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Podoplanin is a novel myoepithelial cell marker in pleomorphic adenoma and other salivary gland tumors with myoepithelial differentiation

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Abstract

The expression of podoplanin, one of the representative immunohistochemical markers for lymphatic endothelium, is upregulated in various kinds of cancers. Based on our previous studies, we have developed a hypothesis that podoplanin plays a role in cell adhesion via its association with extracellular matrix (ECM). Since salivary pleomorphic adenoma is histologically characterized by its ECM-enriched stroma, we firstly wanted to explore the expression modes of podoplanin in pleomorphic adenoma and related salivary tumors by immunohistochemistry. In normal salivary gland, podoplanin was specifically localized in myoepithelial cells, which were also positively labeled by antibodies against P63, of the intercalated duct as well as acini. In pleomorphic adenoma, podoplanin was colocalized with P63 and CD44 in basal cells of glandular structures as well as in stellate/spindle cells in myxochondroid matrices, where perlecan and hyaluronic acid were enriched. The expression of podoplanin was confirmed at both protein and mRNA levels in pleomorphic adenoma cell systems (SM-AP1 and SM-AP4) by using immunofluorescence, western blotting, and reverse transcription polymerase chain reaction. Podoplanin was localized on the cell border as well as in the external periphery of the cells. Moreover, podoplanin expression was also confirmed in tumor cells with myoepithelial differentiation in myoepithelioma and intraductal papilloma. The results indicate that podoplanin can be regarded as a novel myoepithelial marker in salivary gland tumors and suggest that podoplanin’s communication with ECM molecules is essential to phenotypic differentiation to myoepithelial cells.

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References

  1. Breiteneder-Geleff S, Matsui K, Soleiman A, Meraner P, Poczewski H, Kalt R, Schaffner G, Kerjaschki D (1997) Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am J Pathol 151:1141–1152

    PubMed  CAS  Google Scholar 

  2. Fukunaga M (2005) Expression of D2-40 in lymphatic endothelium of normal tissues and in vascular tumours. Histopathology 46:396–402

    Article  PubMed  CAS  Google Scholar 

  3. Tateyama H, Sugiura H, Yamatani C, Yano M (2011) Expression of podoplanin in thymoma: its correlation with tumor invasion, nodal metastasis, and poor clinical outcome. Hum Pathol 42:533–540

    Article  PubMed  CAS  Google Scholar 

  4. Kunita A, Kashima TG, Ohazama A, Grigoriadis AE, Fukayama M (2011) Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma. Am J Pathol 179:1041–1049

    Article  PubMed  CAS  Google Scholar 

  5. Rodrigo JP, Garcia-Carracedo D, Gonzalez MV, Mancebo G, Fresno MF, Garcia-Pedrero J (2010) Podoplanin expression in the development and progression of laryngeal squamous cell carcinomas. Mol Cancer 9:48

    Article  PubMed  Google Scholar 

  6. Tsuneki M, Maruyama S, Yamazaki M, Cheng J, Saku T (2012) Podoplanin expression profiles characteristic of odontogenic tumor-specific tissue architectures. Pathol Res Pract 208:140–146

    Article  PubMed  CAS  Google Scholar 

  7. Funayama A, Cheng J, Maruyama S, Yamazaki M, Kobayashi T, Syafriadi M, Kundu S, Shingaki S, Saito C, Saku T (2011) Enhanced expression of podoplanin in oral carcinomas in situ and squamous cell carcinomas. Pathobiology 78:171–180

    Article  PubMed  CAS  Google Scholar 

  8. Tsuneki M, Maruyama S, Yamazaki M, Cheng J, Saku T (2011) Cell adhesive function of podoplanin in oral squamous cell carcinoma. J Oral Biosci 53: S125

  9. Hata M, Ueki T, Sato A, Kojima H, Sawa Y (2008) Expression of podoplanin in the mouse salivary glands. Arch Oral Biol 53:835–841

    Article  PubMed  CAS  Google Scholar 

  10. Ianez RF, Buim ME, Coutinho-Camillo CM, Schultz R, Soares FA, Lourenco SV (2010) Human salivary gland morphogenesis: myoepithelial cell maturation assessed by immunohistochemical markers. Histopathology 57:410–417

    Article  PubMed  Google Scholar 

  11. Maruyama S, Cheng J, Shingaki S, Tamura T, Asakawa S, Minoshima S, Shimizu Y, Shimizu N, Saku T (2009) Establishment and characterization of pleomorphic adenoma cell systems: an in-vitro demonstration of carcinomas arising secondarily from adenomas in the salivary gland. BMC Cancer 9:247

    Article  PubMed  Google Scholar 

  12. Saku T, Furthmayr H (1989) Characterization of the major heparan sulfate proteoglycan secreted by bovine aortic endothelial cells in culture. Homology to the large molecular weight molecule of basement membranes. J Biol Chem 264:3514–3523

    PubMed  CAS  Google Scholar 

  13. Tsuneki M, Cheng J, Maruyama S, Ida-Yonemochi H, Nakajima M, Saku T (2008) Perlecan-rich epithelial linings as a background of proliferative potentials of keratocystic odontogenic tumor. J Oral Pathol Med 37:287–293

    Article  PubMed  CAS  Google Scholar 

  14. Tsuneki M, Yamazaki M, Cheng J, Maruyama S, Kobayashi T, Saku T (2010) Combined immunohistochemistry for the differential diagnosis of cystic jaw lesions: its practical use in surgical pathology. Histopathology 57:806–813

    Article  PubMed  Google Scholar 

  15. 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 107:563–569

    Article  PubMed  CAS  Google Scholar 

  16. 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 456:473–482

    Article  PubMed  CAS  Google Scholar 

  17. 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 177:1004–1016

    Article  PubMed  CAS  Google Scholar 

  18. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, Ren H, Fan YH, Feng L, Lee JJ, Kim E, Hong WK, Lippman SM, Mao L (2008) Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol 26:354–360

    Article  PubMed  Google Scholar 

  19. Metwaly H, Maruyama S, Yamazaki M, Tsuneki M, Abé T, Jen KY, Cheng J, Saku T (2012) Parenchymal-stromal switching for extracellular matrix production on invasion of oral squamous cell carcinoma. Hum Pathol 43:1973–1981

    Google Scholar 

  20. Ikarashi T, Ida-Yonemochi H, Ohshiro K, Cheng J, Saku T (2004) Intraepithelial expression of perlecan, a basement membrane-type heparan sulfate proteoglycan reflects dysplastic changes of the oral mucosal epithelium. J Oral Pathol Med 33:87–95

    Article  PubMed  CAS  Google Scholar 

  21. Maruyama S, Cheng J, Yamazaki M, Liu A, Saku T (2009) Keratinocyte growth factor colocalized with perlecan at the site of capsular invasion and vascular involvement in salivary pleomorphic adenomas. J Oral Pathol Med 38:377–385

    Article  PubMed  CAS  Google Scholar 

  22. Saku T, Cheng J, Okabe H, Koyama Z (1990) Immunolocalization of basement membrane molecules in the stroma of salivary gland pleomorphic adenoma. J Oral Pathol Med 19:208–214

    Article  PubMed  CAS  Google Scholar 

  23. Dardick I (1996) Pleomorphic adenoma (benign mixed tumor). Color atlas/text of salivary gland tumor pathology. Igaku-Shoin Medical, New York, pp 75–92

    Google Scholar 

  24. Zarbo RJ (2002) Salivary gland neoplasia: a review for the practicing pathologist. Mod Pathol 15:298–323

    Article  PubMed  Google Scholar 

  25. Bilal H, Handra-Luca A, Bertrand JC, Fouret PJ (2003) P63 is expressed in basal and myoepithelial cells of human normal and tumor salivary gland tissues. J Histochem Cytochem 51:133–139

    Article  PubMed  CAS  Google Scholar 

  26. Takai Y, Dardick I, Mackay A, Burford-Mason A, Mori M (1995) Diagnostic criteria for neoplastic myoepithelial cells in pleomorphic adenomas and myoepitheliomas. Immunocytochemical detection of muscle-specific actin, cytokeratin 14, vimentin, and glial fibrillary acidic protein. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:330–341

    Article  PubMed  CAS  Google Scholar 

  27. Saku T, Okabe H, Yagi Y, Sato E, Tsuda N (1984) A comparative study on the immunolocalization of keratin and myosin in salivary gland tumors. Acta Pathol Jap 34:1031–1040

    CAS  Google Scholar 

  28. de Araujo VC, Altemani A, Furuse C, Martins MT, de Araujo NS (2006) Immunoprofile of reactive salivary myoepithelial cells in intraductal areas of carcinoma ex-pleomorphic adenoma. Oral Oncol 42:1011–1016

    Article  PubMed  Google Scholar 

  29. Dardick I, Stratis M, Parks WR, DeNardi FG, Kahn HJ (1991) S-100 protein antibodies do not label normal salivary gland myoepithelium. Histogenetic implications for salivary gland tumors. Am J Pathol 138:619–628

    PubMed  CAS  Google Scholar 

  30. Swelam W, Ida-Yonemochi H, Maruyama S, Ohshiro K, Cheng J, Saku T (2005) Vascular endothelial growth factor in salivary pleomorphic adenomas: one of the reasons for their poorly vascularized stroma. Virchows Arch 446:653–662

    Article  PubMed  CAS  Google Scholar 

  31. Cheng J, Irie T, Munakata R, Kimura S, Nakamura H, He RG, Lui AR, Saku T (1995) Biosynthesis of basement membrane molecules by salivary adenoid cystic carcinoma cells: an immunofluorescence and confocal microscopic study. Virchows Arch 426:577–586

    Article  PubMed  CAS  Google Scholar 

  32. Kimura S, Cheng J, Ida H, Hao N, Fujimori Y, Saku T (2000) Perlecan (heparan sulfate proteoglycan) gene expression reflected in the characteristic histological architecture of salivary adenoid cystic carcinoma. Virchows Arch 437:122–128

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) and for JSPS Fellows (M. Tsuneki), with additional funding from the Iwadare Scholarship Foundation, Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Oral Pathology, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan

    Masayuki Tsuneki, Satoshi Maruyama, Manabu Yamazaki, Ahmed Essa, Tatsuya Abé, Hamzah Ali Babkair, Md Shahidul Ahsan, Jun Cheng & Takashi Saku

  2. Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, Japan

    Satoshi Maruyama, Tatsuya Abé & Takashi Saku

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  1. Masayuki Tsuneki
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  2. Satoshi Maruyama
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  3. Manabu Yamazaki
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  4. Ahmed Essa
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  5. Tatsuya Abé
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  6. Hamzah Ali Babkair
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  7. Md Shahidul Ahsan
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  8. Jun Cheng
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  9. Takashi Saku
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Correspondence to Takashi Saku.

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Tsuneki, M., Maruyama, S., Yamazaki, M. et al. Podoplanin is a novel myoepithelial cell marker in pleomorphic adenoma and other salivary gland tumors with myoepithelial differentiation. Virchows Arch 462, 297–305 (2013). https://doi.org/10.1007/s00428-012-1359-z

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  • DOI: https://doi.org/10.1007/s00428-012-1359-z

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