En France comme dans la majorité des pays développés, le cancer de la prostate est le plus fréquent chez l’homme. Il est clairement établi que les altérations génétiques et épigénétiques sont des événements communs dans les cancers de la prostate, se traduisant par l’expression aberrante de gènes critiques. La méthylation des histones participe à la régulation de l’expression des gènes dans la cellule. La marque épigénétique H3K27me3 est associée à la répression génique et se trouve dérégulée dans les cancers de la prostate. Ses niveaux sont déterminés par l’équilibre entre les activités de la méthyltransférase d’histone EZH2 et de la déméthylase d’histone JMJD3. Afin de comprendre le mécanisme de dépôt de H3K27me3 dans la tumorigenèse prostatique, le travail de cette thèse s’est orienté sur l’évaluation simultanée de l’impact de JMJD3 et de EZH2. Dans un premier temps, les niveaux d’expression de JMJD3 et de EZH2 ont été montrés augmentés simultanément dans le cancer de la prostate. Cette augmentation est corrélée à un enrichissement de ces deux protéines sur le promoteur des gènes RARβ2, ERα, RGMA, AR et PGR. Dans un deuxième temps, une analyse transcriptomique a permis d’identifier une signature génique corrélée avec le niveau d’agressivité de la tumeur. L’utilisation des « épidrogues » GSK-J4 et DZNeP ciblant JMJD3 et EZH2 permettent de moduler l’expression de ces gènes. L’ensemble de ces résultats caractérise JMJD3 et EZH2 comme des facteurs clés dans le processus de tumorigenèse prostatique. Le panel de gènes identifié devrait permettre de développer de potentiels marqueurs de diagnostic mais également de pronostic dans le cancer de la prostate et sa modulation par les « épidrogues » permettra de développer de nouvelles stratégies thérapeutiques. / In France like in majority of developed countries, prostate cancer is the most common cancer in men. It has been clearly established that genetic and epigenetic alterations are common events in prostate cancer resulting in aberrant gene expression. Histone methylation are involved in gene expression of cells. The H3K27me3 epigenetic mark is a repressive mark and it is deregulated in prostate cancer. H3K27me3 levels are determined by the balance between histone methyltransferase EZH2 and histone demethylase JMJD3 activities. In order to understand the mechanism of H3K27me3 deposition in prostatic tumorigenesis, this thesis focused on the simultaneous assessment of the impact of JMJD3 and EZH2.Firstly, expression levels of JMJD3 and EZH2 were shown to be simultaneously increased in prostate cancer. The increase is correlated to both protein enrichments on RARβ2, ERα, RGMA, AR and PGR gene promotors. Secondly, transcriptomic analysis identified gene signature correlated with tumor aggressiveness. The utilization of GSK-J4 and DZNeP epidrugs targeting JMJD3 and EZH2 allowed us to modulate gene expressionOur results characterized JMJD3 and EZH2 as key factors in prostatic tumorigenesis process. The identified gene panel would be able to develop potential diagnostic and prognostic markers in prostate cancer and their modulation by epidrugs would make new therapeutic strategies.

The isoprenoid biosynthetic pathway (IBP) has been highly implicated in a number of cellular malignancies, including proliferation, invasion, and migration. Epidemiological studies have found clinically relevant inhibitors of the IBP, such as the statin family and nitrogenous bisphosphonates, reduce the risk of prostate cancer advancement. In vitro work has implicated statin's and nitrogenous bisphosphonate's inhibition of GGPP and protein geranylgeranylation as the components responsible for their reduction of prostate cancer progression. However, their depletion of nearly all isoprenoid intermediates as well as their organ specificities make understanding the specific role of protein geranylgeranylation in prostate cancer metastasis impossible. Consequently, we have developed a novel library of seven alkyl bisphosphonate ethers found to potently reduce GGDPS with little to no activity against the related FDPS enzyme. Inhibition of GGDPS in three human prostate cancer cell lines reduced GGPP and protein geranylgeranylation without affecting protein farnesylation, translating into a reduction in cell migration and invasion. Interestingly, the GGDPS inhibitors reduced protein geranylgeranylation at lower concentrations in the highly metastatic PC3 cell line as compared to the less metastatic LNCaP and 22Rv1 cell lines. Additionally, the PC3 cell line was found to have higher levels of endogenous IBP intermediates as compared to the less metastatic cells. Translation in vivo using two murine models of human prostate cancer metastasis found a reduction in soft tissue tumor burden that corresponded to a biochemical reduction in protein geranylgeranylation. In conclusion, selective reduction of GGPP and protein geranylgeranylation was sufficient to reduce the metastatic potential of prostate cancer in vitro and in vivo.

Le cancer de la prostate est la deuxième cause de décès masculins par cancer dans les pays industrialisés. PTEN est le gène suppresseur de tumeur le plus souvent muté ou délété dans les cancers de la prostate. Notre étude montre que la perte de Pten induit la prolifération des PEC menant à la formation de PIN. L’hyperprolifération des PEC engendre une réponse de dommages à l’ADN suivie de l’entrée en sénescence des PEC. Des études épidémiologiques ont montré que de faibles taux de Vitamine D sont associés à des cancers agressifs. Nos résultats montrent que Vdr et le Gemini-72, un analogue hypocalcémique de la Vitamine D, a des activités anti-inflammatoires et anti-prolifératives pendant la formation des PIN. De plus, le Gemini-72 induit l’apoptose des PEC sénescentes, module la réponse immunitaire et ainsi réduit le nombre de PIN de haut grade et la réaction stromale. Ainsi, notre étude démontre l’importance de l’axe Vitamine D/VDR dans la carcinogenèse prostatique. / Prostate cancer is the 2nd leading cause of cancer-related deaths in males of western societies. Mutations or deletion of the PTEN locus are common in prostate cancer, and are associated with metastasis and resistance to therapeutic castration. Our results show that Pten-loss induces the proliferation of PEC leading to the formation of PIN. The hyperproliferation of PEC induces DDR followed by senescence entry of PEC. Epidemiological studies highlighted that low Vitamin D levels correlate with aggressive prostate cancer. We show that Vdr and Gemini-72, an hypocalcemic Vitamin D analog, have anti-proliferative and anti-inflammatory activities during PIN formation. Moreover, the Gemini-72 induces apoptosis in senescent cells, modulates the immune response and consequently decreases the number of High Grade PIN and reduces the stromal reaction. Thus, our study demonstrate the major role of Vitamin D signaling in prostate carcinogenesis.

>Magister Scientiae - MSc / This study sought to identify the bottlenecks in the promotion of Zimbabwean Traditional Medicines (ZTMs) towards improving the national healthcare delivery system. The indigenous medicines lost value and recognition to the Conventional Western Medicines introduced by the British colonialist since 1871 and is still dominating the national healthcare delivery system. There are growing challenges to ensure accessibility of affordable drugs especially for primary healthcare. The World Health Organization (WHO) and United Nations (UN) is in support of re-engaging indigenous medical interventions to achieve the Millennium development goals. Indigenous Traditional Medicine Knowledge-Based Systems (ITMKS) form the basis of the main source of health care for about 80% of the population in the developing countries. The implementation of the Zimbabwe Traditional Medicines Policy (ZTMP) has been at a stand-still since inception in 2007. The research used mixed methods involving qualitative and quantitative approaches. Data was collected through desk and field research. Questionnaires and focus group discussions were used to record perceptions and attitudes of key informants. The stakeholders included Traditional Health Practitioners (THPs), Medical Doctors, Pharmacists, Medical Research Council of Zimbabwe (MRCZ) staff, Medicines Control Authority of Zimbabwe (MCAZ), Traditional Medical Practitioner’s Council (TMPC), Zimbabwe National Traditional Healers Association (Zinatha), Ministry of Health and Childcare, WHO, Higher Education Institutions (UZ School of Pharmacy staff and students), Christian Groups, NGOs and Prostate Cancer Patients in Harare CBD. The stakeholders sampling framework was obtained from the list of registered practitioners. The stakeholder mapping involved selection of 5 key informants from each focus group obtained through random selection. The Snowball sampling technique was used to follow the closest 5 key informants in each focus group. The key findings established that 80% of respondents agreed to the integration of ZTM. The major bottlenecks were lack of modern dosage forms and standardization to determine quality, safety and efficacy of the ZTM. The study suggests that in order to fast track the integration process, a bottom up implementation strategy providing ZTM advocacy, capacity building in the institutionalization and training of ZTMPs, pharmacists and CMP need to be engaged for a favorable and quick buy-in. The study also recommends further analysis of the Indigenous Knowledge Systems (IKS) areas of specialization in pharmaceutical practice in order to improve treatment outcomes.

Le cancer de la prostate est un véritable problème de santé publique qui se situe au premier rang des cancers incidents chez l’homme. Les cellules tumorales ont un métabolisme différent des cellules normales, et cibler le métabolisme des cellules cancéreuses est devenu une stratégie thérapeutique prometteuse. La metformine est un médicament couramment prescrit contre le diabète de type II, qui possède des propriétés anti-tumorales et affecte le métabolisme des cellules cancéreuses. L'augmentation de la lipogenèse est observée dans nombreux cancers dont le cancer de la prostate. Nous montrons que la metformine inhibe la lipogenèse dans les cellules cancéreuses de prostate via un déficit énergétique cellulaire. En effet, l’ATP est diminuée de façon dose dépendante par la metformine et cette diminution est significativement corrélée avec l'inhibition de la lipogenèse. De plus, la metformine induit un gonflement des mitochondries et une désorganisation des crêtes mitochondriales dans les cellules cancéreuses de prostate. De façon intéressante, nous observons que la metformine provoque une augmentation des flux calciques et un relargage du calcium du réticulum endoplasmique. Nous émettons l'hypothèse que ce calcium s'accumule dans la mitochondrie ce qui pourrait générer un gonflement de celles-ci. En réponse à ces signaux calciques ou à la diminution de la fonctionnalité des mitochondries, la metformine stimule la biogenèse mitochondriale dans les cellules cancéreuses de prostate. En conclusion, cette étude a permis de mieux comprendre les mécanismes moléculaires et cellulaires induits par la metformine dans le cancer de la prostate. / Prostate cancer is a major public health problem. Tumor cells have a different metabolism than normal cells, and targeting cancer cells metabolism becomes a promising therapeutic strategy. Metformin is a commonly prescribed anti-diabetic drug which has anti-tumor properties. Increased lipogenesis is a common feature of cancer cells including prostate cancer. We show that metformin effect on lipogenesis is due to a cellular energy deficit. Lipogenesis requires ATP and the decrease in ATP induced by metformin is significantly correlated with the inhibition of lipogenesis. Furthermore, we demonstrate that metformin induces mitochondrial swelling and disruption of cristae in prostate cancer cells. Interestingly, we show that metformin triggers a calcium flux and the release of calcium from the endoplasmic reticulum. We hypothesize that the accumulation of calcium into the mitochondria generates its swelling. In addition, we show that metformin stimulates mitochondrial biogenesis in prostate cancer cells. In conclusion, this study allowed to better understand the molecular and cellular mechanisms induced by metformin in prostate cancer.

Abstract not available

<p>Prostatacancer är den vanligaste tumörsjukdomen bland män som innebär en process där tankar och känslor har sin påverkan. Uppsatsens huvudsyfte har varit att ta reda på hur män som får sin prostatacancer diagnos upplever sin livssituation. Av intresse var att få hur deras identitet påverkats och veta vilka strategier de använder för att göra livet hanterbart. Hela arbetet genomsyrades av den fenomenologiska och den hermeneutiska vetenskapsfilosofiska positionen. Uppsatsen var en kvalitativ studie där halvstrukturerade intervjuer användes. Genom att ha intervjuat två män som har haft prostatacancer, en läkare och en kurator valdes fyra teman för analysen: familj, socialt liv/omgivning/fritid, arbete och behandlingar. I varje tema utkristalliserades identiteten och de copingstrategierna männen använder som även analyseras under varje tema. Teorin om coping, kristeorin och det psykodynamiska perspektivet användes som analysverktyg. Resultatet gav en ökad förståelse för hur männens reaktioner, tankar, känslor och agerande kan se ut vid en prostatacancer diagnos. Samtidigt gav uppsatsen en bild av hur identiteten blir påverkade och hur männen upplever detta i olika sammanhang. I uppsatsen framkom att identiteten förknippas ofta med sexualiteten. Både inom litteraturen och inom undersökningen som sådan framkom behovet av forskning inom de områden den aktuella uppsatsen berörde.</p>

<p>Prostate cancer is the most common type of cancer in men in Europe and the USA. Some prostate tumours are regarded as stiffer than the surrounding normal tissue, and therefore it is of interest to be able to reliably measure prostate tissue stiffness. The methods presently used to detect prostate cancer are inexact, and new techniques are needed. In this licentiate thesis resonance sensor technology, with its ability to measure tissue stiffness, was applied to normal and cancerous prostate tissue.</p><p>A piezoelectric transducer element in a feedback system can be set to vibrate at its resonance frequency. When the sensor element contacts an object a change in the resonance frequency is observed, and this feature has been utilized in sensor systems to describe physical properties of different objects. For medical applications it has been used to measure stiffness variations due to various pathophysiological conditions.</p><p>An impression-controlled resonance sensor system was used to quantify stiffness in human prostate tissue in vitro using a combination of frequency change and force measurements. Measurements on prostate tissue showed statistically significant (p < 0.001) and reproducible differences between normal healthy tissue and tumour tissue when using a multivariate parameter analysis. Measured stiffness varied in both the normal tissue and tumour tissue group. One source of variation was assumed to be related to differences in tissue composition. Other sources of error could be uneven surfaces, different levels of dehydration of the prostates, and actual differences between patients.</p><p>The prostate specimens were also subjected to morphometric measurements, and the sensor parameter was compared with the morphology of the tissue with linear regression. In the probe impression interval 0.5–1.7 mm, the maximum coefficient of determination was R2 ≥ 0.60 (p < 0.05, n = 75). An increase in the proportion of prostate stones (corpora amylacea), stroma, or cancer in relation to healthy glandular tissue increased the measured stiffness. Cancer and stroma had the greatest effect on the measured stiffness. The deeper the sensor was pressed, the greater, i.e., deeper, volume it sensed.</p><p>It is concluded that prostate cancer increases the measured stiffness as compared with healthy glandular tissue, but areas with predominantly stroma or many stones could be more difficult to differentiate from cancer. Furthermore, the results of this study indicated that the resonance sensor could be used to detect stiffness variations in human prostate tissue in vitro, and especially due to prostate cancer. This is promising for the development of a future diagnostic tool for prostate cancer.</p>

Prostate cancer is responsible for a substantial loss of life and burden of suffering among adult males. Evidence suggests that the risk of morbidity and mortality from prostate cancer can be reduced through specific screening and dietary practices (MCI, 2002; Ries et al., 2002). Further evidence suggests that screening can be encouraged by promoting health enhancing behaviors (e.g. regular preventative exams and discussing cancer with others) in the early adult years; yet nearly all studies of prostate cancer have focused on men over the age of forty. As a result, little is known about men's health-seeking behaviors related to prostate cancer including information-seeking behavior and intentions to screen or what men know of prostate cancer. Some evidence suggests that men may know as much (or more) about breast cancer in women as they know about prostate cancer (Chamot & Perneger, 2002). This pilot study sought to expand the current foundational research on men 18 to 40 years of age. The study was designed to a) describe young men's information-seeking behavior for prostate cancer; b) describe young men's knowledge of prostate cancer; c) contrast young men's information-seeking behavior and knowledge of prostate cancer with information-seeking behavior and knowledge for breast cancer; d) examine the correlation among constructs of the Health Belief Model (perceived susceptibility, perceived severity, perceived benefits, perceived barriers, knowledge, cues to action) and intention to talk with others (family, friends, and physicians) about prostate cancer; and e) examine the correlation among constructs of the Health Belief Model and intention to seek a regular age-appropriate preventative physical examination. This cross-sectional study utilized a 46-question, multiple page, Internet-based survey. The survey was administered to 513 men between the ages of 18 and 40 years of age at Oregon State University. One hundred and five male students responded and completed the survey. Correlated groups t-tests, and Wilcoxan-signed rank tests were applied to examine differences in scores for prostate and breast cancer for various information-seeking behaviors. Hierarchical multiple correlation was applied to evaluate the relationship among constructs of the Health Belief Model. Lastly, one-way analysis of variance, and the Mann-Whitney Test were applied to analyze the independent relationships between various modifying factors of the Health Belief Model (educational attainment, income level, health status, and race) and intention. The findings of the study indicate that men talk with few others about prostate cancer, and generally are exposed to less information about prostate cancer than breast cancer. The study also demonstrated low knowledge among young adult males regarding both prostate and breast cancer, and indicated that substantial progress can be made to better inform males about these cancers. Lastly, results suggest that constructs of the Health Belief Model are correlated with intention to seek a regular preventative examination and intention to discuss prostate cancer with others. Together, the findings of this study highlight the need to improve knowledge of prostate cancer among men, increase early health-seeking behaviors, and encourage dialogue among men about prostate cancer and breast cancer. / Graduation date: 2005

Research has shown that men treated for localized prostate cancer (PC) experience physical side effects of treatment that can compromise emotional well being (EWB). Psychosocial factors such as social support can buffer decrements in EWB associated with cancer treatment. The Social Cognitive Processing (SCP) model proposes that communication between the patient and their social support network results in greater processing of cancer adjustment related information and that such processing mediates the relationship between social support and better EWB. Few studies have investigated this relationship in PC populations. The current study sought to evaluate the SCP model in a sample of men who have undergone treatment for localized PC. The study (N=260) was conducted in an ethnically (37% Caucasian, 37% Hispanic, 15% African American) and demographically diverse sample using a cross-sectional design. After controlling for factors significantly associated with EWB (ethnicity, medical co-morbidities and number of years of education), results indicated that higher levels of social support were significantly related with higher levels of EWB (beta=.30, p<.01). Results also showed that two measures of cognitive processing (illness coherence and cognitive processing as a coping strategy) partially mediated the relationship between social support and EWB (illness coherence: z=2.28, p<.05; cognitive processing as a coping strategy: z=2.00, p<.05). Furthermore, perceived stress appeared to moderate the overall mediation model (beta=.91, p<.01) such that cognitive processing mediated the relationship between social support and EWB for individuals perceiving low levels of stress (z=1.90, p<.05), but not for individuals perceiving high levels of stress (z=.09, p>.05). Results suggest the importance of cognitive processing and perceived stress as potential targets for future intervention work designed to improve the psychosocial adjustment of PC patients following treatment.