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Erschienen in: Virchows Archiv 2/2018

12.07.2017 | Original Article

The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity

verfasst von: Nina Zidar, Emanuela Boštjančič, Marija Malgaj, Nina Gale, Tadej Dovšak, Vojko Didanovič

Erschienen in: Virchows Archiv | Ausgabe 2/2018

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Abstract

Epithelial-mesenchymal transition (EMT) has emerged as a possible mechanism of cancer metastasizing, but strong evidence for EMT involvement in human cancer is lacking. Our aim was to compare oral spindle cell carcinoma (SpCC) as an example of EMT with oral conventional squamous cell carcinoma (SCC) with and without nodal metastases to test the hypothesis that EMT contributes to metastasizing in oral SCC. Thirty cases of oral SCC with and without nodal metastasis and 15 cases of SpCC were included. Epithelial (cytokeratin, E-cadherin), mesenchymal (vimentin, N-cadherin), and stem cell markers (ALDH-1, CD44, Nanog, Sox-2) and transcription repressors (Snail, Slug, Twist) were analyzed immunohistochemically. We also analyzed the expression of microRNAs miR-141, miR-200 family, miR-205, and miR-429. SpCC exhibited loss of epithelial markers and expression of mesenchymal markers or coexpression of both up-regulation of transcription repressors and down-regulation of the investigated microRNAs. SCC showed only occasional focal expression of mesenchymal markers at the invasive front. No other differences were observed between SCC with and without nodal metastases except for a higher expression of ALDH-1 in SCC with metastases. Our results suggest that SpCC is an example of true EMT but do not support the hypothesis that EMT is involved in metastasizing of conventional SCC. Regarding oral SCC progression and metastasizing, we have been facing a shift from the initial enthusiasm for the EMT concept towards a more critical approach with “EMT-like” and “partial EMT” concepts. The real question, though, is, is there no EMT at all?
Literatur
1.
Zurück zum Zitat Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890CrossRefPubMed Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890CrossRefPubMed
3.
Zurück zum Zitat De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G et al (2008) Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol 130:481–494CrossRefPubMedPubMedCentral De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh G et al (2008) Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol 130:481–494CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746CrossRefPubMed Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746CrossRefPubMed
6.
Zurück zum Zitat Smith A, Teknos TN, Pan Q (2013) Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol 49:287–292CrossRefPubMed Smith A, Teknos TN, Pan Q (2013) Epithelial to mesenchymal transition in head and neck squamous cell carcinoma. Oral Oncol 49:287–292CrossRefPubMed
7.
Zurück zum Zitat Yilmaz M, Christofori G (2010) Mechanisms of motility in metastasizing cells. Mol Cancer Res 8:629–642CrossRefPubMed Yilmaz M, Christofori G (2010) Mechanisms of motility in metastasizing cells. Mol Cancer Res 8:629–642CrossRefPubMed
8.
Zurück zum Zitat Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736CrossRefPubMedPubMedCentral Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Ocana OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22:709–724CrossRefPubMed Ocana OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22:709–724CrossRefPubMed
10.
Zurück zum Zitat Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476CrossRefPubMedPubMedCentral Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530CrossRefPubMedPubMedCentral Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Chui MH (2013) Insights into cancer metastasis from a clinicopathologic perspective: epithelial-mesenchymal transition is not a necessary step. Int J Cancer 132:1487–1495CrossRefPubMed Chui MH (2013) Insights into cancer metastasis from a clinicopathologic perspective: epithelial-mesenchymal transition is not a necessary step. Int J Cancer 132:1487–1495CrossRefPubMed
13.
Zurück zum Zitat Tarin D (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000CrossRefPubMed Tarin D (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000CrossRefPubMed
14.
Zurück zum Zitat Tarin D (2012) Inappropriate gene expression in human cancer and its far-reaching biological and clinical significance. Cancer Metastasis Rev 31:21–39CrossRefPubMed Tarin D (2012) Inappropriate gene expression in human cancer and its far-reaching biological and clinical significance. Cancer Metastasis Rev 31:21–39CrossRefPubMed
15.
Zurück zum Zitat Tarin D (2013) The role of the host stroma in cancer and its therapeutic significance. Cancer Met Rev 32:553–566CrossRef Tarin D (2013) The role of the host stroma in cancer and its therapeutic significance. Cancer Met Rev 32:553–566CrossRef
16.
Zurück zum Zitat Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S, Farah CS (2012) Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and vimentin-in oral squamous cell carcinogenesis and transformation. Oral Oncol 48:997–1006CrossRefPubMed Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S, Farah CS (2012) Epithelial to mesenchymal transition (EMT) biomarkers—E-cadherin, beta-catenin, APC and vimentin-in oral squamous cell carcinogenesis and transformation. Oral Oncol 48:997–1006CrossRefPubMed
17.
Zurück zum Zitat Pectasides E, Rampias T, Sasaki C, Perisanidis C, Kouloulias V, Burtness B et al (2014) Markers of epithelial to mesenchymal transition in association with survival in head and neck squamous cell carcinoma (HNSCC). PLoS One 9:e94273CrossRefPubMedPubMedCentral Pectasides E, Rampias T, Sasaki C, Perisanidis C, Kouloulias V, Burtness B et al (2014) Markers of epithelial to mesenchymal transition in association with survival in head and neck squamous cell carcinoma (HNSCC). PLoS One 9:e94273CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Zhang S, Zhou X, Wang B, Zhang K, Liu S, Yue K et al (2014) Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol 50:809–817CrossRefPubMed Zhang S, Zhou X, Wang B, Zhang K, Liu S, Yue K et al (2014) Loss of VHL expression contributes to epithelial-mesenchymal transition in oral squamous cell carcinoma. Oral Oncol 50:809–817CrossRefPubMed
19.
Zurück zum Zitat da Silva SD, Alaoui-Jamali MA, Soares FA, Carraro DM, Brentani HP, Hier M et al (2015) TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. Cancer 120:352–362CrossRef da Silva SD, Alaoui-Jamali MA, Soares FA, Carraro DM, Brentani HP, Hier M et al (2015) TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. Cancer 120:352–362CrossRef
20.
Zurück zum Zitat da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA et al (2015) Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clin Exp Metastasis 32:55–63CrossRefPubMed da Silva SD, Morand GB, Alobaid FA, Hier MP, Mlynarek AM, Alaoui-Jamali MA et al (2015) Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma. Clin Exp Metastasis 32:55–63CrossRefPubMed
21.
Zurück zum Zitat Angadi PV, Patil PV, Angadi V, Mane D, Shekar S, Hallikerimath S et al (2016) Immunoexpression of epithelial mesenchymal transition proteins E-cadherin, β-catenin, and N-cadherin in oral squamous cell carcinoma. Int J Surg Pathol 24:696–703CrossRefPubMed Angadi PV, Patil PV, Angadi V, Mane D, Shekar S, Hallikerimath S et al (2016) Immunoexpression of epithelial mesenchymal transition proteins E-cadherin, β-catenin, and N-cadherin in oral squamous cell carcinoma. Int J Surg Pathol 24:696–703CrossRefPubMed
22.
Zurück zum Zitat Kimura I, Kitahara H, Ooi K, Kato K, Noguchi N, Yoshizawa K et al (2016) Loss of epidermal growth factor receptor expression in oral squamous cell carcinoma is associated with invasiveness and epithelial-mesenchymal transition. Oncol Lett 11:201–207CrossRefPubMed Kimura I, Kitahara H, Ooi K, Kato K, Noguchi N, Yoshizawa K et al (2016) Loss of epidermal growth factor receptor expression in oral squamous cell carcinoma is associated with invasiveness and epithelial-mesenchymal transition. Oncol Lett 11:201–207CrossRefPubMed
23.
Zurück zum Zitat Zidar N, Gale N, Kojc N, Volavšek M, Cardesa A, Alos L et al (2008) Cadherin-catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head and neck. Virchows Arch 453:267–274CrossRefPubMed Zidar N, Gale N, Kojc N, Volavšek M, Cardesa A, Alos L et al (2008) Cadherin-catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head and neck. Virchows Arch 453:267–274CrossRefPubMed
24.
Zurück zum Zitat Kojc N, Zidar N, Gale N, Poljak M, Fujs Komlos K, Cardesa A et al (2009) Transcription factors Snail, Slug, Twist, and SIP1 in spindle cell carcinoma of the head and neck. Virchows Arch 454:549–555CrossRefPubMed Kojc N, Zidar N, Gale N, Poljak M, Fujs Komlos K, Cardesa A et al (2009) Transcription factors Snail, Slug, Twist, and SIP1 in spindle cell carcinoma of the head and neck. Virchows Arch 454:549–555CrossRefPubMed
25.
Zurück zum Zitat Zidar N, Boštjančič E, Gale N, Kojc N, Poljak M, Glavač D et al (2011) Down-regulation of microRNAs of the miR-200 family and miR-205, and an altered expression of classic and desmosomal cadherins in spindle cell carcinoma of the head and neck-hallmark of epithelial-mesenchymal transition. Hum Pathol 42:482–488CrossRefPubMed Zidar N, Boštjančič E, Gale N, Kojc N, Poljak M, Glavač D et al (2011) Down-regulation of microRNAs of the miR-200 family and miR-205, and an altered expression of classic and desmosomal cadherins in spindle cell carcinoma of the head and neck-hallmark of epithelial-mesenchymal transition. Hum Pathol 42:482–488CrossRefPubMed
26.
Zurück zum Zitat Díaz-López A, Moreno-Bueno G, Cano A (2014) Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag Res 6:205–216PubMedPubMedCentral Díaz-López A, Moreno-Bueno G, Cano A (2014) Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag Res 6:205–216PubMedPubMedCentral
27.
Zurück zum Zitat Díaz-Martín J, Díaz-López A, Moreno-Bueno G, Castilla MÁ, Rosa-Rosa JM, Cano A, Palacios J (2014) A core microRNA signature associated with inducers of the epithelial-to-mesenchymal transition. J Pathol 232:319–329CrossRefPubMed Díaz-Martín J, Díaz-López A, Moreno-Bueno G, Castilla MÁ, Rosa-Rosa JM, Cano A, Palacios J (2014) A core microRNA signature associated with inducers of the epithelial-to-mesenchymal transition. J Pathol 232:319–329CrossRefPubMed
28.
Zurück zum Zitat Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83CrossRefPubMed Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83CrossRefPubMed
29.
Zurück zum Zitat Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68:7846–7854CrossRefPubMed Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF et al (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68:7846–7854CrossRefPubMed
30.
Zurück zum Zitat Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601CrossRefPubMed Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601CrossRefPubMed
31.
Zurück zum Zitat Lamouille S, Subramanyam D, Blelloch R et al (2013) Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol 25:200–207CrossRefPubMedPubMedCentral Lamouille S, Subramanyam D, Blelloch R et al (2013) Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol 25:200–207CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Zidar N, Boštjančič E, Jerala M, Kojc N, Drobne D, Štabuc B et al (2016) Downregulation of microRNAs of the miR-200 family and up-regulation of Snail and Slug in inflammatory bowel diseases—hallmark of epithelial-mesenchymal transition. J Cell Mol Med 20:1813–1820CrossRefPubMedPubMedCentral Zidar N, Boštjančič E, Jerala M, Kojc N, Drobne D, Štabuc B et al (2016) Downregulation of microRNAs of the miR-200 family and up-regulation of Snail and Slug in inflammatory bowel diseases—hallmark of epithelial-mesenchymal transition. J Cell Mol Med 20:1813–1820CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Latham GJ (2010) Normalization of microRNA quantitative RT-PCR data in reduced scale experimental designs. Methods Mol Biol 667:19–31CrossRefPubMed Latham GJ (2010) Normalization of microRNA quantitative RT-PCR data in reduced scale experimental designs. Methods Mol Biol 667:19–31CrossRefPubMed
34.
Zurück zum Zitat Bryne M (1998) Is the invasive front of an oral carcinoma the most important area for prognostication? Oral Dis 4:70–77CrossRefPubMed Bryne M (1998) Is the invasive front of an oral carcinoma the most important area for prognostication? Oral Dis 4:70–77CrossRefPubMed
35.
Zurück zum Zitat Du L, Yang Y, Xiao X, Wang C, Zhang X, Wang L et al (2011) Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral Oncol 47:709–713CrossRefPubMed Du L, Yang Y, Xiao X, Wang C, Zhang X, Wang L et al (2011) Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral Oncol 47:709–713CrossRefPubMed
36.
Zurück zum Zitat Kokko LL, Hurme S, Maula SM, Alanen K, Grénman R, Kinnunen I et al (2011) Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinoma. Oral Oncol 47:510–516CrossRefPubMed Kokko LL, Hurme S, Maula SM, Alanen K, Grénman R, Kinnunen I et al (2011) Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinoma. Oral Oncol 47:510–516CrossRefPubMed
37.
Zurück zum Zitat Watanabe M, Ohnishi Y, Inoue H, Wato M, Tanaka A, Kakudo K et al (2014) NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma. Oncol Lett 7:35–40CrossRefPubMed Watanabe M, Ohnishi Y, Inoue H, Wato M, Tanaka A, Kakudo K et al (2014) NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma. Oncol Lett 7:35–40CrossRefPubMed
38.
Zurück zum Zitat Zhou C, Sun B (2014) The prognostic role of the cancer stem cell marker aldehyde dehydrogenase 1 in head and neck squamous cell carcinomas: a meta-analysis. Oral Oncol 50:1144–1148CrossRefPubMed Zhou C, Sun B (2014) The prognostic role of the cancer stem cell marker aldehyde dehydrogenase 1 in head and neck squamous cell carcinomas: a meta-analysis. Oral Oncol 50:1144–1148CrossRefPubMed
39.
Zurück zum Zitat Chou MY, Hu FW, Yu CH, Yu CC (2015) Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. Oral Oncol 51:31–39CrossRefPubMed Chou MY, Hu FW, Yu CH, Yu CC (2015) Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells. Oral Oncol 51:31–39CrossRefPubMed
Metadaten
Titel
The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity
verfasst von
Nina Zidar
Emanuela Boštjančič
Marija Malgaj
Nina Gale
Tadej Dovšak
Vojko Didanovič
Publikationsdatum
12.07.2017
Verlag
Springer Berlin Heidelberg
Erschienen in
Virchows Archiv / Ausgabe 2/2018
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-017-2192-1

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