Objectifs: Notre travail avait pour objectif la prédiction du risque de récidive du cancer de prostate localisé à partir d’une caractérisation multimodale de ce cancer comprenant des facteurs anatomopathologiques, des biomarqueurs tissulaires et des paramètres quantitatifs originaux issus de l’IRM pré-thérapeutique, ainsi que l'élaboration d'une méthodologie pour l'évaluation des corrélations existantes entre ces différents facteurs. Matériel et méthodes : La valeur pronostique de la nouvelle classification ISUP, de l'infiltration lympho-vasculaire, de l'expression des marqueurs Ki67, Survivin et Caveolin-1 a été évaluée sur de larges cohortes multicentriques de patients avec cancer de prostate traité par prostatectomie radicale, en analyse multivariée avec calcul des C-index correspondants. L'intérêt, notamment pronostique, de la radiomique, correspondant à l'extraction et l'étude de caractéristiques quantitatives d'imagerie, a été évalué dans le cancer de prostate par une revue systématique de la littérature. L'intérêt de descripteurs texturaux issus de l'IRM pour la prédiction du risque de récidive biologique a été évalué dans une cohorte monocentrique de patients traités par radiothérapie externe. Dans une étude préliminaire basée sur 8 patients, une méthodologie a été proposée pour la reconstruction 3D de la pièce de prostatectomie et son recalage avec l'imagerie pré-opératoire. Ce travail a alors permis une mise en correspondance des données biologiques tumorales et les données quantitatives de l'imagerie. Des classifieurs pour l'identification et la caractérisation tumorale ont été construits et validés. Résultats : Nos travaux ont confirmé que la nouvelle classification ISUP, l'infiltration lymphovasculaire, et l'expression de Ki-67, Survivin, et Caveolin-1 sur la pièce de prostatectomie étaient associées à des caractéristiques pathologiques défavorables dans le CaP et au risque de récidive biologique après prostatectomie radicale. Cependant, leurs valeurs pronostiques sont limitées comparé aux facteurs pronostiques standards. La radiomique est un domaine prometteur pour l'identification et la caractérisation tumorale dans le CaP mais son intérêt pronostique reste à démontrer. Nos travaux confirment sa valeur pronostique pour les patients traités par radiothérapie externe. Avec une erreur moyenne de recalage de 5 mm, notre méthodologie de recalage nous a ensuite permis de proposer une mise en correspondance des données biologiques tumorales basées sur le score de Gleason et l'expression de marqueurs tissulaires. Cette mise en correspondance a permis l'élaboration de classifieurs permettant de prédire la présence de tumeurs et estimer leur score de Gleason avec des résultats satisfaisants. L'évaluation de l'expression immunohistochimique de marqueurs tissulaires reste limitée. Conclusion : Ces travaux confirment la valeur pronostique de marqueurs issus de l'étude quantitative de l'imagerie pré-opératoire, ainsi que de l'analyse anatomopathologique et immunohistochimique de la pièce de prostatectomie. Une méthodologie de mise en correspondance et de corrélation de ces différents marqueurs a été proposée avec des résultats préliminaires justifiant la poursuite des travaux sur une cohorte de patients plus importante. / Objective: The aim of this work was the prediction of prostate cancer recurrence based on a multimodal characterization of this cancer including pathological markers, tissue biomarkers, and quantitative parameters from Magnetic Resonance Imaging (MRI), and to propose a method to assess correlations between these factors. Material and methods: The prognostic values of the new ISUP groups, the lymphovascular invasion, the expressions of Ki67, Survivin et Caveolin-1 were assessed in large multicentric and international cohorts of patients with prostate cancer treated with radical prostatectomy. A review of the literature investigated the use and the performance of radiomics and texture analysis to predict prostate cancer recurrence. The prognostic value of MRI features including Haralick’s texture features to predict biochemical recurrence after prostate cancer radiotherapy was assessed in a retrospective cohort of 83 patients. In a preliminary study including eight patients, a method to correlate in-vivo observations from pre-operative imaging with biological findings from radical prostatectomy using quantitative analysis was proposed. Résultats: Our studies confirmed the new ISUP groups, the lymphovascular invasion, the expressions of Ki67, Survivin and Caveolin-1 were associated with adverse pathologic features and prostate cancer recurrence after radical prostatectomy. However, these factors did not add clinically relevant information to established models. Our review of the literature revealed radiomics was promising for tumor identification and characterization but that few studies assessed its prognostic value. We demonstrated T2-w Haralick’s features were predictors of biochemical recurrence after prostate cancer radiotherapy. With a mean error of 4.90mm, our method to register prostate whole mount histology to in-vivo MRI resulted in the construction of classifiers to predict the presence of tumor, Gleason score, and Ki67 expression. Conclusion : Our work confirm the prognostic value of different markers from tissue, pathological pre-operative imaging analyses. Our method of registration and correlation of these markers leads to promising preliminary results that justify further evaluation with larger cohorts of patients.

Changes in recent decades in morbidity and mortality of prostate cancer (CAP) is making if a public health problem in several countries, including Brazil. Several studies provide evidence that inflammatory processes and oxidative stress are considered important mechanisms involved in the pathogenesis and progression of CAP, as they induce aberrant cell growth, proliferation and neoplastic transformation of cells. Considering the interaction of these different mechanisms to the CAP, the objective of this study was to evaluate the levels of C-reactive protein (CRP), considered a biomarker of inflammation, as well as the assessment of ischemia modified albumin (IMA) and the ability reduction of iron in plasma (FRAP), novel biomarkers of oxidative stress in patients with CAP. This study included 30 healthy subjects and 25 patients with CAP, which had measured CRP levels, IMA, FRAP, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, uric acid, creatinine, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), adenosine deaminase (ADA), prostate specific antigen total (tPSA), free prostate specific antigen (fPSA) and fraction of free PSA (fPSA%). The concentrations of tPSA, PCR and IMA were significantly higher in patients with CAP, whereas the concentrations of FRAP and fPSA%, were significantly lower in these same patients. It was also possible to observe significant correlations between% fPSA and CRP (r = -0.5059, P <0.001) and tPSA and CRP (r = 0.5104, P <0.001). These results suggest that oxidative and inflammatory processes are increased in prostate cancer, and there is a reduction in the antioxidant defenses in this pathology. / As mudanças nas últimas décadas no perfil de morbi-mortalidade do câncer de próstata (CAP) vem se tornando um problema de saúde pública em vários países, inclusive no Brasil. Vários estudos apresentam evidências de que os processos inflamatórios e o estresse oxidativo são considerados importantes mecanismos envolvidos na patogênese e progressão do CAP, pois induzem o crescimento celular aberrante, a proliferação e a transformação neoplásica das células. Considerando a interação destes diferentes mecanismos com o CAP, o objetivo deste estudo foi avaliar os níveis de proteína C-reativa (PCR), considerado um biomarcador de processo inflamatório, assim como avaliar os níveis de albumina modificada pela isquemia (IMA) e da capacidade de redução do ferro no plasma (FRAP), novos biomarcadores de estresse oxidativo, em pacientes com CAP. Este estudo incluiu 30 indivíduos saudáveis e 25 pacientes com CAP, que tiveram dosados os níveis de PCR, IMA, FRAP, glicose, colesterol total, HDL colesterol, LDL colesterol, triglicérides, ácido úrico, creatinina, albumina, aspartato aminotransferase (AST), alanina aminotransferase (ALT), adenosina desaminase (ADA), antígeno prostático específico total (tPSA), antígeno prostático específico livre (fPSA) e fração livre do PSA (fPSA%). As concentrações de tPSA, PCR e IMA foram significativamente maiores em pacientes com CAP, enquanto que as concentrações de FRAP e fPSA%, foram significativamente menores nestes mesmos pacientes. Também foi possível observar correlações significativas entre fPSA% e PCR (r = - 0,5059, P < 0,001) e tPSA e PCR (r = 0,5104, P < 0,001). Estes resultados sugerem que os processos inflamatórios e oxidativos estão aumentados no câncer da próstata, assim como há uma redução das defesas antioxidantes nesta patologia.

L’IRM représente une modalité d’imagerie du cancer de la prostate qui occupe une place de plus en plus importante pour le diagnostic positif. D’autres indications sont en cours de validation pour établir le pronostique, pour guider le traitement et pour assurer le suivi après traitement notamment partiel. La première partie de ce travail a porté sur les études cliniques de l’IRM dans la sélection des candidats à une surveillance active. Les performances de l’IRM particulièrement dans la détection des cancers antérieurs permettront de réduire le risque de sous-estimation initiale des tumeurs et par conséquent le risque de la reclassification au cours des protocoles de surveillance active. La seconde partie de ce travail a porté sur la corrélation entre les anomalies de signal à l’IRM et les zones tumorales et non tumorales intra-prostatiques. La validation d’une technique simple et reproductible de recalage a permis ensuite une corrélation des anomalies de signal enregistrées sur l’IRM et des paramètres histo-pathologiques quantitatifs des pièces opératoires de prostatectomie. / MRI is an increasingly important imaging modality for prostate cancer diagnosis. Further indications are being validated in prostate cancer to establish the prognostic, to guide treatment and to follow up patients especially after partial treatment. The first part of this work has focused on clinical studies of MRI in patient selection for active surveillance. The performance of MRI particularly in the detection of anterior cancers would reduce the risk of initial underestimation of tumor burden and therefore reduce the risk of reclassification during active surveillance protocols. The second part of this work has focused on the correlation between the signal abnormalities on MRI and intra-prostatic areas. We used a simple and reproducible technique for MRI and histopathology registration and we correlated signal abnormalities recorded on MRI with quantitative histopathological parameters at prostatectomy surgical specimens.

Aims: The purpose of the research was to investigate the benefits of a hereditary colorectal cancer registry in the management of patients and families with Lynch syndrome. In study one, a systematic review was performed to quantify the impact of registration and screening on colorectal cancer (CRC) incidence and mortality, with comparison between familial adenomatous polyposis (FAP) and Lynch syndrome (LS). In study two, a regional Lynch syndrome registry was utilised to evaluate the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) and investigate novel methods for engaging at-risk relatives, including an enhanced role for the general practitioner (GP). In study three, the registry was used to investigate proposed associations between Lynch syndrome and prostate and bladder cancer. In study four, mismatch repair-deficient (dMMR) CRCs from Lynch syndrome patients and randomised-controlled trials (RCTs) were used to evaluate a novel prognostic biomarker, beta-2 microglobulin (B2M). Methods: An electronic database search was conducted to identify studies describing CRC incidence and/or mortality in FAP or LS, with comparison of either: 1) screened and unscreened patients or 2) patients ‘before and after’ establishment of the registry. Using the Manchester regional Lynch syndrome registry database, the uptake of predictive testing and colorectal screening among FDRs was assessed with Kaplan-Meier analysis. Novel strategies for improving engagement were explored via a patient advisory group discussion and a regional primary care questionnaire. Cases of prostate and bladder cancer in male mutation carriers and their male FDRs were identified, and cumulative and relative risks were calculated, using expected rates from cancer registry data. DNA from 350 dMMR CRC specimens from Lynch syndrome patients and RCTs were tested for B2M mutations using Sanger sequencing, and correlated with clinical outcome. Results: 43 studies were included in the systematic review (33 FAP; 10 Lynch). Registry-based screening was associated with a significant reduction in CRC incidence and in Lynch syndrome, CRC-related mortality was negligible in those undergoing surveillance. 242 Lynch syndrome families were recorded on the Manchester Lynch syndrome registry. 329 of 591 (55.7%) eligible FDRs had undergone predictive testing. Uptake was significantly lower in males and younger age groups (<25 yrs). Compliance with colorectal screening was excellent following a mutation positive predictive test but poor in untested individuals (97.3% vs 35.0%). Eight prostate cancers were identified in 821 male LS mutation carriers and male FDRs. MSH2 mutation carriers had a ten-fold increased risk of prostate cancer (RR 10.41; 95%CI 2.80, 26.65) but no association with bladder cancer was identified. 69/286 (24.1%) of dMMR CRCs contained significant B2M mutations. B2M mutations were associated with complete absence of recurrence (0/39) during follow-up in the QUASAR trial (stage II), compared with 14/77 (18.2%) in wild-type B2M (p=0.005). Conclusion: Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in FAP and LS (Level 2a evidence, Grade B recommendation). Funding and managerial support for registries should be made available. Uptake of predictive testing and colorectal screening in Lynch syndrome could be substantially improved, particularly among males and younger age groups, but this requires advances in communication with at-risk relatives. It is unlikely that GPs will actively participate without considerable support from genetics services. A trial of PSA screening in MSH2 mutation carriers from 50 years would be appropriate. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC.

No description available.

The work presented herein is a method optimization for biomolecule detection and identification using Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI). MALDI-MSI is a unique form of mass spectrometry that is highly multiplexed; it can simultaneously retain location information of the mass of multiple ions, allowing for correlation of morphology or pathology to reconstructed ion heat maps. There were three main objectives for the research - 1) A method optimization of sample preparation techniques for bottom-up proteomic MALDI-MSI was performed. This included the optimization of tissue wash steps, trypsin digestion incubation times, and matrix deposition techniques. The results included identifying the appropriate pH for the wash steps to optimize trypsin digestion, an overnight trypsin incubation to allow for complete digestion, and the inclusion of MCAEF – Matrix Coating Assisted by an Electric Field – during matrix coating for enhanced spectra. 2) An unbiased statistical data processing workflow for simultaneous processing of multiple datasets was performed. This was done using a thyroid hormone treated tadpole dataset to gain insight into the metabolism of anuran metamorphosis. Results found included a finalized data processing workflow that detected 5000 metabolite features from five organs were detected in pre-metamorphic tadpoles. Of these detected metabolites, 136 were significantly affected upon exposure to thyroid hormone and 64 metabolites were putatively identified. 3) A sample preparation technique for metabolomic analysis of formalin-fixed paraffin embedded (FFPE) colorectal liver metastasis samples was performed. Results included the importance of using a high mass resolution mass spectrometer while emphasizing more appropriate use of fresh-frozen tissue sections for metabolomic analysis. / Graduate

Ces travaux de thèse s’inscrivent dans le contexte de la prédiction de la toxicité en radiothérapie du cancer de la prostate. Dans l'objectif d'analyser les corrélations spatiales entre la dose et les effets secondaires cette problématique est abordée dans un cadre d'analyse de population. La mise en correspondance inter-individus de l'anatomie et de la distribution de dose planifiée soulève des difficultés liées aux fortes variabilités anatomiques et au faible contraste des images CT considérées. Nous avons envisagé différentes stratégies de recalage non-rigide exploitant les informations relatives aux structures anatomiques, aux combinaisons intensité-structure, ou aux relations inter-structures. Les méthodes proposées s'appuient notamment sur l’utilisation de descripteurs structurels des organes tels que les cartes de distances euclidiennes ou du champ scalaire solution de l’équation de Laplace. Ces méthodes ont permis d'améliorer significativement la précision de la mise en correspondance, tant au niveau anatomique que dosimétrique. Les plus performantes ont été utilisées pour analyser une population de 118 individus. Les comparaisons statistiques des distributions de dose entre les patients souffrant ou non de saignements rectaux ont permis d’identifier une sous-région du rectum où la dose semble corrélée à la toxicité. La sous-région rectale identifiée apparaît potentiellement impliquée et hautement prédictive du risque de saignement. L'approche proposée permet d’améliorer les performances des modèles mathématiques de prédiction de la toxicité. / This thesis deals with the issue of predicting the toxicity within the context of prostate cancer radiotherapy. With the aim of analyzing the spatial correlations between dose and side effects, this problem is addressed in a population analysis framework. Inter-individual matching of both the anatomy and planned dose distribution raises difficulties related to high anatomical variability and low contrast in the CT images. We considered different strategies for non-rigid registration involving the use of information on anatomical structures, intensity-structure combinations, or inter-structures relations. The proposed methods are primarily based on the use of structural descriptors of organs such as Euclidean distance maps or scalar field solution of the Laplace equation. These methods allowed us to significantly improve the accuracy of the matching, at both the dosimetric and the anatomical level. The most accurate matching strategy has been used for analyzing a population of. Statistical comparisons of dose distributions between patients with or without rectal bleeding have been used to identify a rectal sub-region likely correlated with toxicity. The identified rectal sub-region appears potentially involved in side effects and highly predictive of the risk of bleeding. The proposed approach makes it possible to improve the performance of mathematical models for predicting the toxicity.

Les cancers de la prostate sont classés en deux catégories. Les cancers de haut grade se distinguent des cancers de bas grade par une plus forte agressivité et un pronostic plus mauvais. Lorsqu’ils deviennent résistants à l’hormonothérapie, les cancers de haut grade sont traités par une chimiothérapie basée sur les taxanes. Néanmoins, les taux de réponse restent faibles. Il existe donc un réel besoin quant à l'identification d'alternatives thérapeutiques qui soient spécifiques de ce type de tumeur. Dans cette optique, notre travail a été de proposer une telle alternative par une approche qui prenne en compte la génétique spécifique des cancers de haut grade. Nous avons exploité une signature de 86 gènes dont le niveau d’expression permet de discriminer entre les tumeurs de haut et de bas grade. Par une approche in silico originale utilisant la banque de données du NCI, nous avons identifié 382 corrélations entre le niveau d’expression de 50 gènes et la sensibilité à 139 agents antiprolifératifs. Parmi ces corrélations, nous avons identifié une signature de 9 gènes qui est spécifique de la réponse à l’oxaliplatine. Cette signature a été confirmée sur le plan fonctionnel dans les lignées cancéreuses prostatiques DU145 et LNCaP. Nous avons donc fourni la preuve de concept que notre approche permet d’identifier de nouvelles molécules pouvant être utilisées en alternative aux taxanes pour traiter spécifiquement les cancers de haut grade. Cette stratégie permet aussi d’identifier de nouveaux marqueurs (gènes) régulant la sensibilité à certains médicaments. Nos résultats démontrent par exemple le rôle des gènes SHMT, impliqués dans la régulation du métabolisme monocarboné, dans la sensibilité spécifique à l’oxaliplatine par un mécanisme qui fait intervenir, du moins en partie, une dérégulation du niveau de méthylation global de l’ADN. / Prostate cancers are classified in two categories. High grade cancers are distinguished from low grade cancers by their higher agressivity and worse prognostic. When they become refractory to hormone therapy, high grade cancers are treated with a taxane-based chemotherapy. However, response rates remain low. Therefore, there is a real need for the discovery of new therapeutic alternatives which are specific for this type of tumors. For that purpose, our work aimed at proposing such an alternative with a strategy that took into account the high grade genetic background. We exploited a signature of 86 genes for which expression level could distinguish between low grade and high grade tumours. With an original in silico approach, we searched the NCI databases and identified 382 correlations between 50 genes and the sensitivity to 139 antiproliferative agents. Among these, a signature of 9 genes was able to specifically predict cell response to oxaliplatin. This signature was validated at the functional level in two prostate cancer cell lines, DU145 and LNCaP. We have thus provided the proof-of-concept that our approach allows the identification of new drugs that can be used alternatively to taxanes in order to specifically treat high grade prostate cancers. This strategy also allows the identification of new markers (genes) regulating the sensitivity to various drugs. Our results demonstrate for example the implication of SHMT genes, which are involved in the regulation of the one-carbon metabolism, in the specific sensitivity to oxaliplatin, by a mechanism which involves, at least in part, the deregulation of the global level of DNA methylation.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-12T16:47:10Z No. of bitstreams: 1 nataliaanadecarvalho.pdf: 891159 bytes, checksum: 0385c7f940e28e40c5101bfbe6ceaba8 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:16:46Z (GMT) No. of bitstreams: 1 nataliaanadecarvalho.pdf: 891159 bytes, checksum: 0385c7f940e28e40c5101bfbe6ceaba8 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:17:07Z (GMT) No. of bitstreams: 1 nataliaanadecarvalho.pdf: 891159 bytes, checksum: 0385c7f940e28e40c5101bfbe6ceaba8 (MD5) / Made available in DSpace on 2016-01-25T17:17:07Z (GMT). No. of bitstreams: 1 nataliaanadecarvalho.pdf: 891159 bytes, checksum: 0385c7f940e28e40c5101bfbe6ceaba8 (MD5) Previous issue date: 2015-07-28 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Pesquisa qualitativa utilizando a abordagem teórico-filosófico-metodológico de Martin Heidegger, com o objetivo de desvelar o vivido do homem após o diagnóstico de câncer de próstata. O projeto foi encaminhado ao Comitê de Ética e Pesquisa da Universidade Federal de Juiz de Fora, para cumprimento dos aspectos éticos e legais, atendendo à Resolução n° 466/2012 do Conselho Nacional de Saúde, sendo deferido com o parecer nº 525.352. O cenário constitui-se de um Hospital de Ensino da Zona da Mata Mineira e teve como participantes quinze homens que receberam o diagnóstico de câncer de próstata. Os depoimentos foram colhidos por meio da entrevista fenomenológica e emergiram, das estruturas essenciais, as Unidades de Significado. A compreensão vaga e mediana dos significados, primeiro momento metódico, possibilitou a elaboração do fio condutor para a análise interpretativa hermenêutica, segundo momento metódico. Desvelou-se à luz do pensamento de Heidegger que o homem, quando recebe o diagnóstico de câncer de próstata, sentese ameaçado pela doença e por suas consequências, desenvolvendo o movimento da angústia imprópria apresentando o temor, pavor, horror e terror. O ser-aí-apósdiagnóstico- de-câncer-de-próstata, lançado na sua facticidade, expressa um movimento de inautenticidade determinado pelo impessoal, ficando exposto ao falatório e à ambiguidade de tudo o diz a respeito ao câncer de próstata, e, assim, apresenta-se de-caídos. Evidenciaram-se as invisibilidades dos profissionais e serviços de saúde no atendimento a esse homem, marcados pela inautenticidade e impessoalidade. Este estudo, considerando os sentidos desvelados, enfatiza a contribuição para a melhoria da qualidade da assistência ao homem, ratificando ser necessário atender não somente à dimensão física, mas aos aspectos emocionais, sociais e espirituais, frente às atuais Políticas Públicas de Saúde do Homem. E que estas e outras reflexões possibilitam novas fontes de atuação à saúde do homem, além de contribuírem no atendimento às suas necessidades quando diagnosticado com câncer de próstata. / Qualitative research based on Heideggerian's theoretical, philosophical and methodological approach, in order to unveil the lived experiences of men after the diagnosis of prostate cancer. The project was submitted to the Research Ethics Committee of the Federal University of Juiz de Fora, for ethical and legal issues according to National Health Council Resolution n° 466/2012 and was accepted under n° 525.352. The research setting was a teaching hospital at Zona da Mata Mineira and the subjects were fifteen men diagnosed with prostate cancer. Interviews were conducted through phenomenological interviews and some units of signification have emerged from essential structures. Vague and median understanding, the first methodical moment, allowed the development of the central research thread towards the interpretive hermeneutic analysis, called the second methodical moment. In light of Heidegger's thought, it has been shown that the moment this man is diagnosed with prostate cancer he feels threatened by the disease and its consequences, reporting an improper anguish with fear, dread, horror and terror. The being-thereafter- diagnosis-of-prostate-cancer in his facticity reveals an inauthenticity determined by the impersonal being exposed to chattering and the ambiguity over all the aspects related to prostate cancer leading him to decay. The invisibilities of professionals and health services characterized by inauthenticity and impersonality were present in delivering care to man. Regarding the senses unveiled this study emphasizes the contribution provided to improve the quality care delivered to men showing how necessary it is to consider not only physical but emotional, social and spiritual aspects, in view of current Public Policies on Male Health. Furthermore these insights and many others may enable new sources of assistance targeting men’s health, helping to meet their needs when they have to face diagnosis of prostate cancer.

O câncer de próstata é o segundo câncer mais freqüentemente diagnosticado em homens. Durante o crescimento tumoral, as células neoplásicas interagem com a matriz extracelular (MEC). Analisamos o efeito de C16, peptídeo derivado da clivagem da MEC, sobre a migração, invasão e regulação dos invadopódios em células de câncer de próstata (DU145). Ensaios de migração e invasão demonstraram que C16 promoveu um aumento da atividade migratória e invasiva de células DU145 de maneira dose dependente. Demonstramos que o peptídeo estimula a fosforilação de Src. Ensaios de degradação em substrato fluorescente mostraram que C16 promoveu a formação de invadopódios de células DU145. O immunoblot nos revelou que este peptídeo também estimula a expressão de Tks4, Tks5, cortactina e MT1-MMP. C16 estimulou a produção de espécies reativas de oxigênio, importantes para o fenótipo invasivo das células tumorais. Nossos resultados sugerem que o peptídeo C16 regula migração, invasão, invadopódios e suas moléculas-chave e a geração de espécies reativas de oxigênio em células DU145. / Prostate cancer is the second most frequently diagnosed cancer in males. During tumor growth, neoplastic cells interact with the extracellular matrix (ECM) Our Laboratory has demonstrated that peptides derived from ECM cleavage are involved in migration, invasion and invadopodia formation in different tumor cell lines. Invadopodia activity depends on expression of the proteins Tks4, Tks5, cortactin, MT1-MMP, as well as reactive oxygen species (ROS) generation. Migration and invasion assays in chemotaxis chambers demonstrated that C16 increased migration and invasion activities of DU145 cells in a dose-dependent manner. We observed that the peptide stimulated phosphorylation of Src. Fluorescent substrate degradation assay showed that C16 increased invadopodia activity of DU145 cells. Immunoblot revealed that this peptide stimulated Tks4, Tks5, cortactin and MT1-MMP expression. Furthermore, C16 increased ROS production. Our results strongly suggested that C16 regulates migration, invasion, invadopodia key-molecules, and ROS generation in DU145 cells.