Com o aumento da expectativa de vida no Brasil e a possibilidade de detecção precoce através de programas de rastreamento, o câncer de próstata, tem sido considerado um problema de saúde pública. Em um programa de rastreamento voluntário realizado no Hospital de Clínicas de Porto Alegre entre os anos de 1996 e 2000, 3.056 pacientes foram submetidos a um estudo transversal com o objetivo de determinar a prevalência e características do câncer de próstata na amostra. Para a análise estatística foi utilizado o teste qui-quadrado com nível de significância de p < 0,05.A idade média da amostra foi de 60,4 anos e a prevalência do câncer de próstata foi de 2,61%, sendo crescente com o aumento da idade. A sensibilidade e especificidade do PSA foram, respectivamente, 93,8% (IC = 85,4% a 97,7%) e 82,5% (IC = 81,1% a 83,8%), utilizando como ponto de corte do PSA o valor de 4ng/ml. O toque retal apresentou sensibilidade de 60% (IC = 48,4% a 70,6%) e especificidade 83,3% (IC = 81,9% a 84,6%). O número de biópsias realizadas para se diagnosticar um paciente com câncer de próstata foi de 11,9 e variou conforme a faixa etária. No estadiamento clínico, 51,3% dos pacientes eram T1C e 83,75% dos tumores estavam clinicamente confinados ao órgão. Enquanto estudos prospectivos e randomizados que tenham como desfecho a mortalidade não definirem o real papel do diagnóstico precoce do câncer depróstata, os programas de rastreamento devem ser realizados. Este estudo vem ao encontro da necessidade de conhecer a distribuição e as características da doença nas diversas regiões do país. / With the increase in life expectancy in Brazil and the possibility of early detection through screening programs, prostate cancer is being considered a public health problem. In a voluntary screening program performed in Hospital de Clínicas de Porto Alegre between the years of 1996 and 2000, 3,056 patients participated in a cross sectional study with the objective of determining the prevalence and features of prostate cancer in the sample. For statistical analysis, qui square test was performed considering a significance level of p < 0.05. The mean age of the sample was 60.4 years, and the prevalence of prostate cancer was 2.61%, increasing with age. The sensitivity and specificity of PSA were, respectively, 93.8% (CI = 85.4% to 97.7%) and 82.5% (CI = 81.1% to 83.8%) considering 4 ng/ml as the cut-off point for PSA. Rectal examination had a sensitivity of 60% (CI = 48.4% to 70.6%) and a specificity of 83.3% (CI = 81.9% to 84.6%). The amount of biopsies performed for diagnosing a patient with prostate cancer was 11.9 and varied according to age. In clinical staging, 51.3% of patients were T1C and 83.75% of tumors were clinically confined to the organ. While prospective and randomized trials with mortality as the endpoint do not define the real role of early diagnosis in prostate cancer, screening programs should be performed. This study meets the need for knowing the distribution and characteristics of the disease in the different regions of the country.

Orientador: Sara Teresinha Olalla Saad / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-16T20:55:53Z (GMT). No. of bitstreams: 1 Lazarini_Mariana_D.pdf: 4089908 bytes, checksum: bf5ee8f74ac7dfe4c18c3e84bdeeecff (MD5) Previous issue date: 2010 / Resumo: Importante passo para a compreensão dos processos fisiopatológicos das neoplasias é a identificação de genes diferencialmente expressos e das funções biológicas de cada proteína codificada por estes genes. Rho GTPase activating protein 21 (ARHGAP21) é uma proteína pertencente à família RhoGAP, que interage com ARF-GTPases e com alfa-catenina, modulando a dinâmica da actina associada às membranas do Golgi e à integridade das junções aderentes. O objetivo geral do presente estudo foi investigar as funções da proteína ARHGAP21 em células endoteliais e de adenocarcinoma de próstata com relação à viabilidade celular, ciclo celular, migração, adesão e expressão gênica. Neste trabalho foi demonstrado que ARHGAP21 possui atividade RhoGAP para RhoA e RhoC. Em células HUVECs (Human Umbilical Vein Endothelial Cells), foi observada uma localização nuclear e citoplasmática de ARHGAP21 e sua depleção induziu alterações no ciclo celular. Além disso, ensaios de microarranjos de DNA em HUVECs demonstraram modulação de genes como PAI-1, BNIP3, staniocalcina 1 e podocalyxin. Em linhagens celulares de adenocarcinoma de próstata (LNCaP e PC-3), também foi observada uma localização nuclear e citoplasmática de ARHGAP21. A diminuição da expressão desta proteína em células PC-3 resultou em redução da viabilidade e da migração celular em fibronectina. Com relação à viabilidade celular, a inibição de ARHGAP21 tem efeito adicional ao agente quimioterápico cisplatina. Em células LNCaP, por sua vez, foi observada uma menor adesão em matrigel e fibronectina das células submetidas à inibição da expressão de ARHGAP21, em comparação às células controle. Experimentos de microarranjos de DNA e RT-PCR quantitativo em tempo real em células de adenocarcinoma de próstata submetidas à inibição de ARHGAP21 demonstraram expressão alterada dos genes TGF-beta induced e dos genes BNIP3, staniocalcina 1 e podocalyxin, que também foram modulados nas células HUVECs com inibição da expressão de ARHGAP21. Em conclusão, o presente estudo identificou ARHGAP21 como uma proteína com importantes funções em células endoteliais e de adenocarcinoma de próstata, através da regulação da viabilidade, adesão e migração celular. Os achados aqui descritos sugerem que ARHGAP21 pode ser uma molécula alvo para a terapia de neoplasias, provavelmente através da sua função como reguladora da atividade de RhoA e RhoC / Abstract: One step in the path towards building a comprehensive molecular portrait of human cancer is the definition of differentially expressed genes and the function of their coding proteins. Rho GTPase activating protein 21 (ARHGAP21) is a RhoGAP protein, which interacts with ARF-GTPases and alpha-catenin, controlling actin dynamics on Golgi membranes and the integrity of adherens junctions, respectively. The aim of the present study was to investigate ARHGAP21 functions on endothelial and prostate cancer cells regarding to cell viability, cell cycle, migration, adhesion and gene expression. This study demonstrated that ARHGAP21 has RhoGAP activity for RhoA and RhoC. ARHGAP21 localized in the nucleus and cytoplasm of HUVECs (Human Umbilical Vein Endothelial Cells) and its depletion alteres the cell cycle phases. Furthermore, microarrays assays in HUVECs ARHGAP21 knockdown demonstrated modulation of genes such as PAI-1, BNIP3, stanniocalcin 1 and podocalyxin. In the prostate adenocarcinoma cell lines (LNCaP and PC-3), ARHGAP21 is also located in the nucleus and cytoplasm. Depletion of this protein in PC-3 cells resulted in decrease of cell viability and migration in fibronectin. Regarding to cell viability, inhibition of ARHGAP21 has an additional effect on cisplatin chemotherapeutic agent. In LNCaP cells, a lower adhesion was observed in matrigel and fibronectin of cells subjected to inhibition of ARHGAP21 expression compared to control cells. DNA microarray and quantitative RT-PCR experiments on prostate adenocarcinoma cells ARHGAP21 knockdown showed modulation of TGF-beta induced gene expression. The expression of BNIP3, stanniocalcin 1 and podocalyxin was also altered in HUVECs cells ARHGAP21 knockdown. In conclusion, this study identified ARHGAP21 as a protein with important functions in endothelial cells and prostate adenocarcinoma, by regulating cell viability, adhesion and migration. The findings described here suggest that ARHGAP21 may be a molecule target for cancer therapy, probably due to its GAP activity for RhoA and RhoC / Doutorado / Doutor em Fisiopatologia Medica

Orientadores: Akebo Yamakami, Laecio Carvalho de Barros, Laercio Luis Vendite / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Eletrica e de Computação / Made available in DSpace on 2018-08-04T04:11:06Z (GMT). No. of bitstreams: 1 Castanho_MariaJosedePaula_D.pdf: 5605275 bytes, checksum: 589180e36f1eeebf2b8fa1ced3a0a4db (MD5) Previous issue date: 2005 / Resumo: O câncer de próstata é, atualmente, o segundo tipo de câncer com maior incidência entre a população masculina, no Brasil. Estimar o seu estágio, com as informações clínicas disponíveis para decidir a terapia a ser aplicada, é uma tarefa árdua. Neste trabalho, um modelo matemático é elaborado para auxiliar o médico na tomada de decisão. A teoria dos conjuntosfuzzy, por sua capacidade em lidar com incertezas, inerentes aos conceitos médicos, é a ferramenta utilizada, não só para desenvolver o modelo, como também para desenvolver a metodologia para sua avaliação, baseada na análise ROC (Receiver Operating Characteristic). A avaliação foi feita utilizando-se dados obtidos junto ao Instituto Americano do Câncer e permite afinnar que o sistema especialista construí do discrimina pacientes com câncer confinado à próstata daqueles com câncer não-confinado. Considerando a taxa de crescimento como um parâmetro incerto e variável na população, também é apresentado um modelo para descrever o crescimento do tumor / Abstract: Nowadays, prostate cancer is the second most common man cancer diagnosed in Brazil. Predicting the cancer stage from available clinical information to decide the therapy to be used is hard work. ln this study a mathematical model is developed to assist the physician in this task. The fuzzy sets theory provides effective tools to handle and manipulate imprecise data and to make decisions based on such data. As imprecision is a characteristic of medical concepts, this theory is utilized not oniy to develop the model as to develop the methodology for its evaluation, based on ROC (Receiver Operating Characteristic) analysis. To evaluate its performance, data from the American Cancer lnstitute were used. The results indicate that the model is able to discriminate patients with organ-confined disease from those with non-confined cancer. In addition, considering the growth rate as an uncertain, changeable parameter in the population, a model to describe the tumor growth is suggested. / Doutorado / Automação / Doutor em Engenharia Elétrica

As the most frequently diagnosed cancer in North American men, prostate cancer can progress to the androgen independent stage after initial response to androgen ablation therapy. The molecular mechanisms involved in the hormonal progression of prostate cancer are not completely understood. Here, we analyze changes in the transcriptome of prostate cancer cells at different stages of progression to reveal potential mechanisms. Applying Affymetrix GeneChip technology, we identified the transcriptomes in response to stimulation of androgen and PKA pathways in human prostate cancer cells. In addition to PSA, other common target genes were identified. Genes differentially expressed in response to androgen and stimulation of the PKA pathway in vitro were also differentially expressed during hormonal progression in vivo. Upon androgen stimulation, androgen receptor binds to a functional androgen response element within the promoter region of SESN1, a p53 targeted gene, and represses its expression. The expression of SESN1 was induced by castration in LNCaP xenografts, but the expression was eventually suppressed again in the androgen independent stage of prostate cancer. Knockdown of SESN1 promoted the proliferation of prostate cancer cells. Expression patterns of androgen-regulated genes in androgen independent tumours were revealed to be more similar to that from before castration than to the tumors under androgen ablation. The β-catenin, a potent coactivator of the androgen receptor, and Wnt pathway was deregulated in androgen-independent tumours. There was increased nuclear colocalization and interaction of androgen receptor and β-catenin with hormonal progression of prostate cancer. This study provides insight into hormonal effects on prostate cancer and possible pathways involved in the development of androgen independent disease, as well as potential therapeutic targets. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

The mechanism by which prostate cancer progresses from androgen dependence (AD) to androgen independence/castration resistance (AI/CR) is currently a major focus of prostate cancer-related research. Prostate cancers that progress to a state of AI/CR are typically resistant to most standard types of treatments. Due to its primary role in driving normal prostate cell growth and proliferation, the androgen receptor (AR) is believed to play a key role in progression. Coregulators, or any proteins which may either enhance or abrogate AR activity, are considered to be one of the potential mechanisms by which AR function may become impaired. Cyclin G-associated kinase (GAK) was initially identified as a potential coregulator of AR in a Tup 1 repressed transactivation system. A LNCaP cDNA library was screened for proteins which interacted with the NH2-terminus of AR. GAK was isolated from three independent library clones using two different AR baits (AR 1-549 and AR 1-646). This interaction was confirmed via GST pulldown and coimmunoprecipitation experiments, and preliminary luciferase assays suggested that GAK activates AR in a hormone dependent manner. In this study, my objectives were to validate GAK’s role as a coregulator of AR and to determine if overexpressing GAK affects progression to AI. In vitro luciferase assays whereby GAK was either overexpressed or knocked down in both LNCaP and PC3 cells did not significantly affect AR activity. Xenograft experiments utilizing a doxycycline (DOX) inducible lentiviral LNCaP-GAK overexpressing stable cell line demonstrated that while GAK may not play a significant role in modulating AR activity, it may adopt a more subtle role enhancing tumour take and tumour volume growth rate in vivo. While these results could not confirm GAK to be a direct coregulator of AR, it is entirely possible that GAK may influence prostate cancer progression, albeit indirectly. Recent publications report a growing amount of evidence suggesting GAK’s involvement in the critical cellular process of clathrin coated vesicle endocytosis, the dysregulation of which could potentially indirectly affect AR regulated genes. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Le cancer de la prostate est le cancer le plus fréquent chez les hommes dans la plupart des pays développés. C'est le cancer le plus fréquent chez les hommes en France (73.609 cas en 2014) et en Colombie (9564 cas en 2014). En outre, c'est la troisième cause de décès par cancer chez les hommes dans les deux pays (9,3 % en France et 7,1 % en Colombie en 2014). L'une des techniques de traitement est la radiothérapie externe, qui consiste à délivrer un rayonnement ionisant à une cible clinique, à savoir la prostate et les vésicules séminales. En raison des variations anatomiques au cours du traitement, qui consiste en environ 40 fractions de rayonnement délivrant une dose totale allant de 70 à 80Gy, des marges de sécurité sont définies autour de la cible tumorale lors de la planification du traitement. Ceci entraîne des portions d'organes sains voisins de la prostate - la vessie et le rectum - à être inclus dans le volume cible, pouvant conduire à des événements indésirables affectant les fonctions urinaires (hématurie et cystite, entre autres) ou rectale (saignement rectal, incontinence fécale, Etc.). La vessie présente les plus grandes variations de forme entre fractions de traitement, provoquées par des changements continus de volume. Ces variations de forme introduisent des incertitudes géométriques qui rendent difficile l'évaluation de la dose réellement délivrée à la vessie pendant le traitement. Ces incertitudes limitent la possibilité de modéliser une relation dose-volume pour la toxicité génito-urinaire tardive (GU). Le projet QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) a déclaré que la relation dose-réponse pour la toxicité gastro-intestinale tardive (GI) était loin d'être établie. Les variables dosimétriques obtenues à partir de la tomodensitométrie de planification peuvent être faiblement représentative de la dose effectivement administrée. En conséquence, il est crucial de quantifier les incertitudes produites par les variations inter-fraction de la vessie afin de déterminer les facteurs dosimétriques qui affectent les complications GU tardives. Le but de cette thèse était donc de caractériser et de prédire les incertitudes produites par les variations géométriques de la vessie entre les fractions de traitement, en utilisant uniquement la tomodensitométrie de planification comme information d'entrée. En pratique clinique, une seule tomodensitométrie est disponible au moment de la planification du traitement pour un patient typique, alors que des images supplémentaires peuvent être acquises en cours de traitement. Dans cette thèse une approche population a été utilisée pour obtenir suffisamment de données pour apprendre les directions les plus importantes du mouvement et de la déformation de la vessie en utilisant l'analyse en composante principales (ACP). Comme dans les travaux de référence, ces directions ont ensuite été utilisées pour développer des modèles basés population pour prédire et quantifier les incertitudes géométriques de la vessie. Cependant, nous avons utilisé une analyse longitudinale afin de caractériser correctement la variance du patient et les modes spécifiques du patient à partir de la population. Nous avons proposé d'utiliser un modèle à effets mixtes (ME) et une ACP hiérarchique pour séparer la variabilité intra et inter-patients afin de contrôler les effets de cohorte confondus. Finalement, nous avons présenté des modèles sur l'APC comme un outil pour quantifier des incertitudes de la dose produit par le mouvement et déformation de la vessie entre fractions. / Prostate cancer is the most common cancer amongst the male population in most developed countries. It is the most common cancer amongst the male population in France (73.609 cases in 2014) and in Colombia (9564 cases in 2014). It is also the third most common cause of cancer deaths in males in both countries (9.3% and 7.1% in France and in Colombia in 2014, respectively). One of the standard treatment methods is external radiotherapy, which involves delivering ionizing radiation to a clinical target, namely the prostate and seminal vesicles. Due to the uncertain location of organs during treatment, which involves around forty (40) radiation fractions delivering a total dose ranging from 70 to 80Gy, safety margins are defined around the tumor target upon treatment planning. This leads to portions of healthy organs neighboring the prostate or organs at risk — the bladder and rectum — to be included in the target volume, potentially resulting in adverse events affecting patients’ urinary (hematuria and cystitis, among others) or rectal (rectal bleeding, fecal incontinence, etc.) functions. The bladder is notorious for presenting the largest inter-fraction shape variations during treatment, caused by continuous changes in volume. These variations in shape introduce geometric uncertainties that render assessment of the actual dose delivered to the bladder during treatment difficult, thereby leading to dose uncertainties that limit the possibility of modeling dose-volume response for late genitourinary (GU) toxicity. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) project has stated that a similar dose-response to that of late gastrointestinal (GI) toxicity is far from being established. The dosimetric variables obtained from the planning CT prove to be very poor surrogates for the real delivered dose. As a result, it appears crucial to quantify uncertainties produced by inter-fraction bladder variations in order to determine dosimetric factors that affect late GU complications. The aim of this thesis was thus to characterize and predict uncertainties produced by geometric variations of the bladder between fractions, using solely the planning CT as input information. In clinical practice, a single CT scan is only available for a typical patient during the treatment planning while on-treatment CTs/CBCTs are seldom available. In this thesis, we thereby used a population approach to obtain enough data to learn the most important directions of bladder motion and deformation using principal components analysis (PCA). As in groundwork, these directions were then used to develop population-based models in order to predict and quantify geometrical uncertainties of the bladder. However, we use a longitudinal analysis in order to properly characterize both patient-specific variance and modes from the population. We proposed to use mixed-effects (ME) models and hierarchical PCA to separate intra and inter-patient variability to control confounding cohort effects. . Subsequently, we presented PCA models as a tool to quantify dose uncertainties produced by bladder motion and deformation between fractions.

>Magister Scientiae - MSc / Prostate Cancer is the leading cause of cancer-related death in males in the Western world. It is a common biological disease originating from the reproductive system of the male namely, the prostate gland, usually in older patients (over the age of 50) and with a family history of this disease. The disease shows clinical aggressiveness due to genetic alterations of gene expression in prostate epithelial cells. Prostate cancer is currently diagnosed by biopsy and prostate cancer screening via the Prostate-Specific Antigen (PSA) blood test. Early detection is critical and although PSA was discovered to aid in the diagnoses of this cancer at its early stages, it has a disadvantage due to its low specificity thus causing unnecessary biopsies of healthy individuals and overtreatment of patients. Although various studies and efforts have been made to identify the ideal biomarker for prostate cancer and many even being applied to clinical use, it is still challenging and has not replaced the best-known biomarker PSA. PSA test has minimal invasive characteristics, at relatively low cost together with high sensitivity but low specificity. Biomarker discovery is a challenging process and a good biomarker has to be sensitive, specific and its test highly standardized and reproducible as well as identify risk for or diagnose a disease, assess disease severity or progression, predict prognosis or guide treatment. Computational biology plays a significant role in the discovery of new biomarkers, the analyses of disease states and the validation of potential biomarkers. Bioinformatic approaches are effective for the detection of potential micro ribonucleic acid (miRNA) in cancer. Altered miRNA expression may serve as a biomarker for cancer diagnosis and treatment. Small non-protein coding RNA, miRNA are small regulatory RNA molecules that modulate the expression of their target genes. miRNAs influence numerous cancer-relevant processes such as proliferation, cell cycle control, apoptosis, differentiation, migration and metabolism. Discovery and existence of extracellular miRNAs that circulate in the blood of cancer patients has raised the possibility that miRNAs may serve as novel diagnostic markers. Since a single miRNA is said to be able to target several mRNAs, aberrant miRNA expression is capable of disrupting the expression of several mRNAs and proteins. Biomarker discovery for prostate cancer of mRNA and miRNA expression are strongly needed to enable more accurate detection of prostate cancer, improve prediction of tumour aggressiveness and facilitate diagnosis. The aim of this project was to focus on functional analyses of genes and their protein products regulated by previously identified miRNA in prostate cancer using bioinformatics as a tool. Most proteins function in collaboration with other proteins and therefore this study further aims to identify these protein-protein interactions and the biological relevance of these interactions as it relates to Prostate cancer. Various computational databases were used such as STRING, DAVID and GeneHub-GEPIS for functional analyses of these miRNA regulated genes. The main focus was on the 21 genes regulated by several miRNAs identified in a previous study. Results from this study identified six genes; ERP44, GP1BA, IFNG, SEPT2, TNFRSF13C and TNFSF4, as possible diagnostic biomarkers for prostate cancer. These results are promising, since the targeted biomarkers would be easily detectable in bodily fluids with the Gene Ontology (GO) analysis of these gene products showing enrichment for cell surface expression. The six genes identified in silico were associated to transcription factors (TFs) to confirm regulatory control of these TFs in cancer promoting processes and more specifically prostate cancer. The CREB, E2F, Nkx3-1 and p53 TFs were discovered to be linked to the genes IFNG, GP1BA, SEPT2 and TNFRSF13C respectively. The expression of these TFs show strong association with cancer and cancer related pathways specifically prostate cancer and thus demonstrates that these genes can be assessed as possible biomarkers for prostate cancer. The prognostic and predictive values of the candidate genes were evaluated to assess their relationship to prognosis of this disease by means of several in silico prognostic databases. The results revealed expression differences for the majority of the candidate genes were not significantly sufficient to be distinguished as strong prognostic biomarkers in several prostate cancer populations. Although one marker, GP1BA was supported as having prognostic value for prostate cancer based on it's statistical pvalue in one of the prostate cancer patient datasets used. Another candidate gene SEPT2 showed promise as it has some prognostic value in the early stages of the disease. Although the results yielded, based on the in silico analysis, were not the discovery of an ideal diagnostic marker based on the set criteria in this study, further analysis using a molecular approach qRT-PCR can be considered for a detailed followup study on selected candidate genes to evaluate their roles in disease initiation and progression of prostate cancer using cell lines as well as patient samples. / CSIR

Numerous studies have demonstrated that tumour cells have the ability to alter immune function to create an immune suppressed environment. This allows tumour cells to escape immune surveillance and consequently the tumour can progress. Dendritic and T cells have critical roles in immune activation and tolerance and are thus major targets of tumour-mediated immune suppression. Understanding the mechanism(s) by which tumour cells modulate the immune system will facilitate the development of immune system-based therapies for cancer treatments. In this study we sought to determine the nature of, and cellular and molecular mechanisms underlying, changes in immune status during tumour progression using mouse models of prostate cancer. Detailed analysis of the immunological status in a mouse prostate dysplasia model (12T-7slow) revealed that immune suppression accompanied tumour progression. We found that T cells isolated from tumour-bearing hosts were hypo-responsive to antigen stimulation. Furthermore, we demonstrated that CD4+CD25+ regulatory T cells were responsible, at least in part, for this alteration. Anti-CD25 antibody treatment reduced, but did not prevent, tumour growth in either a transplanted prostate tumour model or a spontaneously developing prostate tumour model. In addition, an altered dendritic cell phenotype and an elevated frequency of CD4+CD25+ regulatory T cells were observed within the tumour mass. Similar alterations were observed in the prostate-specific Pten knockout mice which develop advanced prostate adenocarcinoma. Interestingly, evidence of immune activation, such as an increased frequency of activated T cells, was detected in the tumour microenvironment in both mouse prostate tumour models. To identify factors that may play critical roles in the altered immune cell phenotype observed in the tumour microenvironment, a global gene expression profiling analysis was carried out to evaluate the changes in immune-related gene expression patterns. This analysis provided additional evidence for the co-existence of immune suppression and immune activation. Moreover, subsequent analyses suggested that one differentially expressed transcript, interferon regulatory factor 7, and its target genes might be involved in modulating immune cells and/or tumour progression. Taken together, these studies have important implications for designing specific and effective anti-tumour immune therapy strategies that involve manipulation of tumour cells, dendritic cells and regulatory T cells. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate

Vinclozolin (VCZ), an antiandrogenic fungicide, is an endocrine disrupting chemical that is known to possess high affinity for the androgen receptor (AR) and modulate expression of critical androgen-dependant genes in the prostate. In this study, viability and expression of AR, NKX3.1 and CYP3A4 genes were measured in androgen-sensitive prostate cells LNCaP after exposure to VCZ and VCZ treated with S9 microsomes in a time and dose dependent manner. NKX3.1 is an androgen regulated gene that plays a vital role in prostate development. CYP3A4 is involved in xenobiotic metabolism. VCZ decreased the viability at high doses after 48 hours which was slightly mitigated by treatment with S9 metabolites. Expression of NKX3.1 and CYP3A4 was upregulated while an initial downregulation of AR was observed. NKX3.1 upregulation corroborates with possibility of antiandrogens to act as androgens in LNCaP. The results illustrate that VCZ can interfere with the expression of critical prostate genes.

Le phénomène métastatique est important à comprendre puisque de manière irrémédiable, une fois engagé, il conduit le plus souvent au décès des patients. Le cancer de la prostate représente un bon modèle car sa progression du stade hormono-dépendant vers le stade d'hormono-échappement s’accompagne par l’apparition de métastases. Les Protease Activated Receptors (PAR1-4) sont des récepteurs qui jouent un rôle important dans l'hémostase et l'inflammation et dont l’implication dans la prolifération et l'invasion des cellules tumorales a été décrite dans plusieurs tissus. L’étude comparative de l'expression in vitro de PAR1 a confirmé son rôle dans la prolifération et l'invasion des lignées prostatiques normales et tumorales hormono-sensibles comme hormono-indépendantes. Son expression in vivo dans des tissus prostatiques à différents stades pathologiques a montré une surexpression de PAR1 chez les patients ayant atteint le stade d'hormono-échappement, associée à un mauvais pronostic. Son absence s’avère par contre de bon pronostic chez les patients hormonodépendants. L'ensemble des résultats obtenus nous permet de proposer PAR1 comme un nouveau marqueur pronostique pour le cancer de la prostate. L’activation des PARs, comme celle de plusieurs récepteurs de chémokines, apparaît comme un élément fondateur de la transition vers l’état métastatique. Le décryptage de cette combinatoire permettra de mieux comprendre les phénomènes impliqués dans cette transition et permettra de développer des thérapies ciblées pour prévenir l’apparition délétère de métastases / Metastasis is nowadays an important field of research as, once engaged, patients will generally die from their metastatic cancer. Prostate cancer represents an interesting model as its progression from hormone-naïve to hormone-independent status lead to metastatic disease. Protease Activated Receptors (PAR1-4) are G-protein-coupled receptors that play crucial roles in blood coagulation and inflammation but that are likely to play fundamental role in tumor cells proliferation and invasion. In vitro analysis of PAR1 expression in prostate cancer cell lines has confirmed the role of PAR1 in prostate cancer proliferation and invasion. Its expression in vivo in prostate cancer tissues have shown a constant surexpression in hormonerefractory ones, associated with a worse prognosis. However, its absence in hormone-naïve tissues is associated with a good prognosis. These results prompted us to recommend PAR1 as a new prognostic marker associated with prostate cancer progression. PAR activation, as well as several chemokine receptors, seems to be a founder feature of cancer transition to metastasis. Deciphering the pattern of receptor activation will allow a better understanding of the events that drive transition to metastasis and thus the development of new specific targeted therapeutics aimed at stopping deleterious metastatic evolution