Sotiriou C., Viale G., Badve S., Adams S., Willard-Gallo K., Loi S. International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015 Feb; 26(2): 259–71. doi: 10.1093/annonc/mdu450.

10. Lyons J.G., Lobo E., Martorana A.M., Myerscough M.R. Clonal diversity in carcinomas: its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions. Clin Exp Metastasis. 2008; 25(6): 665–77. doi: 10.1007/s10585-007-9134-2.

11. Neelakantan D., Drasin D.J., Ford H.L. Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis. Cell Adh Migr. 2015; 9(4): 265–76. doi: 10.4161/19336918.2014.972761.

12. Cercelaru L., Stepan A.E., Mărgăritescu C., Osman A., Popa I.C., Florescu M.M., Simionescu C.E., Mărgăritescu O.C. E-cadherin, β-catenin and Snail immunoexpression in laryngeal squamous cell carcinoma. Rom J MorpholEmbryol. 2017; 58(3): 761–6.

13. Göppel J., Möckelmann N., Münscher A., Sauter G., Schumacher U. Expression of Epithelial-Mesenchymal Transition Regulating Transcription Factors in Head and Neck Squamous Cell Carcinomas. Anticancer Res. 2017 Oct; 37(10): 5435–5440. doi: 10.21873/anticanres.11971.

14. Duray A., Demoulin S., Hubert P., Delvenne P., Saussez S. Immune suppression in head and neck cancers: a review. Clin Dev Immunol. 2010; 2010: 701657. doi: 10.1155/2010/701657.

15. Czystowska M., Gooding W., Szczepanski M.J., Lopez-Abaitero A., Ferris R.L., Johnson J.T., Whiteside T.L. The immune signature of CD8(+) CCR7(+) T cells in the peripheral circulation associates with disease recurrence in patients with HNSCC. Clin Cancer Res. 2013 Feb 15; 19(4): 889–99. doi: 10.1158/1078-0432.CCR-12-2191.

16. dos Santos M., Mercante A.M., Louro I.D., Gonçalves A.J., deCarvalho M.B., daSilva E.H., daSilva A.M. HIF1-alpha expression predicts survival of patients with squamous cell carcinoma of the oral cavity. Clin Cancer Res. 2013 Feb 15; 19(4): 889–99. doi: 10.1158/1078-0432.CCR-12-2191.

17. Ames B.N., Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002 Sep; 2(9): 694–704. doi: 10.1038/nrc886.

18. Bird R.P. The Emerging Role of Vitamin B6 in Inflammation and Carcinogenesis. Adv Food Nutr Res. 2018; 83: 151–194. doi: 10.1016/bs.afnr.2017.11.004.

19. Wei S.C., Yang J. Forcing through Tumor Metastasis: The Interplay between Tissue Rigidity and Epithelial-Mesenchymal Transition. Trends Cell Biol. 2016; 26(2): 111–20. doi: 10.1016/j.tcb.2015.09.009.

20. Mandal R., Şenbabaoğlu Y., Desrichard A., Havel J.J., Dalin M.G., Riaz N., Lee K.W., Ganly I., Hakimi A.A., Chan T.A., Morris L.G. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016 Oct 20; 1(17): e89829. doi: 10.1172/jci.insight.89829.

21. Fridlender Z.G., Sun J., Kim S., Kapoor V., Cheng G., Ling L., Worthen G.S., Albelda S.M. Polarization of tumor-associated neutrophil phenotype by TGF-beta: «N1» versus «N2» TAN. Cancer Cell. 2009 Sep 8; 16(3): 183–94. doi: 10.1016/j.ccr.2009.06.017.

22. Kumar A.T., Knops A., Swendseid B., Martinez-Outschoom U., Harshyne L., Philp N., Rodeck U., Luginbuhl A., Cognetti D., Johnson J., Curry J. Prognostic Significance of Tumor-Associated Macrophage Content in Head and Neck Squamous Cell Carcinoma: A Meta- Analysis. Front Oncol. 2019 Jul 23; 9: 656. doi: 10.3389/fonc.2019.00656.

23. Kumar D., New J., Vishwakarma V., Joshi R., Enders J., Lin F., Dasari S., Gutierrez W.R., Leef G., Ponnurangam S., Chavan H., Ganaden L., Thornton M.M., Dai H., Tawfik O., Straub J., Shnayder Y., Kakarala K., Tsue T.T.,Girod D.A., Van Houten B., Anant S., Krishnamurthy P., Thomas S.M. Cancer-Associated Fibroblasts Drive Glycolysis in a Targetable Signaling Loop Implicated in Head and Neck Squamous Cell Carcinoma Progression. Cancer Res. 2018; 78(14): 3769–82. doi: 10.1158/0008-5472.CAN-17-1076.

24. Stakheyeva M., Riabov V., Mitrofanova I., Litviakov N., Choynzonov E., Cherdyntseva N., Kzhyshkowska J. Role of the Immune Component of Tumor Microenvironment in the Efficiency of Cancer Treatment: Perspectives for the Personalized Therapy. Curr Pharm Des. 2017; 23(32): 4807–4826. doi: 10.2174/1381612823666170714161703.