Phytochemicals are widely noted for their role in chemoprevention. Potato (Solanum tuberosum L.) is the third most important food crop worldwide and is considered a significant source of antioxidants, providing an ideal delivery system for beneficial compounds. The anti-proliferative and pro-apoptotic properties of potato bioactive compounds have been reported in vitro on human prostate cancer cell lines. However, in vivo studies are limited, and more information is needed to determine the chemopreventive properties of potato in the diet. The objective of this study was to evaluate the effects of potato bioactives on prostate cancer in vivo using a mouse model. Athymic nude mice received xenografts of human prostate cancer cells (PC-3) and were administered extracts of potato bioactives from either the white flesh Solanum bulbocastanum (PI243510) or CO112F2-2P/P (purple-flesh Colorado selection), while control mice received water. Neither potato extract provided a significant reduction in tumor growth nor reduced levels of the pro-angiogenic protein VEGF, but the S. bulbocastanum extract reduced expression of metastasis associated protein 1 (MTA1) in tumors, and both potato extracts reduced MTA1 expression in lungs, suggesting the need for further research on the potential chemopreventive or chemotherapeutic properties of potato bioactives.

Breast cancer is the most common malignancy diagnosed among women and is the first cause of neoplastic death in women globally. In the last decade our understanding of breast cancer biology has increased and led to the development of a number of targeted therapies, one of which is targeting the cell apoptosis pathway. One of the new targeting pathways under investigation, which was found to be involved in both cell apoptosis and cell proliferation processes, is the sphingolipid signalling pathway. The sphingolipid pathway represents a group of intracellular and extracellular bioactive lipid molecules, including ceramide, ceramide- 1-phosphate, sphingosine, and sphingosine-1-phosphate (S1P). In my research, I focused on the role S1P plays in breast cancer and its potential application as a therapeutic agent. I examined the effects of S1P on the apoptosis, proliferation, and cytotoxicity of different types of breast cancer cell lines in vitro. In addition, I evaluated the effect of both low and high doses of S1P when co-administrated with anticancer drugs commonly used in breast cancer treatment in vitro and in vivo. Moreover, I studied the S1P cellular distribution following exogenous administration. My results demonstrate that S1P can selectively induce apoptosis in breast cancer cells without harming normal breast cells and that S1P is more effective against aggressive breast cancer cells. Another major finding of my study is that S1P can increase the efficacy of chemotherapies against human breast cancer cells. Although S1P cannot directly substitute the current chemotherapies, S1P may function as a good candidate for combination therapy. Furthermore, my work showed that the pro-apoptotic and anti-proliferative effect of S1P is correlated with its intracellular action and that chronic exposure of exogenous S1P in vivo is not toxic to the major organs. Certainly, S1P inclusion in breast cancer treatment modalities may decrease the morbidity and mortality of breast cancer patients and improve clinical outcomes. Further investigations are required to understand the mechanism by which S1P induces apoptosis and inhibits cell proliferation.

In developed countries, breast cancer is the commonest malignancy among women. Understanding the mechanisms involved in breast cancer progression and the influence of the microenvironment on cancer cell proliferation, results in better treatments. This study aimed to optimise breast cancer xenograft rates using a novel chamber developed for tissue engineering purposes. The established tumours were subjected to enzyme digestion, creating a single cell suspension, which was then injected into immunocompromised mice at primary, metastatic and intra-cardiac sites. The resulting tumours in the mammary fat pad (MFP) and bone were compared using species-specific reverse-transcription polymerase chain reaction (RT-PCR) and cDNA microarray, to examine the influence of the microenvironment on gene expression. The achieved xenograft graft rates of 25% were similar to those previously reported. The matrix metalloproteinase family of enzymes (MMPs) degrade extracellular matrix, influencing invasion and migration of malignant cells. RT-PCR results showed that the majority of the MMPs expressed in the cancers were stromal rather than tumour in origin. MT1-MMP, MMP-2 and MMP-11 had significantly higher expression levels in the MFP than in the bone, but MMP-9 was expressed more in the bone than MFP. There was also an up-regulation of stromal production of MT1-MMP and MMP-13 in the MFP in the presence of tumour. This may have significance when considering which MMPs are the most appropriate targets for inhibition during cancer treatment. The most significant of the differentially expressed genes on microarray analysis were trefoil factor 1 (TFF1) and insulin growth-factor binding protein 3 (IGFBP-3), both expressed significantly more in tumours from the MFP than the bone. The thesis presented demonstrates some of the complexities of tumour-stromal interactions and supports Paget’s seed-soil theory, confirming in several ways the variation in gene expression in breast cancer between primary and metastatic sites.

Molecular probes capable of detecting colorectal cancer (CRC) are needed for early CRC diagnosis. The objective of this study was to characterize c[CTPSPFSHC]OH (TCP-1), a small peptide derived from phage display selection, for targeting human CRC xenografts using technetium-99m ((99m)Tc)-labeled TCP-1 and fluorescent cyanine-7 (Cy7)-labeled form of the peptide (Cy7-TCP-1). (99m)Tc-TCP-1 was generated by modifying TCP-1 with succinimidyl-6-hydrazino-nicotinamide (S-HYNIC) followed by radiolabeling. In vitro saturation binding experiments were performed for (99m)Tc-TCP-1 in human HCT116 colon cancer cells. SCID mice with human HCT116 cancer xenografts were imaged with (99m)Tc-TCP-1 or control peptide using a small-animal SPECT imager: Group I (n=5) received no blockade; Group II (n=5) received a blocking dose of non-radiolabeled TCP-1. Group III (n=5) were imaged with (99m)Tc-labeled control peptide (inactive peptide). SCID mice with human PC3 prostate cancer xenografts (Group IV, n=5) were also imaged with (99m)Tc-TCP-1. Eight additional SCID mice bearing HCT116 xenografts in dorsal skinfold window chambers (DSWC) were imaged by direct positron imaging of (18)F-fluorodeoxyglucose ((18)F-FDG) and fluorescence microscopy of Cy7-TCP-1. In vitro(99m)Tc-HYNIC-TCP-1 binding assays on HCT 116 cells indicated a mean Kd of 3.04±0.52nM. In cancer xenografts, (99m)Tc-TCP-1 radioactivity (%ID/g) was 1.01±0.15 in the absence of blockade and was reduced to 0.26±0.04 (P<0.01) with blockade. No radioactive uptake was observed in the PC3 tumors with (99m)Tc-TCP-1 or HCT116 tumors with inactive peptide. Cy7-TCP-1 activity localized not only in metabolically active tumors, as defined by (18)F-FDG imaging, but also in peritumoral microvasculature. In conclusion, TCP-1 probes may have a distinct targeting mechanism with high selectivity for CRC and tumor-associated vasculature. Molecular imaging with TCP-1 probes appears promising to detect malignant colorectal lesions.

Les cellules souches cancéreuses mammaires sont considérées d'initier et d'être responsable du développement des tumeurs. Un certain nombre de marqueurs ont été proposées, mais la question sur la définition de la CSC dans les cancers du sein RE+ reste ouverte. Nous avons utilisé les lignées MCF7 et T47D comme modèles RE+ et les SUM159 comme RE- pour rechercher les fractions cellulaires enrichies des CSC. Nous avons utilisé un panel de marqueurs tels qu'ALDH, CD44/CD24, combiné avec la formation de mammosphères. Les xénogreffes dérivées de patients (PDXs) de cancer du sein ont également été analysées. ALDH+ et/ou CD44+/CD24- définie des fractions cellulaires enrichies en cellules initiatrices de mammosphères et la capacité de différenciation dans les SUM159 et T47D, mais pas dans les MCF7. Nous avons demandé si cela pourrait être lié à différents statuts de p53. Dans ce but, nous avons généré des cellules MCF7shP53 et a montré une augmentation nette de fraction CD44+/CD24- dans ces cellules et une formation accrue de mammosphères. Cependant, les fractions triées ALDH+ ou CD44+/CD24- ont augmenté la formation de mammosphères d'un facteur 2 maximal. Nous voulions enrichir les CSC (basées sur l'initiation de mammosphères), les cellules en monocouche et en mammosphères sont exposées sous faible tension d'oxygène (<2%) pendant 7 jours, elles sont ensuite caractérisées sur la base de leur expression d'un certain nombre de marqueurs de différenciation soit par FACS soit par immunofluorescence. Dans les mammosphères des lignées RE+, les cellules ont passé à un phénotype bipotent CK5+/CK8+ et augmenté la fraction CD24+/CD44-. La même tendance a été observée parallèlement dans les cellules incubées en hypoxie. En outre, les sphères ne portent pas d'augmentation de la tumorigénicité. En conclusion, les cellules formant les mammosphères correspondent à un sous-ensemble avec un phénotype spécifique qui ne portent pas d'augmentation de la tumorigénicité. / Breast cancer stem cells (BCSCs) are believed to initiate and sustain tumor development. A number of markers have been proposed but open questions remain on the definition of CSC in ER+ breast cancer. We used MCF7 and T47D BCCL as ER+ models and the SUM159 BCCL for ER- to search for BCSC enriched subpopulations. We used a panel of markers such as ALDH, CD44/CD24, combined with mammosphere formation. Breast patient derived xenografts (PDX) were also analyzed. ALDH+ and/or CD44+/CD24- define fractions of cells enriched in mammosphere initiation and differentiation capacity in SUM159 and T47D, but not in MCF7. We asked whether this could be linked to different p53 statuses. To this aim, we generated MCF7-shp53 cells and showed a net increase in CD44+/CD24- in these cells and increased mammosphere formation. However, sorted ALDH+ or CD44+/CD24- cells increased mammosphere formation at most by a factor 2. We wanted to further enrich for CSC (based on mammosphere initiation), cultured 2D and mammosphere cells to low oxygen (<2%) for 7 days and characterized the cells on the basis of their expression of a number of differentiation markers by either FACS or immunofluorescence. In mammosphere of ER+ BCCL cells switched to a bipotent CK5+/CK8+ phenotype and increased the CD24+/CD44- fraction. Parallel findings were made with cells incubated under low O2. Furthermore, spheres do not bear increased tumorigenicity. In conclusion mammosphere forming cells correspond to a specific phenotypic subset of breast cancer cells that do not bear increased tumorigenicity.

La leucémie aiguë lymphoblastique T (LAL-T) est une hémopathie maligne représentant environ 15% des LAL pédiatriques et 25% des LAL de l'adulte. Malgré l'amélioration de la prise en charge des LAL, le devenir des patients atteints de LAL-T reste péjoratif avec environ 30% de rechute dans les deux années suivant le diagnostic. En effet, les LAL-T constituent un groupe de leucémies particulièrement hétérogène dans lequel différents oncogènes sont activés dans des combinaisons diverses. De ce fait, l'identification de voies oncogéniques pouvant être ciblées thérapeutiquement reste un des défis majeurs dans la recherche translationnelle des LAL-T. Au cours de ma thèse, je me suis intéressée au mode d'activation de deux oncogènes majeurs dans les LAL-T: les oncogènes MYC et TAL1. Nous avons montré que l'hyperactivation de la voie AKT, notamment à travers les mutations perte de fonction du gène PTEN induisait une augmentation de la protéine MYC. Nos résultats suggèrent que les axes MYC et PTEN/AKT pourraient représenter des cibles thérapeutiques potentielles dans les LAL-T. Nous avons alors conduit une étude pharmacologique révélant qu'in vitro plusieurs drogues induisent l'apoptose ou l'arrêt de prolifération des cellules de LAL-T. Par ailleurs, certaines de ces drogues sont responsables d'une inhibition de l'expression de MYC. L'efficacité de ces drogues est maintenant testée in vivo grâce à des souris immunodéficientes xénogreffées avec des cellules de LAL-T primaires humaines. / T-Cell Acute Lymphoblastic Leukemia (T-ALL) are malignant proliferations of thymocytes which represents around 15% of pediatric and 25% of adult ALL. Despite indisputable therapeutic progress, T-ALL remains of poor prognosis and about 30% of cases relapse within the first 2 years following diagnosis. In fact T-ALL is a heterogeneous disease in which different oncogenes are activated in various combinations and this represents a major hurdle in the molecular analysis of T-ALL oncogenesis. During my thesis I investigated how MYC and TAL1, two key oncogenes in T-ALL, are activated. We showed that hyperactivation of AKT pathway, notably through PTEN loss-of-function mutations, gives rise to an increase of MYC protein level. Our data suggest that in T-ALL, MYC and PTEN/AKT axis may represent potential therapeutic targets. Then, we performed a pharmacological study which shows that, in vitro, several drugs lead to apoptosis or proliferation arrest of T-ALL cells. Moreover, some of those drugs impede MYC expression. The efficacy of these compounds are now tested in vivo using immunodeficient mice engrafted with primary human T-ALL blasts.

Após exodontia e instalação de implantes imediatos o sítio edêntulo sofre uma substancial remodelação óssea. O objetivo do presente estudo foi avaliar a remodelação dos tecidos moles e da tábua óssea vestibular em alvéolos pósexodontia e em implantes imediatos em cães com um biotipo periodontal fino, com a associação de um material de enxerto. Oito cães tiveram a espessura da gengiva de um lado da mandíbula reduzida, os pré-molares mandibulares extraídos em cirurgia sem retalho e 4 implantes foram instalados de cada lado à 1,5 mm da tábua óssea vestibular. Os demais alvéolos foram utilizados para o estudo da dinâmica de cicatrização alveolar. Os sítios foram aleatoreamente alocados em: GT (grupo teste) = gengiva fina; GT + ME (GT com material de enxerto); GC (grupo controle) = gengiva normal; e GC + ME (GC com material de enxerto). Espessura da tábua óssea vestibular (ETOV), espessura de gengiva queratinizada (EGQ), largura alveolar (LA), altura de retração gengival (RG) e profundidade de sondagem (PS) foram avaliados clinicamente. Após 12 semanas os cães foram sacrificados e as amostras processadas para as análises de micro-tomografia computadorizada, histologia, histomorfometria, fluorescência e imunohistoquímica. Uma ETOV fina foi observada em todos os cães. Os procedimentos pré-cirúrgicos reduziram a EGQ nos grupos teste, com alterações mínimas na LA. Não houve diferenças estatísticas significantes entre os grupos para os parâmetros clínicos. Em todos os grupos o alvéolo ou o gap vestibular foram preenchidos por osso neoformado e uma leve reabsorção da tábua óssea vestibular foi observada, sem diferença estatística entre os grupos. Nos alvéolos pós-exodontia uma taxa de mineralização numericamente maior foi observada nos grupos que receberam material de enxerto em 12 semanas. A espessura do osso vestibular foi um fator fundamental na reabsorção da tábua óssea vestibular, mesmo com cirurgia sem retalho. Diminuir a gengiva para uma espessura crítica ou a adição de um biomaterial, em um biotipo fino pré-existente, não influenciou os resultados. / After tooth extraction and immediate implant placement the edentulous site undergo marked bone remodeling. The aim of the present study was to evaluate soft tissues and buccal bone remodeling in fresh extraction sockets and immediate implants in dogs with a thin periodontal biotype, with the association of a graft material. The gingiva of 8 dogs was thinned at one side of the mandible, mandibular premolars were extracted without flaps, and 4 implants were installed on each side at 1.5 mm from the buccal bone. The remaining sockets were used for the study of the alveolar healing dynamic. The sites were randomly assigned into: TG (test group) = thin gingiva; TG + GM (TG with grafting material); CG (control group) = normal gingiva; and CG + GM (CG with grafting material). Buccal bone thickness (BBT), thickness of keratinized tissue (TKT), alveolar width (AW), gingival recession height (GR) and probing depth (PD) were clinically evaluated. After 12 weeks the dogs were sacrificed and the samples were processed for microtomographic, histological, histomorphometric, fluorescence and immunohistochemistric analysis. A thin BBT was observed in all the dogs. The pre-surgical procedures reduced gingival thickness in the test groups, with minimal changes of the AW. There were no statistically significant differences among the groups for the clinical parameters. In all the groups the socket or the buccal gap was filled with newly formed bone and a slight buccal bone loss was observed, with no statistical difference among the groups. In the extraction sockets a numerically higher mineralization rate was observed for the grafted groups at 12 weeks. The thickness of the buccal bone was a fundamental factor on buccal bone plate resorption, even with a flapless approach. To reduce the gingival thickness or the addition of a biomaterial, in a thin biotype, did not influence the results.

Após exodontia e instalação de implantes imediatos o sítio edêntulo sofre uma substancial remodelação óssea. O objetivo do presente estudo foi avaliar a remodelação dos tecidos moles e da tábua óssea vestibular em alvéolos pósexodontia e em implantes imediatos em cães com um biotipo periodontal fino, com a associação de um material de enxerto. Oito cães tiveram a espessura da gengiva de um lado da mandíbula reduzida, os pré-molares mandibulares extraídos em cirurgia sem retalho e 4 implantes foram instalados de cada lado à 1,5 mm da tábua óssea vestibular. Os demais alvéolos foram utilizados para o estudo da dinâmica de cicatrização alveolar. Os sítios foram aleatoreamente alocados em: GT (grupo teste) = gengiva fina; GT + ME (GT com material de enxerto); GC (grupo controle) = gengiva normal; e GC + ME (GC com material de enxerto). Espessura da tábua óssea vestibular (ETOV), espessura de gengiva queratinizada (EGQ), largura alveolar (LA), altura de retração gengival (RG) e profundidade de sondagem (PS) foram avaliados clinicamente. Após 12 semanas os cães foram sacrificados e as amostras processadas para as análises de micro-tomografia computadorizada, histologia, histomorfometria, fluorescência e imunohistoquímica. Uma ETOV fina foi observada em todos os cães. Os procedimentos pré-cirúrgicos reduziram a EGQ nos grupos teste, com alterações mínimas na LA. Não houve diferenças estatísticas significantes entre os grupos para os parâmetros clínicos. Em todos os grupos o alvéolo ou o gap vestibular foram preenchidos por osso neoformado e uma leve reabsorção da tábua óssea vestibular foi observada, sem diferença estatística entre os grupos. Nos alvéolos pós-exodontia uma taxa de mineralização numericamente maior foi observada nos grupos que receberam material de enxerto em 12 semanas. A espessura do osso vestibular foi um fator fundamental na reabsorção da tábua óssea vestibular, mesmo com cirurgia sem retalho. Diminuir a gengiva para uma espessura crítica ou a adição de um biomaterial, em um biotipo fino pré-existente, não influenciou os resultados. / After tooth extraction and immediate implant placement the edentulous site undergo marked bone remodeling. The aim of the present study was to evaluate soft tissues and buccal bone remodeling in fresh extraction sockets and immediate implants in dogs with a thin periodontal biotype, with the association of a graft material. The gingiva of 8 dogs was thinned at one side of the mandible, mandibular premolars were extracted without flaps, and 4 implants were installed on each side at 1.5 mm from the buccal bone. The remaining sockets were used for the study of the alveolar healing dynamic. The sites were randomly assigned into: TG (test group) = thin gingiva; TG + GM (TG with grafting material); CG (control group) = normal gingiva; and CG + GM (CG with grafting material). Buccal bone thickness (BBT), thickness of keratinized tissue (TKT), alveolar width (AW), gingival recession height (GR) and probing depth (PD) were clinically evaluated. After 12 weeks the dogs were sacrificed and the samples were processed for microtomographic, histological, histomorphometric, fluorescence and immunohistochemistric analysis. A thin BBT was observed in all the dogs. The pre-surgical procedures reduced gingival thickness in the test groups, with minimal changes of the AW. There were no statistically significant differences among the groups for the clinical parameters. In all the groups the socket or the buccal gap was filled with newly formed bone and a slight buccal bone loss was observed, with no statistical difference among the groups. In the extraction sockets a numerically higher mineralization rate was observed for the grafted groups at 12 weeks. The thickness of the buccal bone was a fundamental factor on buccal bone plate resorption, even with a flapless approach. To reduce the gingival thickness or the addition of a biomaterial, in a thin biotype, did not influence the results.

Introdução: O carcinoma espinocelular (CEC) representa 7% de todos os novos casos de câncer no mundo, sendo o carcinoma espinocelular o tipo mais frequente. Tanto o comportamento biológico quanto o crescimento dos tumores devem ser melhores entendidos, uma vez que a sobrevida dos pacientes apresentou discreta melhora nas últimas décadas. Os modelos PDX foram desenvolvidos para estudar a biologia tumoral e principalmente os mecanismos de crescimento e proliferação através da manutenção da arquitetura e microambiente tumoral do tumor original. Os retinóides possuem a capacidade de restaurar o crescimento e a diferenciação de células normais através da ação dos receptores retinóides nucleares (RARs e RXRs) que são os principais mediadores destas ações que ao sofrerem alterações na sua expressão podem levar ao desenvolvimento e manutenção de tumores. No estudo da carcinogênese o modelo PDX é uma importante ferramenta pois mantém a arquitetura e microambiente do tumor original melhorando a compreensão de algumas vias, entre estas o processo de EMT/MET, na diferenciação das células tronco tumorais e quais receptores nucleares podem estar influenciando nestas vias. Objetivos: Analisar os padrões de comportamento biológico - tempo de formação e expansão do tumor e a manutenção dos padrões histológicos e de arquitetura do tumor original - em F0 e F1 no modelo PDX (xenoenxerto derivado de paciente) das amostras de centro de tumor e epitélio adjacente em camundongos Balb C/nude e avaliar a expressão gênica dos receptores retinóides, ALDH1 e marcadores do processo de EMT/MET por RT-PCR em PDX de carcinoma espinocelular oral em comparação com a amostra dos pacientes doadores nas passagens F(0) e F(1). Método: 24 camundongos Balb C/Nude, divididos em 2 grupos TG(I) – tumor graft paciente (I) e TG(II) – tumor graft paciente (II), subdivididos em 4 grupos de 3 animais: (A) – receberam PDX do centro do tumor; (B) – receberam PDX de epitélio adjacente ao tumor (margem de segurança cirúrgica); (C) receberam PDX de um animal do grupo (A); (D) receberam PDX de um animal do grupo (B). E Após estas fases, as amostras coletadas serão avaliadas por RT-PCR para comparação das expressões gênicas entre a amostra original (CT e EA) com os PDX´s nas passagens F(0) e F(1). Resultados: formação de tumores em todos os grupos – tanto do PDX de fragmento de centro do tumor quanto do PDX do epitélio adjacente. E A expressão gênica dos parâmetros observados não diferem no tumor original e passagem F(0) significativamente diferentes em F(1) (p<0,05). Conclusões: A técnida do PDX para o CEC é possível de ser realizada em menor tempo com a implantação de apenas um fragmento do tumor. Os tumores resultantes do PDX apresentaram tamanho suficiente para novas passagens, bem como para seu 6 uso em estudos de comportamento biológico das células neoplásicas. Quanto ao epitélio adjacente ao tumor (margem de segurança cirúrgica) constatou-se a presença de células tumorais com potencial de promover o crescimento de tumores devendo portanto ser melhor observada nas ressecções. O PDX de primeira passagem F(0) é o que mais se assemelha com o tumor original sendo o melhor para testes terapêuticos e estudos da carcinogênese do CEC oral. Keywords: CECP, modelo PDX, xenoenxerto, margem de segurança cirúrgica, , receptores retinóides, microdissecção a laser. / Introduction: Squamous cell carcinoma (SCC) represents 7% of all new cases of cancer in the world, with squamous cell carcinoma being the most frequent type. Both the biological behavior and the growth of the patients should be better understood, since the patients' survival show unobtrusive improvement in the last decades. PDX models were developed to study a tumor biology and especially the mechanisms of growth and proliferation through maintenance of the architecture and tumor microenvironment of the original tumor. Retinoids have a capacity to restore normal cell growth and differentiation through the action of nuclear retinoid receptors (RARs and RXRs) that are the main mediators and maintenance actions of tumors. In the study of carcinogenesis, the PDX model is an important tool because it maintains an architecture and microenvironment of the original tumor, improving an understanding of some pathways, among them in the EMT / MET process, the difference in tumor stem cells and which nuclear receptors may be influencing these routes. Objectives: To analyze changes in methodology and patterns of biological behavior - time of tumor formation and expansion and maintenance of histological and architectural patterns of the original tumor - in F0 and F1 without PDX model (patient derived xenograft) tumor and adjacent epithelium in Balb C / nude mice and to evaluate the gene expression of retinoid receptors, ALDH1 and EMT / MET process markers by RT-PCR in PDX of oral squamous cell carcinoma compared to a sample of donor patients in F ( 0) and F (1). Method: 24 Balb C / Nude mice, divided into 2 groups TG (I) - patient tumor graft (I) and TG (II) - patient tumor graft (II) subdivided into 4 groups of 3 animals: (A) - received PDX from the center of the tumor; (B) - received epithelial PDX adjacent to the tumor (surgical margin of safety); (C) received PDX from one animal of group (A); (D) received PDX from one animal of group (B). E After these phases, as samples collected for RT-PCR evaluation for comparison of gene expressions between an original sample (CT and EA) with F passages of PDX F (0) and F (1). Results: tumor formation in all groups - both the PDX of the tumor center fragment and the PDX of the adjacent epithelium. E The gene expression of the observed parameters did not differ without original tumor and F (0) differential passage in F (1) (p <0.05). Conclusions: The PDX technique for CPB is possible to be performed in a shorter time with a tumor fragment implantation. Tumors resulting from PDX presented the solution for new passages, as well as for their use in studies of the biological behavior of neoplastic cells. As for the epithelium adjacent to the tumor (surgical margin of safety), a presence of tumor cells with the potential to promote the growth of tumors has been observed and should therefore be better observed in the resections. The first pass PDX F (0) is the one that most closely resembles the 8 original tumor being the best for therapeutic tests and studies of oral SCC carcinogenesis.

Les hémorragies endométriales sont une cause fréquente de consultation gynécologique. Lapparition de ces saignements est probablement facilitée par des perturbations du développement et de la structure des vaisseaux, ce qui est également observé lors dun traitement avec un progestatif à long terme. Toutefois, la raison du déclenchement des hémorragies reste encore obscure. Le but de notre étude a été de développer un modèle de transplantation dendomètre humain chez des souris immunodéficientes afin de déterminer les mécanismes impliqués dans lapparition de saignements utérins lors des menstruations ou liés au traitement local continu par progestatif (lévonorgestrel). Dans ce travail, nous avons étudié les vaisseaux sanguins endométriaux (nombre, taille, maturation), lexpression des enzymes protéolytiques (métalloprotéinases matricielles ou MMPs) et des récepteurs hormonaux aux strogènes et à la progestérone en présence ou non dun progestatif (lévonorgestrel). Nous avons également étudié laction combinée du progestatif et dun inhibiteur de MMPs dans le but de prévenir les saignements utérins. La meilleure compréhension des mécanismes sous-tendant ces pathologies devrait ouvrir des nouvelles perspectives thérapeutiques que le modèle que nous avons mis au point permettra de tester.