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REVIEW ARTICLE
Year : 2013  |  Volume : 2  |  Issue : 3  |  Page : 157-161

The molecular and genetic aspects in the pathogenesis and treatment of ameloblastoma


1 Department of Oral Pathology, Thai Moogambigai Dental College and Hospital, Chennai, Tamil Nadu, India
2 Department of Oral Pathology, Tagore Dental College, Chennai, Tamil Nadu, India
3 Department of Orthodontics, Tagore Dental College, Chennai, Tamil Nadu, India

Date of Web Publication29-Aug-2013

Correspondence Address:
Nadeem Jeddy
Department of Oral Pathology, Thai Moogambigai Dental College and Hospital Golden George Nagar, Mogappair Chennai - 600 107, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2277-8632.117179

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  Abstract 

Ameloblastomas are usually benign, locally aggressive neoplasms derived from the epithelial odontogenic tissues. The tumors are known for their propensity for local recurrence. Different mechanisms have been proposed to explain the mechanism behind the pathogenesis of ameloblastoma. The proper understanding of the pathogenetic mechanism involved in ameloblastoma and its proliferation, aids in constituting proper treatment. Molecules involved in the pathogenesis can serve as markers in long term follow-up. Expression of the ameloblastin and amelogenin genes in these tumors play a role and they potentiate their action through different mechanisms. This review focuses on the molecular changes that occur in ameloblastoma which has a bearing upon its treatment and prognosis.

Keywords: Ameloblastin, amelogenin, markers, odontogenic tissues, pathogenesis


How to cite this article:
Jeddy N, Jeyapradha T, Ananthalakshmi R, Jeeva S, Saikrishna P, Lakshmipathy P. The molecular and genetic aspects in the pathogenesis and treatment of ameloblastoma. J NTR Univ Health Sci 2013;2:157-61

How to cite this URL:
Jeddy N, Jeyapradha T, Ananthalakshmi R, Jeeva S, Saikrishna P, Lakshmipathy P. The molecular and genetic aspects in the pathogenesis and treatment of ameloblastoma. J NTR Univ Health Sci [serial online] 2013 [cited 2019 Sep 16];2:157-61. Available from: http://www.jdrntruhs.org/text.asp?2013/2/3/157/117179


  Introduction Top


Ameloblastomas are usually benign, locally aggressive neoplasms derived from the epithelial odontogenic tissues, which are part of the tooth-forming apparatus. They account for about 1-3% of tumors and cysts of the jaws and about 1% of mandibular and maxillary tumors and cysts. The tumor is more common in the mandible than in the maxilla and shows predilection for various parts of the mandible. It often presents as a slow growing, painless swelling and causing expansion of the cortical bone. In its early stages it is confined to the bone, but large tumors can break through the cortex and involve the soft tissues. Ameloblastomas occur in the third to fifth decades of life with the unicystic type predominating in younger populations. There is no significant racial or gender predisposition.

Ameloblastomas resemble the epithelial component of developing tooth germs. The differentiation level of ameloblastoma cells remains at the cap/bell stage of tooth development. [1] The cytological findings seen in ameloblastoma which could be useful in its early diagnosis are basaloid cells with peripheral palisading with larger, lightly staining polygonal cells and clusters of mesenchymal cells. [2] Histologically, the main tumor cells are columnar, resembling pre-ameloblasts of the enamel organ, and show reversal of polarity with peripheral palisading. The epithelial components surround a central web-like arrangement of spindle-shaped cells resembling stellate reticulum.

The tumors are known for their propensity for local recurrence. The biologic behavior cannot be predicted on the basis of morphology and there is often a delay in the diagnosis also because of its slow-growing nature. Different mechanisms have been proposed to explain the mechanism behind the pathogenesis of ameloblastoma. This review focuses on the molecular changes that occur in ameloblastoma which has a bearing upon its treatment and prognosis.


  Etiopathogenesis Top


The molecular and genetic characteristics of ameloblastomas are poorly understood and the origin of the tumor is still unclear. The cloning and characterization of expression of the ameloblastin and amelogenin genes in these tumors suggests that ameloblastoma arise from the odontogenic apparatus or cells that are potentially capable of forming dental tissue. The potential sources for this tumor are the cell rests of the enamel organ (cell rests of Malassez and cell rests of Serre), epithelial odontogenic cysts (dentigerous cysts), basal cells of the surface epithelium of the jaws and heterotrophic epithelium in other parts of the body.

In the pathogenesis of ameloblastoma different factors have been found to play a role and they potentiate their action through different mechanisms [Table 1]. [3]
Table 1: Mechanisms and Factors Involved in Pathogenesis of Ameloblastoma

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  Tumorigenesis and Tumor Markers Top


Genes involved in the initiation of tooth development, morphogenesis, and cytodifferentiation and tooth patterning include, sonic hedgehog (SHH), patched (PTCH), WNT, activin ßA, bone morphogenetic proteins (BMP2 and BMP4), fibroblast-growth-factor (FGF), PAX9, BARX1, LEF1, DLX1, DLX2, MSX1, and MSX2. [3] There are specific pathways through which the proteins coded by these genes act to bring about the process of tooth development. Alterations in these genes will result in significant alterations in its function resulting in aberrant tooth development.

The transmembrane receptor for Sonic Hedgehog (SHH) and other Hedgehog proteins (HH) is coded by the PTCH1 gene. The functions of the signaling effector Smoothened (SMO) is repressed by PTCH. The binding of SHH to the PTCH1-SMO complex releases SMO, thus, activating GLI family transcription factor gene. The PTCH transcription provides a negative feedback system that restores the balance between HH and PTCH1. Alterations in SHH-pathway genes have been linked to a variety of developmental defects, and there is an evidence of tumor formation resulting from aberrant activation of this pathway in adult life. [4] A high expression of SHH, SMO and GLI protein was reported in ameloblastoma. [5]

During tooth development WNT-3, -4, -6, -7b, -10a, and -10b are encountered in the epithelium only, whereas WNT -5a is expressed in both the epithelium and mesenchyme. [6] WNT may be involved in the formation of the tooth bud and amelogenesis. The WNT signaling pathway involves WNT binding to its receptor causing stabilization of cytoplasmic β catenin and its translocation into the nucleus, where it accelerates the expression of genes related to cell cycle or proliferation. β catenin is associated with cell-cell adhesion and signal transduction in neoplastic odontogenic epithelium. Nuclear accumulation of β catenin was demonstrated in ameloblastomas. [7] Syndecan-1, (CD138) which is known to regulate many biological processes, including odontogenesis plays a role in the WNT induced tumorigenesis of odontogenic epithelium. The loss of Syndecan-1 indicates unfavorable prognosis in epithelial tumors. The decreased expression of Syndecan-1 was seen in ameloblastomas which could attribute to the aggressive behavior of the tumor [8]

PTEN protein functions as an inhibitor of Akt signaling pathway, leading to cell cycle arrest and apoptosis. Its expression was reduced in ameloblastomas compared with teeth germs. [9] FOS protein, encoded by proto-oncogene FOS, belongs to the AP-1 (activating protein-1) family participate in the control of cell proliferation, cell differentiation, apoptosis, and oncogenic transformation. Overexpression of FOS and TNFR1A have been significant in the oncogenic transformation pathway of ameloblastoma [1]

The pre-secretory ameloblasts in the inner enamel epithelium expresses Calretinin (calb2) during odontogenesis. This protein is strongly expressed only in ameloblastomas compared with other odontogenic tumors which may play a role in the transition of the dental lamina remnants to ameloblastoma. [10],[11] Enamelin and sheathlin proteins were not expressed in ameloblastoma, whereas Amelogenin and ameloblastin (involved in dental cytodifferentiation) secreted by differentiated ameloblasts, was expressed by ameloblastoma epithelial cells. Mutations in ameloblastin gene have been identified in ameloblastomas. [12] The tumor cells do not attain functional maturation as secretory phase ameloblasts thereby not expressing the enamel proteins.

Caspase 3 an enzyme in the apoptosis-inducing protease is associated with cell death. Ameloblastoma showed positivity for Caspase 3, in the central area of tumor islands. Bcl2, an anti-apoptotic protein was found mainly in the peripheral basal cell layer of ameloblastoma. 2 distinct patterns - an anti-apoptotic proliferating area and a pro-apoptotic site. P53 homologue plays a role in the differentiation and proliferation of odontogenic epithelial cells and their function is altered in tooth developing and neoplastic odontogenic tissues. [13]

Other mechanisms which have been studied and quoted in the literature are listed. Epigenetics is an event in the pathogenesis of ameloblastoma where the P21 gene undergoes methylation along with alterations in P16 and RB1. [14] TWIST is a transcription protein which works as an epithelial-mesenchymal transition promoter and has been expressed in ameloblastoma playing a role in tumor development. The altered expression of phosphorylated JNK (pJNK) and ERK5 are involved in the oncogenesis and tumor cell differentiation of ameloblastoma.(8). Loss of chromosome 22 and 10 has been seen in ameloblastoma which leads to oncogenesis. [15]

Ki67 positive nuclei in the ameloblastoma are mainly located in peripheral ameloblast-like cells in the follicular, as well as in the plexiform areas of the solid ameloblastoma and in the basal cells of unicystic ameloblastoma. Stellate reticulum-like cells in ameloblastoma and in stellate reticulum cells in developing teeth tend to be negative to this marker. [16] This staining pattern indicates that the cellular proliferation and consequently the ameloblastoma growth are concentrated in the peripheral areas composed by ameloblast-like cells. Ki67 labeling index was higher in tumors displaying high frequency of microsatellite alterations. [17]

Telomerase is a DNA polymerase that synthesizes telomeric DNA repeats which compensates for its loss with each cell division thereby stabilizing the chromosomal structure. TERT is a catalytic subunit of telomerase, whose expression is correlated with telomerase activity. In C-myc protein, a transcription factor encoded by the myc proto-oncogene, directly activates TERT transcription for induction of telomerase activity. TERT was expressed in numerous peripheral columnar or cuboidal cells and some central polyhedral cells of ameloblastomas. Studies have suggested that c-myc protein might act as a regulator of telomerase activity in ameloblastomas. [18] The telomerase activity detected in ameloblastoma reflects tumor characteristics such as ability of local invasion and high recurrence rates.

The invasive ability of ameloblastoma is related to the release of molecules like matrix metalloproteinases, which trigger mitogens to be released, leading to proliferation of ameloblastoma cells. [19],[20] Matrix metalloproteinases especially MMP-2 causes degradation of the matrix thereby promoting invasion and metastasis and also in the induction of angiogenesis. Notch signaling may also contribute to cell differentiation and proliferation of normal and neoplastic odontogenic epithelium. Ameloblastoma by secreting RANKL and TNFa induces osteoclastogenesis which provides the space for the expansion of the tumor in the bone. [21]

Bone Morphogenetic Protein (BMP), member of the transforming growth factor (TGF) super family, is a mesenchymal cell differentiation factor and a morphogen. [22] It plays a critical role in cell proliferation, differentiation, chemotaxis, extracellular matrix production and apoptosis during developmental processes. [6],[23] The expression of these BMPs was found to shift between epithelium and mesenchyme during morphogenesis, implicating its role in the mechanisms of induction and also its association with the expression of other genes, such as MSX1 and MSX2 and SHH. [24] Messenger RNA transcripts for BMPs and their receptors were identified in all types of ameloblastoma. Immunostaining was positive in the neoplastic cells near the basement membrane of the tumors.

FGFs are stimulators of cell proliferation, cell division in dental mesenchyme and epithelium. Odontogenic epithelium expresses FGF-4, -8, -9, and -20 and the mesenchyme expresses FGF-3, -7, and -10(6). The wide expression of FGF-9 in the dental epithelium of the bell stage suggests that this molecule is associated with the terminal differentiation of odontoblasts and ameloblasts. [25]

CDHs, KRT7, NOTCH, and TGFB1 may be involved in disturbances of cell-to-cell adherence junctions and cell-to-cell communication gap-junction communication may be low and cell adhesion lost in ameloblastomas, as described for many types of neoplasia. Such alterations in cell-membrane environment could also increase the locally aggressive growth potential of ameloblastomas.

Though numerous markers are mentioned in pathogenesis, aggressiveness and malignant potential of the tumor, no specific marker has been illustrated for different histopathological variants of ameloblastoma.


  Treatment Top


The size of the tumor, presence of ruptured basal cortical bone, and histological pattern seems to be an important factor for the management of ameloblastoma. Treatment ranges from conservative surgery to radical procedures, which include radiotherapy, curettage and enucleation. Surgery includes removal of at least 1cm of normal bone beyond the tumor margins. The total recurrence rate for most studies has been between 13.3% and 22%. The following treatment modalities were identified in the literature: Enucleation with or without application of carnoyl solution, curettage, surgery with adjuvant cryotherapy, marsupialization, and resection (marginal, segmental, hemi- and total resection. [26] In children due to the rapid regeneration potential and increased rate of growth enucleation can be done as an interim procedure to avoid morbidity. [27] The conventional treatment for various forms of ameloblastoma has shown different prognosis depending upon the site, size, age and aggressiveness of the tumor. No definitive treatment procedures for individual variants are mentioned in the literature.


  Conclusion Top


The proper understanding of the pathogenetic mechanism involved in ameloblastoma and its proliferation aids in constituting proper treatment of choice at an early stage thereby preventing morbidity associated with extensive therapy. Further the molecules involved in the pathogenesis can serve as markers in long term follow-up to predict recurrence.

 
  References Top

1.Heikinheimo K, Jee KJ, Niini T, Aalto Y, Happonen RP, Leivo I, et al. Gene Expression Profiling of Ameloblastoma and Human Tooth Germ by Means of a cDNA Microarray. J Dent Res 2002;81:525-30.  Back to cited text no. 1
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2.Mathew S, Rappaport K, Ali SZ, Busseniers AE, Rosenthal DL. Ameloblastoma: Cytologic findings and literature review. Acta Cytol 1997;41:955-60.  Back to cited text no. 2
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3.Jernvall J, Thesleff I. Reiterative signaling and patterning during mammalian tooth morphogenesis. Mech Dev 2000;92:19-29.  Back to cited text no. 3
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4.Kumamoto H, Ohki K, Ooya K. Expression of Sonic Hedgehog (SHH) signaling molecules in ameloblastomas. J Oral Pathol Med 2004;33:185-90.  Back to cited text no. 4
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5.Gomes CC, Duarte AP, Diniz MG, Gomez RS. Current concepts of ameloblastoma pathogenesis. J Oral Pathol Med 2010;39:585-91.  Back to cited text no. 5
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6.Tompkins K. Molecular mechanisms of cytodifferentiation in mammalian tooth development. Connect. Tissue Res 2006;47:111-8.  Back to cited text no. 6
    
7.Kumamoto H, Ooya K. Immunohistochemical detection of â- catenin and adenomatous polyposis coli in ameloblastomas. J Oral Pathol Med 2005;34:401-6.  Back to cited text no. 7
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8.Leocata P, Villari D, Fazzari C, Lentini M, Fortunato C, Nicotina PA. Syndecan-1 and Wingless-type protein-1 in human ameloblastomas. J Oral Pathol Med 2007;36:394-9.  Back to cited text no. 8
    
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10.Sandra F, Nakamura N, Mitsuyasu T, Shiratsuchi Y, Ohishi M. Two relatively distinct patterns of ameloblastoma: An anti-apoptotic proliferating site in the outer layer (periphery) and a pro-apoptotic differentiating site in the inner layer (centre). Histopathology 2001;39:93-8.  Back to cited text no. 10
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11.Alaeddini M, Etemad-Moghadam S, Baghaii F. Comparative expression of calretinin in selected odontogenic tumours: A possible relationship to histogenesis. Histopathology 2008;52:299-304.  Back to cited text no. 11
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12.Sonoda A, Iwamoto T, Nakamura T, Fukumoto E, Yoshizaki K, Yamada A, et al. The critical role of heparin binding domains of ameloblastin for dental epithelium cell adhesion and ameloblastoma proliferation. J Biol Chem 2009;284:27176-84.  Back to cited text no. 12
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13.Kumamoto H, Ohki K, Ooya K. Expression of p63 and p73 in ameloblastomas. J Oral Pathol Med 2005;34:220-6.  Back to cited text no. 13
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14.Moreira PR, Guimarães MM, Gomes CC, Diniz MG, Brito JA, de Castro WH, et al. Methylation frequencies of cell-cycle associated genes in epithelial odontogenic tumours. Arch Oral Biol 2009;54:893-7.  Back to cited text no. 14
    
15.Nodit L. Allelic loss of tumor suppressor genes in ameloblastic tumors. Modern Pathol 2004;17:1062-7.  Back to cited text no. 15
    
16.Bologna-Molina R, Mosqueda-Taylor A, Paes de Almeida O, Victor Toral R, Gullermo Martines M. Syndecan-1 (CD138) and Ki-67 expression in different subtypes of ameloblastomas. Oral Oncol 2008;44:805-11.  Back to cited text no. 16
    
17.Migaldi M, Sartori G, Rossi G, Cittadini A, Sgambato A. Tumour cell proliferation and microsatellite alterations in human ameloblastoma. Oral Oncol 2008;44:50-60.  Back to cited text no. 17
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18.Kumamoto H, Kinouchi Y, Ooya K. Telomerase activity and telomerase reverse transcriptase (TERT) expression in ameloblastomas. J Oral Pathol Med 2001;30:231-6.  Back to cited text no. 18
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19.Nagatsuka H, Han PP, Tsujigiwa H, Siar CH, Gunduz M, Sugahara T, et al. Heparanase gene and protein expression in ameloblastoma: Possible role in local Invasion of tumor cells. Oral Oncol 2005;41:542-8.  Back to cited text no. 19
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20.Pinheiro JJ, Freitas VM, Moretti AI, Jorge AG, Jaeger RG. Local invasiveness of ameloblastoma. Role played by matrix metalloproteinases and proliferative activity. Histopathology 2004;45:65-72.  Back to cited text no. 20
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21.Sandra F, Hendarmin L, Kukita T, Nakao Y, Nakamura N, Nakamura S. Ameloblastoma induces osteoclastogenesis: A possible role of ameloblastoma in expanding in the bone. Oral Oncol 2005;41:637-4.  Back to cited text no. 21
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22.Moghadam HG, Urist MR, Sandor GK, Clokie CM. Successful mandibular reconstruction using a BMP implant. J Craniofac Surg 2001;12:119-27.  Back to cited text no. 22
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23.Kumamoto H, Ooya K. Expression of bone morphogenetic proteins and their associated molecules in ameloblastomas and adenomatoid odontogenic tumors. Oral Dis 2006;12:163-70.  Back to cited text no. 23
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24.Zhang Y, Zhang Z, Zhao X, Yu X, Hu Y, Geronimo B, et al. A new function of BMP-4: Dual role for BMP4 in regulation of Sonic Hedgehog expression in the mouse tooth germ. Development 2000;127:1431-43.  Back to cited text no. 24
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25.Kettunen P, Thesleff I. Expression and function of FGFs-4, -8, and -9 suggest functional redundancy and repetitive use as epithelial signals during tooth morphogenesis. Dev Dyn 1998;211:256-68.  Back to cited text no. 25
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26.Vohra FA, Hussain M, Mudassir MS. Ameloblastomas and their Management: A review. J Surg Pak 2009;14:136-42   Back to cited text no. 26
    
27.Abdulai AE. Treatment of ameloblastoma of the jaws in children. Ghana Med J 2011;44:35-7.  Back to cited text no. 27
    



 
 
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