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01-06-2019 | Original Article

The stem cell markers expression CD44v6 and podoplanin in lip cancer: clinical significance

Authors: Alexandre Simões Garcia, Agnes Assao, André Lopes Carvalho, Fernando Augusto Soares, Luiz Paulo Kowalski, Denise Tostes Oliveira

Published in: Virchows Archiv | Issue 6/2019

Abstract

This study aimed to analyze the immunoexpression of cancer stem cell markers, CD44v6, and podoplanin in 91 patients with lip squamous cell carcinomas (LSCC). The immunostaining of podoplanin and CD44v6 was evaluated in ten high-power fields (× 400 magnification) at the invasive front of LSCC, using a semi-quantitative score method. Chi-square test or Fisher’s exact test was used to verify the association of podoplanin and CD44v6 expressions with clinicopathologic variables. Spearman’s correlation test was used to analyze the correlation between the two antibodies in lip cancer. Disease-free survival probabilities in 5 and 10 years were estimated according to the Kaplan-Meier method and compared using the log-rank test. The independent effects of the significant variables were analyzed by Cox proportional hazards regression model. A strong podoplanin expression was observed in the membrane and cytoplasm of most lip tumor cells, and this was inversely associated with locoregional recurrence (p = 0.028) and with histopathological grade of malignancy (p = 0.026). Additionally, CD44v6 immunostaining was strongly expressed in the membrane of tumor cells in 95.4% of the LSCC. Patients with strong membranous (p = 0.016) or strong cytoplasmic (p = 0.030) podoplanin-positive tumors resulted in significantly better disease-free survival than those who had podoplanin weak/negative tumors, confirming podoplanin expression as a favorable independent prognostic factor. Podoplanin and CD44v6 were strongly expressed by tumor cells and podoplanin immunoexpression can help to determine lip cancer patients with lower risk for disease recurrence.

Yanamoto S, Yamada S, Takahashi H, Naruse T, Matsushita Y, Ikeda H, Shiraishi T, Seki S, Fujita S, Ikeda T, Asahina I, Umeda M (2014) Expression of the cancer stem cell markers CD44v6 and ABCG2 in tongue cancer: effect of neoadjuvant chemotherapy on local recurrence. Int J Oncol 44(4):1153–1162. https://doi.org/10.3892/ijo.2014.2289 CrossRefPubMed

Athanassiou-Papaefthymiou M, Shkeir O, Kim D, Divi V, Matossian M, Owen JH, Czerwinski MJ, Papagerakis P, McHugh J, Bradford CR, Carey TE, Wolf GT, Prince ME, Papagerakis S (2014) Evaluation of CD44 variant expression in oral, head and neck squamous cell carcinomas using a triple approach and its clinical significance. Int J Immunopathol Pharmacol 27(3):337–349CrossRefPubMedPubMedCentral

Sawant S, Gokulan R, Dongre H, Vaidya M, Chaukar D, Prabhash K, Ingle A, Joshi S, Dange P, Singh AK, Makani V, Sharma S, Jeyaram A, Kane S, D’Cruz A (2016) Prognostic role of Oct4, CD44 and c-Myc in radio-chemo-resistant oral cancer patients and their tumourigenic potential in immunodeficient mice. Clin Oral Investig 20(1):43–56. https://doi.org/10.1007/s00784-015-1476-610.1007/s00784-015-1476-6 CrossRefPubMed

Patel S, Rawal R (2016) Role of miRNA dynamics and cytokine profile in governing CD44v6/Nanog/PTEN axis in oral cancer: modulating the master regulators. Tumour Biol 37(11):14565–14575. https://doi.org/10.1007/s13277-016-5289-210.1007/s13277-016-5289-2 CrossRefPubMed

Baillie R, Tan ST, Itinteang T (2017) Cancer stem cells in oral cavity squamous cell carcinoma: a review. Front Oncol 7:112. https://doi.org/10.3389/fonc.2017.00112 CrossRefPubMedPubMedCentral

Mohanta S, Siddappa G, Valiyaveedan SG, Dodda Thimmasandra Ramanjanappa R, Das D, Pandian R, Khora SS, Kuriakose MA, Suresh A (2017) Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma. Tumour Biol 39(6):1010428317703656. https://doi.org/10.1177/1010428317703656 CrossRefPubMed

Boxberg M, Gotz C, Haidari S, Dorfner C, Jesinghaus M, Drecoll E, Boskov M, Wolff KD, Weichert W, Haller B, Kolk A (2018) Immunohistochemical expression of CD44 in oral squamous cell carcinoma in relation to histomorphologic parameters and clinicopathological factors. Histopathology. https://doi.org/10.1111/his.13496

Vormittag L, Thurnher D, Geleff S, Pammer J, Heiduschka G, Brunner M, Grasl M, Erovic BM (2009) Co-expression of Bmi-1 and podoplanin predicts overall survival in patients with squamous cell carcinoma of the head and neck treated with radio(chemo)therapy. Int J Radiat Oncol Biol Phys 73(3):913–918. https://doi.org/10.1016/j.ijrobp.2008.10.040S0360-3016(08)03681-X CrossRefPubMed

Habiba U, Hida K, Kitamura T, Matsuda AY, Higashino F, Ito YM, Ohiro Y, Totsuka Y, Shindoh M (2017) ALDH1 and podoplanin expression patterns predict the risk of malignant transformation in oral leukoplakia. Oncol Lett 13(1):321–328. https://doi.org/10.3892/ol.2016.5379OL-0-0-5379 CrossRefPubMed

10.

Siar CH, Ishak I, Ng KH (2015) Podoplanin, E-cadherin, beta-catenin, and CD44v6 in recurrent ameloblastoma: their distribution patterns and relevance. J Oral Pathol Med 44(1):51–58. https://doi.org/10.1111/jop.12203 CrossRefPubMed

11.

Dos Santos AA, Oliveira DT, Pereira MC, Faustino SE, Nonogaki S, Carvalho AL, Kowalski LP (2013) Podoplanin and VEGF-C immunoexpression in oral squamous cell carcinomas: prognostic significance. Anticancer Res 33(9):3969–3976

12.

Caetano Ados S, Tjioe KC, Faustino SE, Hanemann JA, Belone Ade F, Soares CT, Oliveira DT (2013) Immunolocalization of podoplanin in benign odontogenic tumours with and without ectomesenchyme. Arch Oral Biol 58(4):408–415. https://doi.org/10.1016/j.archoralbio.2012.06.002S0003-9969(12)00186-0 CrossRefPubMed

13.

Garcia AS, Tjioe KC, Nonogaki S, Soares FA, Soares CT, Lauris JRP, Oliveira DT (2014) Ezrin and podoplanin expressions are associated in invasion front of lip cancer. Head Neck Oncololy 3(1):6

14.

Oliveira DT, de Santis LP, Assao A, Tjioe KC, Nonogaki S, Lauris JR, Soares FA (2014) The relationship between ezrin and podoplanin expressions in keratocystic odontogenic tumors. BMC Oral Health 14:150. https://doi.org/10.1186/1472-6831-14-1501472-6831-14-150 CrossRefPubMedPubMedCentral

15.

Assao A, Nonogaki S, Lauris JR, Carvalho AL, Pinto CA, Soares FA, Kowalski LP, Oliveira DT (2016) Podoplanin, ezrin, and Rho-A proteins may have joint participation in tumor invasion of lip cancer. Clin Oral Investig. https://doi.org/10.1007/s00784-016-1956-310.1007/s00784-016-1956-3

16.

Barros FBA, Assao A, Garcia NG, Nonogaki S, Carvalho AL, Soares FA, Kowalski LP, Oliveira DT (2018) Moesin expression by tumor cells is an unfavorable prognostic biomarker for oral cancer. BMC Cancer 18(1):53. https://doi.org/10.1186/s12885-017-3914-0 CrossRefPubMedPubMedCentral

17.

Costa YF, Tjioe KC, Nonogaki S, Soares FA, Lauris JR, Oliveira DT (2015) Are podoplanin and ezrin involved in the invasion process of the ameloblastomas? Eur J Histochem 59(1):2451. https://doi.org/10.4081/ejh.2015.2451 CrossRefPubMedPubMedCentral

18.

Ozkul Y, Songu M, Imre A, Tunc E, Ozkul Z, Arslanoglu S, Pinar E, Onal K (2016) Early stage squamous cell carcinoma of the lower lip: predictive factors for recurrence. J Laryngol Otol 130(4):369–372. https://doi.org/10.1017/S0022215116000311S0022215116000311 CrossRefPubMed

19.

Martin-Villar E, Scholl FG, Gamallo C, Yurrita MM, Munoz-Guerra M, Cruces J, Quintanilla M (2005) Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 113(6):899–910. https://doi.org/10.1002/ijc.20656 CrossRefPubMed

20.

Martin-Villar E, Megias D, Castel S, Yurrita MM, Vilaro S, Quintanilla M (2006) Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci 119(Pt 21):4541–4553. https://doi.org/10.1242/jcs.03218 CrossRefPubMed

21.

Fernandez-Munoz B, Yurrita MM, Martin-Villar E, Carrasco-Ramirez P, Megias D, Renart J, Quintanilla M (2011) The transmembrane domain of podoplanin is required for its association with lipid rafts and the induction of epithelial-mesenchymal transition. Int J Biochem Cell Biol 43(6):886–896. https://doi.org/10.1016/j.biocel.2011.02.010S1357-2725(11)00066-5 CrossRefPubMed

22.

Martin-Villar E, Fernandez-Munoz B, Parsons M, Yurrita MM, Megias D, Perez-Gomez E, Jones GE, Quintanilla M (2010) Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 21(24):4387–4399. https://doi.org/10.1091/mbc.E10-06-0489E10-06-0489 CrossRefPubMedPubMedCentral

23.

Tsuneki M, Yamazaki M, Maruyama S, Cheng J, Saku T (2013) Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma. Lab Investig 93(8):921–932. https://doi.org/10.1038/labinvest.2013.86labinvest201386 CrossRef

24.

Yu YH, Morales J, Feng L, Lee JJ, El-Naggar AK, Vigneswaran N (2015) CD147 and Ki-67 overexpression confers poor prognosis in squamous cell carcinoma of oral tongue: a tissue microarray study. Oral Surg Oral Med Oral Pathol Oral Radiol 119(5):553–565. https://doi.org/10.1016/j.oooo.2014.12.022S2212-4403(14)01451-5 CrossRefPubMedPubMedCentral

25.

Saghravanian N, Anvari K, Ghazi N, Memar B, Shahsavari M, Aghaee MA (2017) Expression of p63 and CD44 in oral squamous cell carcinoma and correlation with clinicopathological parameters. Arch Oral Biol 82:160–165. https://doi.org/10.1016/j.archoralbio.2017.06.011 CrossRefPubMed

26.

de Moraes FP, Lourenco SV, Ianez RC, de Sousa EA, Silva MM, Damascena AS, Kowalski LP, Soares FA, Coutinho-Camillo CM (2017) Expression of stem cell markers in oral cavity and oropharynx squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 123(1):113–122. https://doi.org/10.1016/j.oooo.2016.09.009 CrossRefPubMed

27.

Ohta M, Abe A, Ohno F, Hasegawa Y, Tanaka H, Maseki S, Kondo E, Kurita K, Nakanishi H (2013) Positive and negative regulation of podoplanin expression by TGF-beta and histone deacetylase inhibitors in oral and pharyngeal squamous cell carcinoma cell lines. Oral Oncol 49(1):20–26. https://doi.org/10.1016/j.oraloncology.2012.06.017S1368-8375(12)00215-1 CrossRefPubMed

28.

Parhar S, Kaur H, Vashist A, Verma S (2015) Role of podoplanin in potentially malignant disorders and oral squamous cell carcinoma and its correlation with lymphangiogenesis. Indian J Cancer 52(4):617–622. https://doi.org/10.4103/0019-509X.178427 IndianJournalofCancer_2015_52_4_617_178427CrossRefPubMed

29.

Monteiro LS, Delgado ML, Ricardo S, do Amaral B, Salazar F, Pacheco JJ, Lopes CA, Bousbaa H, Warnakulasuryia S (2016) Prognostic significance of CD44v6, p63, podoplanin and MMP-9 in oral squamous cell carcinomas. Oral Dis 22(4):303–312. https://doi.org/10.1111/odi.12442 CrossRefPubMed

30.

Shimada Y, Ishii G, Nagai K, Atsumi N, Fujii S, Yamada A, Yamane Y, Hishida T, Nishimura M, Yoshida J, Ikeda N, Ochiai A (2009) Expression of podoplanin, CD44, and p63 in squamous cell carcinoma of the lung. Cancer Sci 100(11):2054–2059. https://doi.org/10.1111/j.1349-7006.2009.01295.xCAS1295 CrossRefPubMed

31.

Yuan P, Temam S, El-Naggar A, Zhou X, Liu DD, Lee JJ, Mao L (2006) Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer 107(3):563–569. https://doi.org/10.1002/cncr.22061 CrossRefPubMed

32.

Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M (2010) Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol 177(2):1004–1016. https://doi.org/10.2353/ajpath.2010.090703S0002-9440(10)60155-1 CrossRefPubMedPubMedCentral

33.

Kreppel M, Scheer M, Drebber U, Ritter L, Zoller JE (2010) Impact of podoplanin expression in oral squamous cell carcinoma: clinical and histopathologic correlations. Virchows Arch 456(5):473–482. https://doi.org/10.1007/s00428-010-0915-7 CrossRefPubMed

34.

Huber GF, Fritzsche FR, Zullig L, Storz M, Graf N, Haerle SK, Jochum W, Stoeckli SJ, Moch H (2011) Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer 129(6):1404–1409. https://doi.org/10.1002/ijc.25795 CrossRefPubMed

35.

Garcia-Montesinos-Perea B, Val-Bernal JF, Saiz-Bustillo R (2005) Epidermoid carcinoma of the lip: an immunohistochemical study. Med Oral Patol Oral Cir Bucal 10(5):454–461PubMed

36.

Cruz MC, Pereira AL, Lopes FF, Nonaka CF, Silva RR, Freitas Rde A, Souza LB, Pinto LP (2009) Immunohistochemical expression of E-cadherin and CD44v6 in squamous cell carcinomas of the lower lip and tongue. Braz Dent J 20(1):64–69CrossRefPubMed

Title: The stem cell markers expression CD44v6 and podoplanin in lip cancer: clinical significance
Authors: Alexandre Simões Garcia
Agnes Assao
André Lopes Carvalho
Fernando Augusto Soares
Luiz Paulo Kowalski
Denise Tostes Oliveira
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 6/2019
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-019-02539-3

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The stem cell markers expression CD44v6 and podoplanin in lip cancer: clinical significance

Abstract

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