Immunohistochemical Analysis of Benign Mixed and Mesenchymal Odontogenic Tumors

Abstract

Benign mixed and mesenchymal odontogenic tumors (ameloblastic fibroma, ameloblastic fibrodentinoma, ameloblastic fibro-odontomas, odontogenic fibroma and odontogenic myxoma) were immunohistochemically examined using antibodies against amelogenin, cytokeratin 19, bcl-2, hepatocyte growth factor (HGF), c-Met, transforming growth factor-b (TGF-b), TGF-b receptors and Ki-67 to know cytodifferentiation, epithelial-mesenchymal interaction and proliferative activity. Expression of amelogenin was detected in odontogenic epithelial cells and enamel matrices in ameloblastic fibro-odontomas, and cytokeratin 19 was expressed in odontogenic epithelial cells, indicating odontogenic epithelial properties. Expressions of bcl-2, HGF, TGF-b, TbR I and TbR II were detected in odontogenic epithelial and mesenchymal cells in mixed and mesenchymal odontogenic tumors, while expression of c-Met was detected in odontogenic epithelial cells. Odontogenic epithelial and mesenchymal cells sporadically showed positive reactions for Ki-67 in mixed and mesenchymal odontogenic tumors, and no apparent differences were obtained among these tumors or between the components. Conclusion: Immunohistochemical localization of HGF, TGF-b and their receptors suggests that these growth factor signaling are effective in the epithelial component in paracrine and autocrine manner in mixed and mesenchymal odontogenic tumors. These results of growth factor signaling suggest that certain epithelial-mesenchymal interactions are related to neoplastic cell growth in these tumors.

Molecular alterations in the development and progression of odontogenic tumors

“…Recently, overexpression of the EGFR family members, Her-2 and Her-3, has been identified in keratocystic odontogenic tumors (26,67). TGF-β and its receptors are expressed in many types of odontogenic tumors, suggesting that they have an important role in cell differentiation and matrix formation via regulation or dysregulation of epithelial-mesenchymal interactions (24,66,(68)(69)(70). HGF and its receptor c-Met, essential for morphogenesis of tooth germs, are expressed in many types of odontogenic tumors, suggesting that they affect epithelialmesenchymal interactions not only in developing teeth but also in neoplastic odontogenic tissues (24,70).…”

“…TGF-β and its receptors are expressed in many types of odontogenic tumors, suggesting that they have an important role in cell differentiation and matrix formation via regulation or dysregulation of epithelial-mesenchymal interactions (24,66,(68)(69)(70). HGF and its receptor c-Met, essential for morphogenesis of tooth germs, are expressed in many types of odontogenic tumors, suggesting that they affect epithelialmesenchymal interactions not only in developing teeth but also in neoplastic odontogenic tissues (24,70). Increased expression of HGF and c-Met in ameloblastic carcinomas and clear cell odontogenic carcinomas implies that HGF signaling might be associated with the malignant potential of epithelial odontogenic tumors (70).…”

“…Other regulators of tooth development, such as HGF and BMP, have been found in odontogenic tumors (24,70,(107)(108)(109). Recently, CD133, Bmi-1, and ATP-binding cassette subfamily G member 2 (ABCG2) have been detected in ameloblastic tumors, suggesting that stem cell-related molecules might control the maintenance of odontogenic tissues (110).…”

“…Expression of amelogenin, enamelin, ameloblastin, and MMP-20 has been recognized in epithelial components of various types of odontogenic tumors (21,24,(111)(112)(113)(114)(115)(116)(117)(118)(119). Mutations of ameloblastin gene have been detected in epithelial odontogenic tumors (118,(120)(121), and ameloblastin-mutant mice develop odontogenic tumors of odontogenic epithelium origin (122).…”

Molecular pathology of odontogenic tumors

“…Uncontrolled cell cycles caused by aberrations of these regulators have been identified in a variety of tumors (82,84). In many types of odontogenic tumors, cell cycle phase/cell proliferation markers, proliferating cell nuclear antigen (PCNA), Ki-67, DNA topoisomerase IIa, and histone H3, reflect proliferation activity and malignant potential (31,33,68,(85)(86)(87)(88)(89)(90)(91)(92). Cyclin D1 is strongly implicated in cell cycle progression by regulating the transition from G1 to S phase, while CKIs, p16 INK4a , p21 WAF1/Cip1 , and p27 Kip1 inhibit cell cycle progression by suppressing cyclin D1 function (83).…”