Made available in DSpace on 2015-03-03T15:38:43Z (GMT). No. of bitstreams: 1 PedroPAS_TESE_1-70.pdf: 4719637 bytes, checksum: 8f16cb0e2326a80cfc947b1ea2b89641 (MD5) Previous issue date: 2012-02-28 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Myofibroblasts are cells that exhibit a hybrid phenotype, sharing the morphological characteristics of fibroblasts and smooth muscle cells, which is acquired during a process called differentiation. These cells then start to express -SMA, a marker that can be used for their identification. Studies suggest that myofibroblasts are related to the aggressiveness of different tumors and that TGF-1 and IFN- play a role in myofibroblast differentiation, stimulating or inhibiting this differentiation, respectively. The objective of this study was to investigate the role of myofibroblasts in epithelial odontogenic tumors, correlating the presence of these cells with the aggressiveness of the tumor. Immunohistochemistry was used to evaluate the expression of TGF-1 and IFN- in myofibroblast differentiation, as well as the expression of MMP-13, which is activated by myofibroblasts, and of EMMPRIN (extracellular matrix metalloproteinase inducer) as a precursor of this MMP. The sample consisted of 20 solid ameloblastomas, 10 unicystic ameloblastomas, 20 odontogenic keratocysts, and 20 adenomatoid odontogenic tumors. For evaluation of myofibroblasts, anti- -SMA-immunoreactive cells were quantified in connective tissue close to the epithelium. Immunoexpression of TGF-1, IFN-, MMP-13 and EMMPRIN was evaluated in the epithelial and connective tissue components, attributing scores of 0 to 4. The results showed a higher concentration of myofibroblasts in solid ameloblastomas (mean of 30.55), followed by odontogenic keratocysts (22.50), unicystic ameloblastomas (20.80), and adenomatoid odontogenic tumors (19.15) (p=0.001). No significant correlation between TGF-1 and IFN- was observed during the process of myofibroblast differentiation. There was also no correlation between the quantity of myofibroblasts and MMP-13 expression. Significant correlations were found between MMP-13 and TGF-1 (r=0.087; p=0.011), between MMP- 13 and IFN- (r=0.348; p=0.003), as well as between EMMPRIN and MMP-13 (r=0.474; p<0.001) and between EMMPRIN and IFN- (r=0.393; p=0.001). The higher quantity of myofibroblasts observed in solid ameloblastomas, odontogenic keratocysts and unicystic ameloblastomas suggests that these cells are one of the factors responsible for the more aggressive biological behavior of these tumors, although the myofibroblast population was not correlated with TGF-1, IFN-, MMP-13 or EMMPRIN. The correlation between MMP- 13 and TGF-1 suggests that the latter induces the expression of this metalloproteinase. The present results also support the well-established role of EMMPRIN as an inducer of MMP-13. Furthermore, the relationship between EMMPRIN and IFN- and between MMP-13 and IFN- suggests synergism in the antifibrotic effect of these markers / Os miofibroblastos s?o c?lulas que apresentam um fen?tipo h?brido exibindo caracter?sticas morfol?gicas de fibroblastos e de c?lulas musculares lisas, sendo a aquisi??o de tal fen?tipo denominada diferencia??o, passando ent?o a expressar a -SMA, a qual ? importante na identifica??o dessas c?lulas. Estudos t?m sugerido que os miofibroblastos apresentam rela??o com a agressividade de diversas les?es e que o seu processo de diferencia??o estaria relacionado ? express?o do TGF- 1 e do IFN- atuando, respectivamente, no est?mulo e na inibi??o dessa diferencia??o. O objetivo deste trabalho foi investigar o papel dos miofibroblastos em les?es odontog?nicas epiteliais, relacionando-os ? agressividade das les?es e analisar por meio da imuno-histoqu?mica, a express?o do TGF- 1 e IFN- no processo de diferencia??o, al?m da an?lise da MMP-13 que ? ativada por miofibroblastos e do indutor de metaloproteinases de matriz (EMMPRIN) como precursor desta MMP. A amostra foi constitu?da por 20 ameloblastomas s?lidos, 10 ameloblastomas unic?sticos, 20 ceratocistos odontog?nicos e 20 tumores odontog?nicos adenomat?ides. Para a avalia??o dos miofibroblastos, foram quantificadas as c?lulas imunorreativas ao anticorpo - SMA presentes no tecido conjuntivo, pr?ximo ao tecido epitelial. As express?es de TGF- 1, IFN- , MMP-13 e EMMPRIN, foram avaliadas no componente epitelial e no conjuntivo, estabelecendo-se o percentual de imunorreatividade e atribuindo-se escores de 0 a 4. A an?lise dos miofibroblastos evidenciou maior concentra??o nos ameloblastomas s?lidos (m?dia de 30,55), seguido pelos ceratocistos odontog?nicos (22,50), ameloblastomas unic?sticos (20,80) e tumores odontog?nicos adenomat?ides (19,15) com valor de p= 0,001. N?o foi encontrada correla??o significativa entre TGF- 1 e IFN- no processo de diferencia??o dos miofibroblastos, bem como na rela??o entre a quantidade de miofibroblastos e a express?o da MMP-13. Constatou-se, correla??o estat?stica entre MMP-13 e TGF- 1 (r= 0,087; p= 0,011) al?m de significante correla??o entre MMP-13 e IFN- (r=0,348; p=0,003). Entre EMMPRIN e MMP-13 verificou-se signific?ncia (r= 0,474; p<0,001) assim como entre EMMPRIN e IFN- (r=0,393; p=0,001). A maior quantidade de miofibroblastos evidenciada nos ameloblastomas s?lidos, ceratocistos odontog?nicos e ameloblastomas unic?sticos sugere que estas c?lulas podem ser um dos fatores respons?veis para um comportamento biol?gico mais agressivo destas les?es, embora a popula??o de miofibroblastos n?o tenha apresentado correla??o com TGF- - 1, IFN- ,MMP-13 e EMMPRIN. Quanto a correla??o evidenciada entre MMP-13 e TGF- 1, isto pode sugerir um papel indutor do TGF- 1 para a express?o da MMP-13, assim como os resultados deste estudo refor?am a rela??o bem estabelecida do EMMPRIN como indutor da MMP-13. Constatou-se tamb?m rela??o entre EMMPRIN e IFN- assim como entre MMP-13 e IFN- sugerindo, dessa forma, um sinergismo na a??o anti-fibr?tica desses marcadores

Introduktion: Ameloblastom (AB), adenomatoid odontogen tumör (AOT), ameloblastiskt fibrom (AF) och odontogent fibrom (OF) är odontogena tumörer som innehåller epiteliala komponenter. Frekvensen av recidiv hos dessa varierar från låg förekomst till relativt hög förekomst. Syftet med denna studie är att undersöka om Ki-67, p53 och BRAF kan användas som prognostiska markörer i recidivmönstret hos dessa tumörer.Material och metod: Studien genomfördes genom immunohistokemi med monoklonala antikroppar av Ki-67, p53 och BRAF på respektive tumör. Tumörerna hämtades från avdelningen för Oral patologi på Malmö högskola. En statistisk analys utfördes med hjälp av Kruskal-Wallis envägs-ANOVA.Resultat: I de tio AB-fallen kunde en hög proliferation och en hög prevalens av muterade p53 ses. I de sju fallen av AOT kunde en måttligt hög proliferation och en generellt hög prevalens av muterade p53, jämförbara med värden för AB, ses. De sju fallen med AF och de fem fallen med OF visade båda en låg proliferation och en låg förekomst av muterade p53. Skillnaden mellan gruppen AB och AOT och gruppen AF och OF visade en signifikant högre infärgningsintensitet för både Ki-67 (p<0.001) och p53(p=0.001) för gruppen med AB och AOT.Konklusion: Proliferations index med Ki-67 och förekomst av p53-mutationer kan användas som en prognostisk markör för recidiv hos AB och AOT. Det är å andra sidan inte tillämpbart för AF och OF. / Introduction: Ameloblastoma (AB), adenomatoid odontogenic tumour (AOT), ameloblastic fibroma (AF) and odontogenic fibroma (OF) are all odontogenic tumours with an epithelial component. The recurrence rate for these odontogenic tumours varies from low frequencies to quite high frequencies. The aim of this study is to evaluate the expression of Ki-67, p53 and BRAF and the possibility of these antibodies acting as prognostic markers in the recurrence pattern of odontogenic tumours.Material and method: An immunohistochemical study using Ki67, p53 and BRAF monoclonal antibodies was performed on 29 paraffin blocks from the respective tumours obtained at the department of Oral Pathology in the Faculty of Odontology at Malmö University. Statistical analysis was performed with Kruskal-Wallis one-way ANOVA.Results: In the series of ten AB cases high proliferation activity and a high prevalence of p53 mutations was observated. In the seven AOT cases a moderately high proliferative activity as well as a generally high prevalence of p53 mutation, comparable to AB, was observed. The seven cases of AF and the five cases of OF demonstrated a low proliferative activity and a low prevalence of p53 mutation. The difference between AB and AOT versus AF and OF as two separate groups, showed a significantly higher staining intensity for both Ki-67 (p < 0.001) and p53 (p = 0.001) in AB and AOT as a group.Conclusion: Ki-67 proliferation index and p53-mutation status can be considered to be a prognostic marker for AB and AOT recurrence. This is, however, not applicable to AF and OF.

A solução de Carnoy é rotineiramente empregada na prática clínica do cirurgião buco-maxilo-facial no tratamento coadjuvante de tumores odontogênicos benignos, por acreditar que ela possa provocar uma osteonecrose local e promover uma margem de segurança à cirurgia. O objetivo do presente trabalho foi verificar em um estudo in vivo, se a solução de Carnoy (substância teste) realmente causa osteonecrose e qual o seu impacto na reparação do tecido ósseo quando comparada com o soro fisiológico 0,9% (substância controle). Para isso, um defeito monocortical de 3 mm de diâmetro foi criado bilateralmente na superfície vestibular da mandíbula de 15 ratos Wistar sendo que, do lado direito foi realizada uma aplicação da solução de Carnoy por 5 minutos e do lado esquerdo, uma aplicação de soro fisiológico 0,9% por cinco minutos. Os animais foram igualmente subdivididos em três grupos para avaliar os efeitos da solução imediatamente, 3 e 10 dias após as aplicações, quando os espécimes foram coletados e preparados para as análises histológicas e estatísticas. Imediatamente e após 3 dias de sua aplicação, a substância teste não demonstrou provocar mais osteonecrose que a controle. No terceiro dia, ocorreu maior formação de coágulo sanguíneo dentro do defeito monocortical após a aplicação da substância controle; contudo, após 10 dias das aplicações, a quantidade de neoformação óssea não foi diferente entre elas. Concluímos que os efeitos da solução de Carnoy sobre o tecido ósseo devem ser questionados, mas seu poder fixativo das células tumorais não pode ser desprezado. / Carnoy\'s solution is routinely used in clinical practice of oral and maxillofacial surgeons in the supplementary treatment of benign odontogenic tumors, given its capacity to cause local osteonecrosis, promoting a safety margin to the procedure. The aim of this study was to verify by an in vivo model, if Carnoy\'s solution (test) causes more osteonecrosis and what is it effect on bone healing when compared to saline solution 0,9% (control). For this, a monocortical defect was created bilaterally at vestibular aspect of 15 Wistar rats mandibles; right side received one 5 minutes Carnoy\'s solution application and left, one 5 minutes saline application. The animals were equally subdivided in three groups to investigate Carnoy\'s effect immediately, three and ten days after applications, when specimens were collected and prepared to histological and statistical analysis. Immediately and three days after its application, test substance did not show more osteonecrosis than control. At third day, it was observed more formation of blood clot inside monocortical defect for control; however, 10 days after applications, bone healing was not different between substances. We conclude that Carnoy\'s solution effects to bone tissue ought to be questioned but its capacity to fixate tumor cells may not be despised.

No description available.

O objetivo desse estudo foi avaliar as características do tecido conjuntivo de 11 folículos pericoronários, 12 cistos dentígeros e de 14 tumores odontogênicos ceratocísticos (TOCs). A amostra foi submetida às técnicas de Hematoxilina e Eosina, Tricrômico de Masson, Picrosírius, Direct Blue e Orceína. Tricrômico de Masson foi utilizado para avaliação de diferenças de densidade e de paralelismo das fibras colágenas, bem como presença de infiltrado linfoplasmocitário. Picrosírius serviu para mensuração da quantidade de fibras colágenas; Direct Blue e Orceína, para identificação do sistema de fibras elásticas. Lâminas coradas por essas três últimas técnicas foram visualizadas em microscopia confocal a laser. Os resultados mostraram semelhança entre o folículo pericoronário e o TOC: paralelismo de fibras colágenas arranjadas em um padrão eminentemente denso, podendo conter uma camada de densidade frouxa junto ao tecido epitelial. As cápsulas de cistos dentígeros eram compostas por fibras colágenas desorganizadas, ou não paralelas, em um arranjo frouxo com presença de infiltrado linfoplasmocitário. Não foi observada marcação para fibras do sistema elástico. Com base nos resultados, conclui-se que a cápsula do TOC representa o estroma da lesão, desempenhando função de suporte e que, diferentemente, o tecido conjuntivo do cisto dentígero é parte da resposta inflamatória. / The aim of this study was to evaluate the connective tissue features of pericoronal follicles, dentigerous cysts and keratocystic odontogenic tumor. The sample was submitted to Hematoxylin-eosin, Masson Trichrome, Picrosirius, Direct Blue and Orcein stains. Masson Trichrome was performed to distinguish collagen fibers density and parallelism, as well as chronic infiltrate presence. Picrosirius was performed to collagen fibers quantification; Direct Blue and Orcein, to elastic system fibers identification. Picrosirius, Direct Blue and Orcein staining slides were observed by means confocal laser scanning microscope. Results showed similar features between pericoronal follicle and keratocystic odontogenic tumor: parallel collagen fibers, more tightly packed collagen fibers, and sometimes a soft layer beneath epithelial tissue. Dentigerous cyst capsule was composed by wound collagen fibers, soft packed, associated to chronic inflammatory infiltrate. It was not observed elastic system fibers labeling. Based on results, it was concluded that keratocystic odontogenic tumor capsule represent the lesion stroma, playing a support role. This finding is different from dentigerous cyst where connective tissue is produced by inflammatory response.

O objetivo desse estudo foi avaliar as características do tecido conjuntivo de 11 folículos pericoronários, 12 cistos dentígeros e de 14 tumores odontogênicos ceratocísticos (TOCs). A amostra foi submetida às técnicas de Hematoxilina e Eosina, Tricrômico de Masson, Picrosírius, Direct Blue e Orceína. Tricrômico de Masson foi utilizado para avaliação de diferenças de densidade e de paralelismo das fibras colágenas, bem como presença de infiltrado linfoplasmocitário. Picrosírius serviu para mensuração da quantidade de fibras colágenas; Direct Blue e Orceína, para identificação do sistema de fibras elásticas. Lâminas coradas por essas três últimas técnicas foram visualizadas em microscopia confocal a laser. Os resultados mostraram semelhança entre o folículo pericoronário e o TOC: paralelismo de fibras colágenas arranjadas em um padrão eminentemente denso, podendo conter uma camada de densidade frouxa junto ao tecido epitelial. As cápsulas de cistos dentígeros eram compostas por fibras colágenas desorganizadas, ou não paralelas, em um arranjo frouxo com presença de infiltrado linfoplasmocitário. Não foi observada marcação para fibras do sistema elástico. Com base nos resultados, conclui-se que a cápsula do TOC representa o estroma da lesão, desempenhando função de suporte e que, diferentemente, o tecido conjuntivo do cisto dentígero é parte da resposta inflamatória. / The aim of this study was to evaluate the connective tissue features of pericoronal follicles, dentigerous cysts and keratocystic odontogenic tumor. The sample was submitted to Hematoxylin-eosin, Masson Trichrome, Picrosirius, Direct Blue and Orcein stains. Masson Trichrome was performed to distinguish collagen fibers density and parallelism, as well as chronic infiltrate presence. Picrosirius was performed to collagen fibers quantification; Direct Blue and Orcein, to elastic system fibers identification. Picrosirius, Direct Blue and Orcein staining slides were observed by means confocal laser scanning microscope. Results showed similar features between pericoronal follicle and keratocystic odontogenic tumor: parallel collagen fibers, more tightly packed collagen fibers, and sometimes a soft layer beneath epithelial tissue. Dentigerous cyst capsule was composed by wound collagen fibers, soft packed, associated to chronic inflammatory infiltrate. It was not observed elastic system fibers labeling. Based on results, it was concluded that keratocystic odontogenic tumor capsule represent the lesion stroma, playing a support role. This finding is different from dentigerous cyst where connective tissue is produced by inflammatory response.

A solução de Carnoy é rotineiramente empregada na prática clínica do cirurgião buco-maxilo-facial no tratamento coadjuvante de tumores odontogênicos benignos, por acreditar que ela possa provocar uma osteonecrose local e promover uma margem de segurança à cirurgia. O objetivo do presente trabalho foi verificar em um estudo in vivo, se a solução de Carnoy (substância teste) realmente causa osteonecrose e qual o seu impacto na reparação do tecido ósseo quando comparada com o soro fisiológico 0,9% (substância controle). Para isso, um defeito monocortical de 3 mm de diâmetro foi criado bilateralmente na superfície vestibular da mandíbula de 15 ratos Wistar sendo que, do lado direito foi realizada uma aplicação da solução de Carnoy por 5 minutos e do lado esquerdo, uma aplicação de soro fisiológico 0,9% por cinco minutos. Os animais foram igualmente subdivididos em três grupos para avaliar os efeitos da solução imediatamente, 3 e 10 dias após as aplicações, quando os espécimes foram coletados e preparados para as análises histológicas e estatísticas. Imediatamente e após 3 dias de sua aplicação, a substância teste não demonstrou provocar mais osteonecrose que a controle. No terceiro dia, ocorreu maior formação de coágulo sanguíneo dentro do defeito monocortical após a aplicação da substância controle; contudo, após 10 dias das aplicações, a quantidade de neoformação óssea não foi diferente entre elas. Concluímos que os efeitos da solução de Carnoy sobre o tecido ósseo devem ser questionados, mas seu poder fixativo das células tumorais não pode ser desprezado. / Carnoy\'s solution is routinely used in clinical practice of oral and maxillofacial surgeons in the supplementary treatment of benign odontogenic tumors, given its capacity to cause local osteonecrosis, promoting a safety margin to the procedure. The aim of this study was to verify by an in vivo model, if Carnoy\'s solution (test) causes more osteonecrosis and what is it effect on bone healing when compared to saline solution 0,9% (control). For this, a monocortical defect was created bilaterally at vestibular aspect of 15 Wistar rats mandibles; right side received one 5 minutes Carnoy\'s solution application and left, one 5 minutes saline application. The animals were equally subdivided in three groups to investigate Carnoy\'s effect immediately, three and ten days after applications, when specimens were collected and prepared to histological and statistical analysis. Immediately and three days after its application, test substance did not show more osteonecrosis than control. At third day, it was observed more formation of blood clot inside monocortical defect for control; however, 10 days after applications, bone healing was not different between substances. We conclude that Carnoy\'s solution effects to bone tissue ought to be questioned but its capacity to fixate tumor cells may not be despised.

O objetivo desse estudo foi avaliar as características do tecido conjuntivo de 11 folículos pericoronários, 12 cistos dentígeros e de 14 tumores odontogênicos ceratocísticos (TOCs). A amostra foi submetida às técnicas de Hematoxilina e Eosina, Tricrômico de Masson, Picrosírius, Direct Blue e Orceína. Tricrômico de Masson foi utilizado para avaliação de diferenças de densidade e de paralelismo das fibras colágenas, bem como presença de infiltrado linfoplasmocitário. Picrosírius serviu para mensuração da quantidade de fibras colágenas; Direct Blue e Orceína, para identificação do sistema de fibras elásticas. Lâminas coradas por essas três últimas técnicas foram visualizadas em microscopia confocal a laser. Os resultados mostraram semelhança entre o folículo pericoronário e o TOC: paralelismo de fibras colágenas arranjadas em um padrão eminentemente denso, podendo conter uma camada de densidade frouxa junto ao tecido epitelial. As cápsulas de cistos dentígeros eram compostas por fibras colágenas desorganizadas, ou não paralelas, em um arranjo frouxo com presença de infiltrado linfoplasmocitário. Não foi observada marcação para fibras do sistema elástico. Com base nos resultados, conclui-se que a cápsula do TOC representa o estroma da lesão, desempenhando função de suporte e que, diferentemente, o tecido conjuntivo do cisto dentígero é parte da resposta inflamatória. / The aim of this study was to evaluate the connective tissue features of pericoronal follicles, dentigerous cysts and keratocystic odontogenic tumor. The sample was submitted to Hematoxylin-eosin, Masson Trichrome, Picrosirius, Direct Blue and Orcein stains. Masson Trichrome was performed to distinguish collagen fibers density and parallelism, as well as chronic infiltrate presence. Picrosirius was performed to collagen fibers quantification; Direct Blue and Orcein, to elastic system fibers identification. Picrosirius, Direct Blue and Orcein staining slides were observed by means confocal laser scanning microscope. Results showed similar features between pericoronal follicle and keratocystic odontogenic tumor: parallel collagen fibers, more tightly packed collagen fibers, and sometimes a soft layer beneath epithelial tissue. Dentigerous cyst capsule was composed by wound collagen fibers, soft packed, associated to chronic inflammatory infiltrate. It was not observed elastic system fibers labeling. Based on results, it was concluded that keratocystic odontogenic tumor capsule represent the lesion stroma, playing a support role. This finding is different from dentigerous cyst where connective tissue is produced by inflammatory response.

Abstract Collagen XVII (BP180) is a transmembrane component of hemidesmosomes, which connect basal keratinocytes to the basement membrane. The extracellular domain of collagen XVII is proteolytically shed from the cell surface and released to the extracellular matrix. Apart from its function in epithelial cell adhesion, collagen XVII has been suggested to participate in keratinocyte motility. The collagen XVII expression pattern was studied in wounds of oral mucosa and in epithelial tumors. During re-epithelialization, collagen XVII was expressed in the keratinocytes distal to the wound edge, but not in the leading cells of the epithelial tip. Collagen XVII upregulation was observed in moderate/severe dysplasias of oral mucosa. In follicular ameloblastomas and basal cell carcinomas, collagen XVII expression was reduced in peripheral cells, whereas cytoplasmic staining was detected in central tumor cells. Tongue squamous cell carcinomas showed increased collagen XVII expression in grade II/III tumors, particularly in areas of invasive growth. The results suggest a correlation between overexpression of collagen XVII and the invasive potential of the tumor. For the first time, the role of collagen XVII in the regulation of malignant migration was explored. The presence of COL15, the cell adhesion domain of collagen XVII, induced migration of tongue squamous cell carcinoma cells in transmigration assays. Experiments with specific function-blocking integrin antibodies revealed that the promigratory function of COL15 is mediated by αv and α5 integrins. The role of the matrix metalloproteinase (MMP) family of proteolytic enzymes in wound re-epithelialization was studied in a transgenic mouse model. In these mice, a specific inhibitor of MMPs, TIMP-1, was overexpressed in cells that normally produce MMP-9. The healing of cutaneous wounds was found to be significantly delayed, but not prevented, due to the impaired ability of keratinocytes to migrate to the wound area. These results suggest that collagen XVII may participate in epithelial tumor progression and invasion by promoting migration of tumor cells. Based on the present study, epithelial cell-derived MMPs play a significant role in the migration of wound keratinocytes during re-epithelialization.

Afin de mieux comprendre les bases physiopathologiques des tumeurs osseuses des mâchoires, nous avons étudié deux modèles de tumeurs associées à des mutations génétiques connues : la tumeur kératokystique odontogène (TKO), liée à la mutation de PTCH1, et le chérubinisme, lié à la mutation de SH3BP2. Au regard des travaux d’oncogénétique, nous formulons l’hypothèse que le développement des tumeurs ostéolytiques bénignes des mâchoires de l’enfant et leur agressivité repose sur un mécanisme génétique. Nous avons montré que la présence d’une mutation de PTCH1 (germinale avec syndrome de Gorlin) dans les TKO était un facteur de mauvais pronostic, stimulant un centre tumoral secondaire, responsable de lésions à distance, mais que cette agressivité pouvait aussi être liée à des mécanismes inflammatoires. Dans le chérubinisme, nous avons montré que la mutation était responsable du phénotype, mais que le type de mutation n’influençait pas le pronostic ni l’agressivité. L’agressivité tumorale est liée au phénotype des cellules géantes multinucléées (cellules myéloïdes à différenciation macrophagique ou ostéoclastique). Nous avons montré, que le modèle murin ne pouvait pas s’appliquer à la pathologie humaine, avec notamment un rôle très secondaire du TNF-α. Enfin nous avons démontré le rôle important de NFATc1 dans la physiopathologie du chérubinisme qui nous a permis de proposer, le tacrolimus, comme le premier agent thérapeutique efficace. Nos résultats suggèrent que les mutations induisent la pathologie et que les changements du microenvironnement (liés à la flore buccale ou à l’éruption dentaire) entretiennent la pathologie. / To determine pathophysiological bases of jawbone tumors, we studied two genetic models of jawbone tumors: keratocystic odontogenic tumors (KOT) associated to PTCH1 mutation and cherubism associated to SH3BP2 mutation. From oncogenetic theory, we postulate that genetic background controls the development of benign children jawbone tumors. From our work, we demonstrated that PTCH1 mutation (germline mutation in Gorlin syndrome) was an unfavorable prognosis factor for KOT, leading to distant and independent daughter tumors. Moreover, we showed, that chorionic inflammation was associated with a high recurrence rate. In cherubism, SH3BP2 mutation produced cherubism phenotype, but the type of mutation did not affect the aggressiveness of the disease. Cherubism aggressiveness was determined by the phenotype of giant multinucleated cells (whether osteoclasts or macrophages). Furthermore, we showed that murine model could not be transposed to human pathology; indeed it appeared that TNF- α did not play a critical role in human cherubism. On the other side, we showed that NFATc1 played a crucial role in cherubism pathophysiology; this observation allowed us to propose, the tacrolimus, as an effective treatment for this disease. Our results suggest that genetic background induced tumor development, and that microenvironment changes (due to flora of the oral cavity and to teeth eruptions) are responsible to the maintenance and the progression of the disease.