Odontogenic tumors are lesions derived from the elements of the tooth-forming apparatus and are found exclusively within the jawbones. This review presents a contemporary outline of our current understanding of the molecular and genetic alterations associated with the development and progression of odontogenic tumors, including apoptosis-related factors, telomerase, cell cycle regulators, growth factors, regulators of tooth development, hard tissue-related proteins, cell adhesion molecules, matrix-degrading proteinases, angiogenic factors, and osteolytic cytokines. It is hoped that better understanding of related molecular mechanisms will help to predict the course of odontogenic tumors and lead to the development of new therapeutic concepts for their management.

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To evaluate age-related differences in the expression of heat shock protein (HSP) 27 in periodontal ligament (PDL) cells at the protein and mRNA levels, we obtained PDL cells from the incisors of rats weighing approximately 150 g (young group) and 350 g (aged group) and seeded the cells in culture dishes. Over 2 weeks of cultivation, PDL cells were subjected to quantitative reverse transcription polymerase chain reaction (RT-PCR) to measure HSP27 mRNA, and HSP27 protein expression was examined by immunofluorescence. HSP27 mRNA expression in the young group increased slightly over the 2 weeks, while in the aged group it increased significantly over the same time period. The expression ratio of HSP27 mRNA in the aged group was higher than in the young group at 14 days. Furthermore, immunofluorescence signals for HSP27 were stronger in the aged group than in the young group. These data reveal that PDL cells vary their expression of HSP27 with age, and suggest that in view of such changes in HSP27 mRNA expression, the self-defense mechanism is enhanced in aged PDL cells although their overall homeostatic conditions are suppressed.

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To evaluate the molecular mechanism underlying the antitumor effect of the 5-fluorouracil (5-FU) family on oral cancers, we examined immunohistochemical profiles for thymidylate synthase (TS), a target of 5-FU, and its catabolizing enzyme, dihydropyrimidine dehydrogenase (DPD) in oral squamous cell carcinomas (SCCs). In addition, we investigated whether TS and DPD might be capable of serving as predictors of the anticancer efficacy of the 5-FU family or as prognostic factors. Immunohistochemistry for TS and DPD was performed on formalin-fixed paraffin sections of initial biopsy specimens from 53 patients with primary oral squamous cell carcinoma who received neoadjuvant chemotherapy with 5-FU and with S-1, an improved equivalent of 5-FU, and we also investigated 16 surgical samples of recurrent or metastatic SCC cases. When immunopositive areas for TS and DPD in five unit fields were determined respectively as their expression ratios, TS expressions in stage III-IV tumors were significantly higher than those in stage I-II tumors. The TS expressions in recurrent/metastatic tumors tended to be higher than those of tumors with no recurrence. Tumors with lower TS and DPD expressions had higher responses to 5-FU (P=0.006). We also found correlations between the TS and DPD expression rates and the response levels to 5-FU. The results indicate that the TS and DPD expressions are capable of serving as predictors of the efficacy of these anticancer agents as well as prognostic factors for oral SCCs.

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The purpose of this study was to evaluate the effects of mechanical loading on cultured osteogenic cells from different stages of bone wound healing. A bone cavity was created in a rat femur, and cells were obtained from the cavity during various phases of wound healing: the blood clot (BC) stage, the development of granulation tissue (GT), and callus formation (CF). After 7 days of primary culture, mechanical loading was applied once a day. Cells without mechanical loading were used as controls. Cell proliferation, alkaline phosphatase (ALP) activity and expression of mRNAs of both bone sialoprotein (BSP) and osteopontin (OPN) were evaluated. Cell proliferation of BC cells was significantly inhibited by mechanical loading. However, GT cells were significantly up-regulated by ALP activity at day 5, as were the expressions of BSP and OPN mRNAs at day 7 by mechanical loading. These results suggest that cells in bone granulation tissues have the ability to transduce mechanical stress to osteogenic differentiation.

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To investigate the roles of autophagy-related molecules in odontogenic tumors, we analyzed the expression of Beclin1 and ATG5 in tissue specimens of 11 tooth germs, 41 ameloblastomas, and 6 malignant ameloblastic tumors by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. RT-PCR and Western blot analyses confirmed expression of Beclin1 and ATG5 in all samples of normal and neoplastic odontogenic tissues. Immunohistochemical reactivity for Beclin1 was evident in odontogenic epithelial cells neighboring the basement membrane in tooth germs, ameloblastomas, and metastasizing ameloblastomas. ATG5 reactivity was found in most epithelial components of tooth germs, while ameloblastomas and metastasizing ameloblastomas showed ATG5 expression in many peripheral and some central neoplastic cells. Immunoreactivity for Beclin1 and ATG5 was evident in granular neoplastic cells in granular cell ameloblastomas, and ameloblastic carcinomas and clear cell odontogenic carcinomas showed Beclin1 and ATG5 expression in most neoplastic cells. These findings suggest that autophagic cell death might contribute to cell kinetics in odontogenic tissues. The molecular machinery for autophagy is possibly involved in oncogenesis and cell differentiation of odontogenic epithelium.

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