Prognostic significance of SOX2 and GPC3 in Ameloblastoma and its malignant counterpart (Ameloblastic Carcinoma)

Abstract

Background: Ameloblastoma is a common benign aggressive odontogenic tumor with a tendency for high recurrence rate. Ameloblastic Carcinoma is the malignant counterpart of Ameloblastoma. However, they are usually difficult to be distinguished from one another. Therefore, using Immunohistochemical markers might be beneficial for diagnosing them accurately.
Objective: Evaluation of SOX2 and GPC3 expressions as well as evaluating their roles in the tumorigenesis and the biological behavior of Ameloblastoma and Ameloblastic Carcinoma.
Methods: Tissue samples are composed of 34 archived histopathologically confirmed cases of (19 Conventional Ameloblastomas, and 15 Ameloblatic Carcinomas). Sections were subjected to Immunohistochemical staining according to a standard protocol by applying antibodies to SOX2, and GPC3.
Results: SOX2 and GPC3 expressions in recurrent Ameloblastoma were significantly higher than non- recurrent cases. Ameloblastic Carcinoma showed the highest immune-reactivity to SOX2 and GPC3 compared to the Conventional Ameloblastoma. Desmoplastic Ameloblastoma showed the highest scores of SOX2 and GPC3 compared to the other subtypes.
Conclusions: SOX2 and GPC3 can be used as a panel for diagnosing the aggressive and the malignant odontogenic tumors accurately. Desmoplastic Ameloblastoma behaves more aggressively than other Conventional Ameloblastoma subtypes.

Keywords

Ameloblastoma / Ameloblastic Carcinoma / Immunohistochemistry / SOX2 / GPC3

References

[1] Bilodeau EA, Collins BM. Odontogenic Cysts and Neoplasms. Sur- gical pathology clinics. 2017; 10(1): 177-222. PMid: 28153133. https://doi.org/10.1016/j.path.2016.10.006

[2] Effiom OA, Ogundana OM, Akinshipo AO, et al. Ameloblastoma: current etiopathological concepts and management. Oral Diseases. 2018; 24(3): 307-316. PMid: 28142213. https://doi.org/10.1111/odi.12646

[3] Braimah R, Uguru C, Ndukwe K. Ameloblastic carcinoma of the jaws: Review of the literature. Journal of Dental and Allied Sciences. 2017; 6(2): 70. https://doi.org/10.4103/jdas.jdas_4_17

[4] Moro A, Foresta E, Gasparini G, et al. Ameloblastic carcinoma of the maxilla: A case report and an updated review of the litera- ture. Oncology Letters. 2016; 12(6): 4339-4350. PMid: 28105148. https://doi.org/10.3892/ol.2016.5272

[5] Nagi R, Sahu S, Rakesh N. Molecular and genetic aspects in the etiopathogenesis of ameloblastoma: An update. Journal of Oral and Maxillofacial Pathology. 2016; 20(3): 497. PMid: 27721617. https://doi.org/10.4103/0973-029X.190954

[6] Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. Journal of Biomedical Science. 2018; 25(1): 1-18. PMid: 29506506. https://doi.org/10.1186/s12929-018-0426-4

[7] Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduction and Targeted Therapy. 2020; 5(1): 1-35. PMid: 32296030. https://doi.org/10.1038/s41392-020-0110-5

[8] Song WS, Yang YP, Huang CS, et al. Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133- positive glioblastoma stem cells. Journal of the Chinese Medical Association. 2016; 79(10): 538-545. PMid: 27530866. https://doi.org/10.1016/j.jcma.2016.03.010

[9] Ren ZH, Zhang CP, Ji T. Expression of SOX2 in oral squamous cell carcinoma and the association with lymph node metastasis (Re- view). Oncology Letters. 2016; 11(3): 1973-1979. PMid: 26998109. https://doi.org/10.3892/ol.2016.4207

[10] Zhang S, Xiong X, Sun Y. Functional characterization of SOX2 as an anticancer target. Signal Transduction and Targeted Therapy. 2020; 5(1): 1-17. PMid: 32728033. https://doi.org/10.1038/s41392-020-00242-3

[11] Zhang M, Zhang X, Luo J, et al. Investigate the Odontogenic Differ- entiation and Dentin-Pulp Tissue Regeneration Potential of Neural Crest Cells. Frontiers in Bioengineering and Biotechnology. 2020; 8: 475. PMid: 32582651. https://doi.org/10.3389/fbioe.2020.00475

[12] Chaudhary S, Islam Z, Mishra V, et al. Sox2: A Regulatory Factor in Tumorigenesis and Metastasis. Current Protein & Peptide Science. 2019; 20(6): 495-504. PMid: 30907312. https://doi.org/10.2174/1389203720666190325102255

[13] Novak D, Hüser L, Elton JJ, et al. SOX2 in development and can- cer biology. Seminars in Cancer Biology. 2020; 67: 74-82. PMid: 31412296. https://doi.org/10.1016/j.semcancer.2019.08.007

[14] Sobhy AM, Fouad HMA, Riad SM, et al. EVALUATION OF SOX2 AS A POTENTIAL STEM CELL MARKER IN BENIGN AND MA-LIGNANT ODONTOGENIC TUMORS. Alexandria Dental Journal. 2019; 44(3): 99-105. https://doi.org/10.21608/adjalexu.2019.63566

[15] Meng P, Zhang YF, Zhang W, et al. Identification of the atypical cadherin FAT 1 as a novel glypican-3 interacting protein in liver cancer cells. Scientific Reports. 2021; 11(1): 40. PMid: 33420124. https://doi.org/10.1038/s41598-020-79524-3

[16] Kolluri A, Ho M. The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer. Frontiers in Oncology. 2019; 9. PMid: 31428581. https://doi.org/10.3389/fonc.2019.00708

[17] Montalbano M, Rastellini C, McGuire JT, et al. Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes iso- lated from patients with hepatocellular carcinoma. Cellular Oncology. 2018; 41(2): 169-184. PMid: 29204978 https://doi.org/10.1007/s13402-017-0364-2

[18] Moek KL, Fehrmann RSN, van der Vegt B, et al. Glypican 3 Overex- pression across a Broad Spectrum of Tumor Types Discovered with Functional Genomic mRNA Profiling of a Large Cancer Database. American Journal of Pathology. 2018; 188(9): 1973-1981. PMid: 29935166. https://doi.org/10.1016/j.ajpath.2018.05.014

[19] Soluk-Tekkes¸in M, Wright JM. The world health organization clas- sification of odontogenic lesions: A summary of the changes of the 2017 (4th) edition. Turk Patoloji Dergisi. 2018; 34(1): 1-18. https://doi.org/10.5146/tjpath.2017.0141028984343

[20] Khan W, Augustine D, Rao R, et al. Stem Cell Markers SOX-2 and OCT-4 Enable to Resolve the Diagnostic Dilemma be- tween Ameloblastic Carcinoma and Aggressive Solid Multicystic Ameloblastoma. Advanced Biomedical Research. 2018; 7(1): 149. PMid: 30596059. https://doi.org/10.4103/abr.abr_135_18

[21] Mendes RB, Dias RB, Figueiredo AL, et al. Glypican-3 distinguishes aggressive from non-aggressive odontogenic tumors: a preliminary study. Journal of Oral Pathology and Medicine. 2017; 46(4): 297-300. PMid: 27647326. https://doi.org/10.1111/jop.12501

[22] Población U, Rayssa B, Cavalcante M, et al. Epithelial Odontogenic Tumors: Analysis of 156 Cases in a Brazilian Population Tumores Odontogénicos Epiteliales: Análisis de 156 Casos En. 2016; 10.https://doi.org/10.4067/S0718-381X2016000100018

[23] Pandey S, Bhutia O, Roychoudhury A, et al. Literature review of 86 cases of mandibular ameloblastic carcinoma. National Jour- nal of Maxillofacial Surgery. 2018; 9(1): 2. PMid: 29937652. https://doi.org/10.4103/njms.NJMS_33_16

[24] Hendra FN, Van Cann EM, Helder MN, et al. Global incidence and profile of ameloblastoma: A systematic review and meta- analysis. Oral Diseases. 2020; 26(1): 12-21. PMid: 30614154. https://doi.org/10.1111/odi.13031

[25] Cadavid AMH, Araujo JP, Coutinho-Camillo CM, et al. Ameloblas- tomas: current aspects of the new WHO classification in an analysis of 136 cases. Surgical and Experimental Pathology. 2019; 2(1): 17. https://doi.org/10.1186/s42047-019-0041-z

[26] Deng L, Wang R, Yang M, et al. Ameloblastic carcinoma: Clinico- pathological analysis of 18 cases and a systematic review. Head and Neck. 2019; 41(12): 4191-4198. PMid: 31444935. https://doi.org/10.1002/hed.25926

[27] Martínez-Martínez M, Mosqueda-Taylor A, Carlos-Bregni R, et al. Comparative histological and immunohistochemical study of ameloblastomas and ameloblastic carcinomas. Medicina Oral, Patolo- gia Oral y Cirugia Bucal. 2017; 22(3): e324-e332. PMid: 28390135. https://doi.org/10.4317/medoral.21901

[28] Prasetyaningtyas N, Jatiatmaja NA, Radithia D, et al. The Response of the Tongue Epithelial on Cigarette Smoke Exposure as a Risk Factor for Oral Cancer Development. European Journal of Dentistry. 2020; 15(02): 320-324. PMid: 33285573. https://doi.org/10.1055/s-0040-1721312

[29] Kwong A. Is Smoking a Risk Factor of Breast Cancer? Novel Ap- proaches in Cancer Study. 2019; 2(3). https://doi.org/10.31031/NACS.2019.02.000540

[30] Intapa C. Analysis of prevalence and clinical features of ameloblas- toma and its histopathological subtypes in Southeast Myanmar and lower Northern Thailand populations: A 13-year retrospective study. Journal of Clinical and Diagnostic Research. 2017; 11(1): ZC102-ZC106. https://doi.org/10.7860/JCDR/2016/23629.9295

[31] Noureldin M, Ragab H. Latest update of odontogenic tumors in Alexandria University, Egypt: A 5-year retrospective study using WHO 2017 classification. Egyptian Dental Journal. 2019; 65(3): 2115-2124. https://doi.org/10.21608/edj.2019.72229

[32] Rozhok A, De Gregori J. A generalized theory of age-dependent carcinogenesis. eLife. 2019; 8: 1-23. PMid: 31034356. https://doi.org/10.7554/eLife.39950

[33] Mahmoud SAM, Amer HW, Mohamed SI. Primary ameloblas- tic carcinoma: Literature review with case series. Polish Journal of Pathology. 2018; 69(3): 243-253. PMid: 30509051. https://doi.org/10.5114/pjp.2018.79544

[34] Nalabolu GRK, Mohiddin A, Hiremath SKS, et al. Epidemiological study of odontogenic tumours: An institutional experience. Journal of Infection and Public Health. 2017; 10(3): 324-330. PMid: 27425795. https://doi.org/10.1016/j.jiph.2016.05.014

[35] Hasheminasab M, Karimi A, Parizi MK, et al. Metastasis of a prostate adenocarcinoma to mandible: A case report and review of literature. Clinical Case Reports. 2020; 8(10): 2063-2066. PMid: 33088553. https://doi.org/10.1002/ccr3.3065

[36] Teleanu RI, Chircov C, Grumezescu AM, et al. Tumor Angiogene- sis and Anti-Angiogenic Strategies for Cancer Treatment. Journal of Clinical Medicine. 2019; 9(1): 84. PMid: 31905724. https://doi.org/10.3390/jcm9010084

[37] El-Naggar AK, Chan JKC, Takata T, et al. The fourth edition of the head and neck World Health Organization blue book: editors’ perspectives. Human Pathology. 2017; 66: 10-12. PMid: 28583885. https://doi.org/10.1016/j.humpath.2017.05.014

[38] Patsa S, Jadav R, Halder G, et al. Demographic and histopathological variation of ameloblastoma: A hospital-based study. Journal of Oral and Maxillofacial Pathology. 2016; 20(2): 230. PMid: 27601814. https://doi.org/10.4103/0973-029X.185937

[39] Smitha T, Priya NS, Hema KN, et al. Ameloblastic carcinoma: A rare case with diagnostic dilemma Case Report. Published online 2019. PMid:30967729. https://doi.org/10.4103/jomfp.JOMFP_318_18

[40] Flucke U. Malignant Neoplasms of the Gnathic Bones. In: Head and Neck Pathology: A Volume in the Series: Foundations in Diagnostic Pathology. Elsevier; 2019. 417-432 p. https://doi.org/10.1016/B978-0-323-47916-5.00016-9

[41] Yiannis C, Mascolo M, Mignogna MD, et al. Expression profile of stemness markers cd138, nestin and alpha-sma in ameloblastic tu- mours. International Journal of Environmental Research and Public Health. 2021; 18(8): 18. PMid: 33917771. https://doi.org/10.3390/ijerph18083899

[42] Hagey DW, Klum S, Kurtsdotter I, et al. SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs. PLoS genetics. 2018; 14(2): e1007224. PMid: 29432416. https://doi.org/10.1371/journal.pgen.1007224

[43] Zhang S, Xiong X, Sun Y. Functional characterization of SOX2 as an anticancer target. Signal Transduction and Targeted Therapy. 2020; 5(1): 135. PMid: 32728033. https://doi.org/10.1038/s41392-020-00242-3

[44] Lei Y, Jaradat JM, Owosho A, et al. Evaluation of SOX2 as a poten- tial marker for ameloblastic carcinoma. Oral surgery, oral medicine, oral pathology and oral radiology. 2014; 117(5): 608-616.e1. PMid: 24603057. https://doi.org/10.1016/j.oooo.2014.01.017

[45] Silva BS de F, Silva LR, de Lima KL, et al. Sox2 and bcl-2 ex- pressions in odontogenic keratocyst and ameloblastoma. Medicina Oral Patologia Oral y Cirugia Bucal. 2020; 25(2): e283-e290. PMid: 31967981. https://doi.org/10.4317/medoral.23348

[46] Pagella P, Catón J, Meisel CT, et al. Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Con- nections with Trigeminal Neurons. Cells. 2020; 9(3): 644. PMid: 32155948. https://doi.org/10.3390/cells9030644

[47] Banerjee A, Kamath V, Sundaram L, et al. OCT4 and SOX2 are reli- able markers in detecting stem cells in odontogenic lesions. Journal of Orofacial Sciences. 2016; 8(1): 16. https://doi.org/10.4103/0975-8844.181920

[48] Gültekin SE, Aziz R, Heydt C, et al. The landscape of genetic al- terations in ameloblastomas relates to clinical features. Virchows Archiv. 2018; 472(5): 807-814. PMid: 29388014. https://doi.org/10.1007/s00428-018-2305-5

[49] Chang DJYF, Tseng DC-H, Lu DPH, et al. Increased sox2-positive cells in braf(v600e) mutated ameloblastomas. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2019; 128(1): e49- e50. https://doi.org/10.1016/j.oooo.2019.02.105

[50] Van Schaijik B, Davis PF, Wickremesekera AC, et al. Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: A review. Journal of Clinical Pathology. 2018; 71(1): 88-91. PMid: 29180509. https://doi.org/10.1136/jclinpath-2017-204815

[51] Vijayakumar G, Narwal A, Kamboj M, et al. Association of SOX2, OCT4 and WNT5A Expression in Oral Epithelial Dysplasia and Oral Squamous Cell Carcinoma: An Immunohistochemical Study. Head and Neck Pathology. Published online January 4, 2020; 1-9. PMid: 31902091. https://doi.org/10.1007/s12105-019-01114-1

[52] Sanjai K, Sangappa SB, Shivalingaiah D, et al. Expression of SOX2 and EGFR in Ameloblastoma, Odontoameloblastoma and Ameloblastic Carcinoma. Journal of Clinical and Diagnostic Re- search. 2018; 12(7): 8-12. https://doi.org/10.7860/JCDR/2018/34269.11800

[53] Li N, Spetz MR, Ho M. The Role of Glypicans in Cancer Progression and Therapy. Journal of Histochemistry and Cytochemistry. 2020; 68(12): 841-862. PMid: 32623934. https://doi.org/10.1369/0022155420933709

[54] Andisheh-Tadbir A, Ashraf MJ, Gudarzi A, et al. Evaluation of Glypican-3 expression in benign and malignant salivary gland tu- mors. Journal of Oral Biology and Craniofacial Research. 2019; 9(1): 63-66. PMid: 30294537. https://doi.org/10.1016/j.jobcr.2018.09.002

[55] Azadeh AT, Elnaz K, Razieh Z. Glypican-3 Expression in Dentiger- ous Cyst, Odontogenic Keratocyst andRadicular Cyst. 2018; 14(3): 305-312.

[56] Gómez-Herrera Z, Molina-Frechero N, Damián-Matsumura P, et al. Proteoglycans as potential biomarkers in odontogenic tumors. Journal of Oral and Maxillofacial Pathology. 2018; 22(1): 98-102. https://doi.org/10.4103/jomfp.JOMFP_151_17

[57] Miura M, Fujinami N, Shimizu Y, et al. Usefulness of plasma full- length glypican-3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery. Oncology Letters. Published online February 5, 2020. https://doi.org/10.3892/ol.2020.11371

[58] Guo M, Zhang H, Zheng J, et al. Glypican-3: A new target for diag- nosis and treatment of hepatocellular carcinoma. Journal of Cancer. 2020; 11(8): 2008-2021. PMid: 32127929. https://doi.org/10.7150/jca.39972

[59] Guo Z, Wang J, Li L, et al. Value of miR-1271 and glypican-3 in evaluating the prognosis of patients with hepatocellular carci- noma after transcatheter arterial chemoembolization. World Jour- nal of Clinical Cases. 2020; 8(16): 3493-3502. PMid: 32913856. https://doi.org/10.12998/wjcc.v8.i16.3493

[60] Andisheh-Tadbir A, Goharian AS, Ranjbar MA. Glypican-3 Expres- sion in Patients with Oral Squamous Cell Carcinoma. Journal of dentistry (Shiraz, Iran). 2020; 21(2): 141-146. https://doi.org/10.30476/DENTJODS.2019.84541.108932582830

[61] Wu Q, Pi L, Le Trinh T, et al. A Novel Vaccine Targeting Glypican-3 as a Treatment for Hepatocellular Carcinoma. Molecular Therapy. 2017; 25(10): 2299-2308. PMid: 28865999. https://doi.org/10.1016/j.ymthe.2017.08.005

[62] Montalbano M, Georgiadis J, Masterson AL, et al. Biology and function of glypican-3 as a candidate for early cancerous trans- formation of hepatocytes in hepatocellular carcinoma (Review). Oncology Reports. 2017; 37(3): 1291-1300. PMid: 28098909. https://doi.org/10.3892/or.2017.5387

[63] Ranjan V, Chakrabarty S, Arora P, et al. Desmoplastic Ameloblas- toma of the Mandible: A Rare Case Report. Journal of Indian Academy of Oral Medicine and Radiology. 2019; 31(1): 36-39. https://doi.org/10.4103/jiaomr.jiaomr