|Year : 2020 | Volume
| Issue : 1 | Page : 35-40
Evaluation of Transforming Growth Factor Beta 1 Expression in Ameloblastoma, Calcifying Odontogenic Cyst and Odontogenic Keratocyst
Nasrollah Saghravanian1, Narges Ghazi1, Amirhosein Habibollahi2, Mohammad Taghi Shakeri3
1 Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Oral and Maxillofacial Radiology, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Community Medicine and Public Health, Mashhad University of Medical Sciences, Mashhad, Iran
|Date of Submission||26-Aug-2019|
|Date of Decision||05-Feb-2020|
|Date of Acceptance||05-Mar-2020|
|Date of Web Publication||12-Jun-2020|
Department of Oral & Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Vakil-Abad Blv., Mashhad
Source of Support: None, Conflict of Interest: None
Introduction: Ameloblastoma is the most common neoplasm of odontogenic epithelium with locally aggressive behavior resulting in recurrence and malignant transformation. Odontogenic cysts are common lesions of the jaws with different biological behavior. Odontogenic keratocyst (OKC) and calcifying odontogenic cyst (COC) with ameloblastoma-like epithelium (ameloblastic type) are more aggressive than other odontogenic cysts. Therefore, these lesions were classified as odontogenic tumors by WHO. Transforming growth factor beta 1 (TGF-β1) is a secretory protein with diverse cellular functions including epithelial differentiation during tooth development and pathological processes such as tumorigenesis. It can function as a strong tumor suppressor gene during initial stages of tumor development. The aim of this study was to evaluate the TGF-β1 expression in ameloblastoma, OKC and COC with varying biological behavior. Materials and Methods: We examined TGF-β1 expression in epithelial and stromal cells of 15OKCs, 15COCs (ameloblastic type) and 15 ameloblastomas by immunohistochemistry. Results: Immunoreactivity was observed in epithelial and stromal cells of all lesions with different degrees. There was statistically significant reduced immunoexpression in epithelial cells of ameloblastomas and COCs compared to OKCs, whereas significant reduced immunoreactivity was reported in stromal cells of OKCs. There was no statistically significant difference between COCs and ameloblastomas in both stromal and epithelial cells immunoreactivity which shows their similar bilological behavior. Conclusion: Reduced TGF-β1 immunoexpression in epithelial cells of ameloblastomas and COCs compared to OKCs could be associated with the primitive phenotype and more invasive biological behavior of these lesions. Reduced stromal expression of TGF-β1 in OK1Cs could be explained by its looser stroma than other studied lesions.
Keywords: Ameloblastoma, odontogenic cyst, TGF-β1
|How to cite this article:|
Saghravanian N, Ghazi N, Habibollahi A, Shakeri MT. Evaluation of Transforming Growth Factor Beta 1 Expression in Ameloblastoma, Calcifying Odontogenic Cyst and Odontogenic Keratocyst. J Orofac Sci 2020;12:35-40
|How to cite this URL:|
Saghravanian N, Ghazi N, Habibollahi A, Shakeri MT. Evaluation of Transforming Growth Factor Beta 1 Expression in Ameloblastoma, Calcifying Odontogenic Cyst and Odontogenic Keratocyst. J Orofac Sci [serial online] 2020 [cited 2020 Jul 2];12:35-40. Available from: http://www.jofs.in/text.asp?2020/12/1/35/286477
| Introduction|| |
Odontogenic cysts are relatively common lesion of oral and maxillofacial region with variant clinical behavior. Odontogenic keratocyst (OKC) is a developmental odontogenic cyst with characteristic histological features. In contrast to other types of cysts, these lesions show a more aggressive behavior and high recurrence rate. WHO has recommended the term kearatocystic odontogenic tumor (KOT) which shows its neoplastic nature.,
Calcifying odontogenic cyst (COC) is an unusual lesion with considerable clinical and histopathological diversity. COC has a spectrum of variants, ranging from a cystic type to solid neoplastic tumor. The cystic lesion may sometimes show ameloblastoma-like epithelium (ameloblastic type) with proliferation into the lumen. Toida in 1998, classified this cystic variant of COC as tumor. He proposed the term “cystic calcifying ghost cell odontogenic tumor” for this type of COC.  In 2005, the World Health Organization (WHO included this lesion in the list of odontogenic tumors under the term “calcifying cystic odontogenic tumor”., Therefore this type of COC with aggressive nature is evaluated in this study.
Ameloblastoma is the most common odontogenic true neoplasm arising from odontogenic epithelium. This benign tumor may exhibit locally aggressive behavior resulting in recurrence and malignant transformation. Follicular and plexiform types of ameloblastoma are two basic patterns with the former being more common.,,,
Transforming growth factor beta (TGF-β) belongs to a family of multifunctional polypeptide growth factors that regulates many cellular processes including cell proliferation, differentiation and apoptosis, cell adhesion and migration, extracellular matrix remodeling, angiogenesis, and repair of wound.,,,
TGF-β has comprised three isoforms (TGF-β1, −β2 and −β3). These isoforms are encoded by separate genes, with TGF- β1 being the main isoform.  Transforming growth factors seem to be involved in tooth development. TGF-β1 signaling may also affect differentiation of neoplastic odontogenic epithelial cells., TGF-β1 acts as a strong tumor suppressor gene during initial stages of tumorigenesis while it can cause progression of malignancy in the next advanced stages.  It has been reported that reduced TGF-β1 immunoreactivity in neoplastic cells may be associated with the malignant transformation of neoplasms of odontogenic epithelium. 
The purpose of this study was to compare TGF-β1 expression in OKC and COC (ameloblastic type), which are tumoral lesions with cystic features, with ameloblastoma as a locally aggressive odontogenic tumor.
| Materials and Methods|| |
Tissue specimens were retrieved from the archive of the Oral and Maxillofacial Pathology of Mashhad Dental School, Iran. Ethical approval for this study (IR.MUMS.DENTISTRY.REC.930972.) was provided by the Ethical Committee of Mashhad University of Medical Sciences, Iran, on 12 April 2015.
The specimens were independently reviewed by two pathologists. In total, 45 samples of patients with OKCs (n = 15, 8 male, 7 female, mean age 25.8 years), COCs (n = 15, 9 male, 6 female, mean age 31.47 years) and plexiform and follicular types of ameloblastomas (n = 15, 8 male, 7 female, mean age 34.33 years), were studied.
Immunohistochemical study was applied on paraffin-embedded 4µm-thick sections. Each section was deparaffinized in xylene and rehydrated with ethanol-decreasing series.
Solution of methanol and 1% H2O2 for 30 minutes was used to block endogenous peroxide activity. In order to antigen retrieval, the sections went through the 0.01 citrate solution (pH 6.0) and were then incubated for 35 minutes. For fifteen minutes, the sections were kept in the same solution and subsequently washed with distilled water for 5 minutes. The following monoclonal antibody was used and applied for 60 minutes at room temperature: anti-TGF-β1 (clone TGF-β, Novocastra Laboratories, Newcastle, UK). Samples were then rinsed in Tris-Buffered Saline (TBS). The novo link polymer detection system was used in the current study. Counterstaining was carried out with Meyer’s Hematoxylin and dehydration was performed through soaking the sections in ethanol.
TGF-β1-stained slides were evaluated two independent investigators. Cytoplasmic reactivity was considered positive regardless of the staining intensity. The extent of epithelium and stromal immunostaining was recorded on a scale of 0–3: 0, no detectable staining; 1+ (mild): less than 20% cytoplasmic staining; 2+ (moderate) :20–50% cytoplasmic staining; and 3+ (strong): more than 50% cytoplasmic staining. For each sample, a mean total score of immunoreactivity (1–3) was calculated.
The data was analyzed using SPSS software (SPSS Inc, Chicago, IL). For comparing the mean percentage of marker expression among different lesions Mann-Whitney-U and Kruskal- Wallis tests were used. P-value < 0.05 was regarded as statistically significant.
| Results|| |
Different degrees of TGF-β expression was observed in all stromal and epithelial cells of the studied samples. Immunostaining is presented in [Figure 1],[Figure 2],[Figure 3] and the data is demonstrated in [Table 1],[Table 2],[Table 3].
|Figure 1 Expression of TGF-β in stellate reticulum-like epithelium (2+) and stroma (3+) of ameloblastoma (400X).|
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|Figure 2 Expression of TGF-β in epithelial cells (2+) and stromal cells (3+) of COC (400X).|
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|Figure 3 Expression of TGF-β in epithelial (3+) and stromal cells (1+) of OKC (400X).|
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|Table 1 Expression of TGF-β in epithelial cells of OKC, COC and ameloblastoma|
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|Table 2 Expression of TGF-β in stromal cells of OKC, COC and ameloblastoma|
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|Table 3 Pairwise comparison of TGF-β expression in epithelial and stromal cells of studied groups|
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Expression of TGF-β in epithelial cells
In most of OKCs, immunoexpression was strong (3+) in the epithelium, whereas for COCs and ameloblastomas moderate (2+) immunoreactivity was reported in most cases. The greatest mean total score was found in OKCs, followed by COCs and ameloblastomas [Table 1]. Statistically significant difference was noted among three groups (P < 0.05). Pairwise comparison of TGF-β immuno-expression was performed. The results are presented in [Table 3]. Significant difference was reported in all the paired groups except comparison of COC with ameloblastoma.
Expression of TGF-β in stromal cells
Evaluation of TGF-β expression in the stroma revealed negative immunoreactivity in most of OKCs, while moderate to strong positivity was observed for most of ameloblastoma and COC cases [Table 2]. Ameloblastomas showed the greatest mean total score followed by COCs and OKCs. Comparing of mean total score for immunoexpression in stromal cells of the lesions among studied lesions showed statistically significant differences (P < 0.05). [Table 3] demonstrates pairwise comparison of TGF-β immunoreactivity in the studied lesions. All paired groups revealed statistically significant difference in all the paired studied groups except comparison of COC with ameloblastoma.
| Discussion|| |
TGF-β1 is a multifunctional growth factor that has been the focus of studies as the mediator of tumorigenesis. It is involved in proliferation, differentiation, cell migration, synthesis and degradation of extracellular matrix. ,,, It regulates different cellular functions and may also play a role in tooth development. TGF-β1 signaling can induce neoplastic differentiation of odontogenic epithelial cells and its impaired signaling can also lead to tumor formation. ,
Based on the aggressive biological behavior of COC with proliferation of ameloblastoma-like epithelium into the lumen and OKC, they have been re-categorized as a benign odontogenic tumors under the terms of calcifying cystic odontogenic tumor and keratocystic odontogenic tumor by WHO. Therefore in the current study, we evaluated TGF-β1 expression in ameloblastoma as locally aggressive odontogenic tumor and cystic lesions with aggressive behavior.
The stromal expression of TGF-β1 in amalebastoma with higher immunoreactivity in desmoplastic type was reported by Takata et al. According to their study higher expression of TGF-β1 in the stroma of desmoplastic ameloblastoma is related to the role of this marker in matrix formation. Iezzi et al. also demonstrated higher expression of TGF-β1 in the stroma of ameloblastomas with higher rate of recurrence. In consistent with these studies we also showed high expression of this marker in stroma of ameloblastoma cases.
Seifi et al evaluated TGF-β1 expression in aspirated fluid of radicular cysts (RC) and odontogenic keratocysts (OKC). They revealed that OKCs with looser stroma show lower immunoreactivity than RCs. In the current study also the lowest stromal immunoreactivity of TGF-β1 was observed in OKC which could be explained by its looser stroma than other studied lesions.
Etemad-Moghadam and Alaeddini evaluated podoplanin and TGF‐β expression in odontogenic cysts and tumors consisting of solid ameloblastomas, adenomatoid odontogenic tumors (AOT), ameloblastic fibromas, odontogenic myxomas (OM), OKC, and COCs. They revealed a significant difference in TGF-β expression among the odontogenic neoplasms in in both epithelial and stromal components of odontogenic lesions, but there was no significant difference in pairwise comparison. In our study we reported significant difference in all the paired groups except comparison of COC with ameloblastoma.
Epithelial-mesenchymal interaction has a crucial role in physiological processes such as odontogenesis and also pathological processes such as tumor formation. TGF-β1 stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT).  It is an important mediator of epithelial-mesenchymal interaction between stromal and neoplastic epithelial cells of epithelial odontogenic tumors. Mutation of TGF-β genes and alteration of their proteins expression result in development of many types of neoplasms. ,,,
Zhong et al investigated the role of epithelial-mesenchymal transition in the pathogenesis and development of odontogenic keratocyst. They reported high expression of TGF-B, a potent EMT inducer, in the epithelium of OKCs. Therefore the authors suggested that EMT might be involved in the locally aggressive behavior of this lesion.  In the current study we also reported strong immunoreactivity in the epithelial cells of OKC cases.
Kurikoa et al. evaluated Slug, Snail, Twist, TGF-β1, and E-cadherin immunoreactivity in follicular and plexiform types of ameloblastoma. They suggested that strong expression of Slug and TGF-β1and the reduced expression of E-cadherin induce EMT and seem to be related to the biological behavior and local invasiveness of ameloblastoma. In the present study, the immunoreactivity of TGF-β1 in the epithelial cells of the studied lesions shows the role of EMT in the pathogenesis of these lesions.
Kumamoto et al. evaluated the expression of TGF-β1 in epithelium and stroma of COC, AOT, calcifying epithelial odontogenic tumor (CEOT), clear cell odonotogenic tumor (CCOT), malignant ameloblastoma and tooth germ. Expression of TGF-β was seen in both stromal and tumoral cells which is in consistent with our results. They demonstrated that TGF-β1 signaling may induce neoplastic differentiation of odontogenic epithelial cells via paracrine and autocrine mechanisms. They also reported that reduced TGF-β immunoreactivity in neoplastic cells of CCOTs and ameloblastic carcinomas may be related to the malignant potential of these lesions. Furthermore CCOTs with more aggressive and metastatic biological behavior showed lower expression of TGF-β1 compared with ameloblastoma. In accordance with these results in the present study the neoplastic epithelial cells of ameloblastoma with more aggressive nature demonstrated lower immunoreactivity compared with COC and OKC cases. It should be noted that there was no significant difference for expression of the marker in epithelium of COCs and ameloblastomas which can show similar biological behavior of these tumors.
Lower immunoreactivity of TGF-β1 was reported in granular cells of granular cell ameloblastoma with more aggressive behavior compared with keratinizing cells of acanthomatous ameloblastoma.  It should be noted that, in the current study we attempted to evaluate the TGF-B expression in epithelial cells as well as stroma of studied groups. We investigated the epithelial immunoreactivity in follicular and plexiform types of ameloblastomas which was lower than stromal immunoexpression.Karathanasi et al. studied TGF-β1 expression and Smad signaling pathway in the epithelium of AOT, ameloblastoma and calcifying cystic odontogenic tumor. Significantly reduced immunoexpression was reported in ameloblastoma lesions. They suggested that impaired TGF-β1/Smad2,3 signaling pathway results in more oncogenic activity of ameloblastoma.
As TGF-β1 normally can function as a tumor suppressor gene with a great inhibitory effect on epithelial cell growth, decreased expression of this marker is an early event during tumor initiation and progression in oral epithelium. Decreased expression of this marker has been reported in oral squamous cell carcinoma and some other cancers.,, TGF-β1 can function as a strong tumor suppressor gene during initial stages of tumorigenesis while it can cause progression of malignancy in the next advanced stages. Therefore reduced TGF-β1 immunoreactivity in ameloblastoma is related to primitive phenotype of this lesion with higher cell proliferation and lower cell differentiation. Other studies ,, also showed decreased apoptotic factors in ameloblastoma compared to AOT and CCOT. We also reported decreased expression of TGF-β1 in epithelium of ameloblastoma that indicates the role of this marker in initial steps of tumorigenesis.
It should be mentioned that statistically significant difference was not observed between COCs and ameloblastomas in both epithelial and stromal cells immunoreactivity which shows the similar nature and biological behavior of these lesions.
| Conclusion|| |
In conclusion, our results show the presence and differential expression of TGF-β1 in the epithelial and stromal cells of the studied groups. As TGF-β1 acts as a strong tumor suppressor gene during initial stages of tumorigenesis, reduced expression of this marker in the epithelial cells of COCs (ameloblastic type) and ameloblastomas compared to OKCs indicates the primitive phenotype of these lesions as well as the role of this marker in neoplastic epithelial cells in initial steps of oncogenesis. There was no statistically significant difference between COCs and ameloblastomas in both stromal and epithelial cells which could be associated with similar nature and biological behavior of these lesions. Reduced stromal expression of TGF-β1 in OKCs could be explained by its looser stroma than other studied lesions.
This study was supported by a grant from the Vice Chancellor of Mashhad University of Medical Sciences, Iran.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]