CTCs have emerged as a potential source of clinical significance. But with numerous isolating systems currently available, the numbers of captured CTCs vary widely. At this point, CellSearch remains the only FDA-approved system with clinical significance whereby the results could be used to monitor patients with metastatic colon, breast, or prostate cancer. However, its inability to isolate CTCs from non-high risk prostate cancer patients or CTCs that are EpCAM-negative has led to criticism. In this study, we have shown that size-based filtration successfully isolates CTCs from patients with localized and metastatic prostate cancer. We have also shown that CTCs can be successfully isolated from low and intermediate risk groups. Additionally, clusters of CTCs were preserved and isolated in all localized risk groups and metastatic patients. Furthermore, we enumerated the isolated CTCs using automated and manual methods in low risk, intermediate risk, high risk, and metastatic prostate cancer. The automated and manual counts were comparable. Moreover, the amounts of clusters and the size of clusters correlated with the status and stage of prostate cancer. / October 2016

Cancer of the prostate (CaP) is the most common malignancy diagnosed in men in the Western society. During the last years, prostate specific antigen (PSA) has been used as a biomarker for CaP, although a high PSA value is not specific for CaP. Thus, there is an urgent need for new and improved diagnostic markers for CaP. In this thesis, the aim was to find a miRNA signature for diagnosis of CaP and to elucidate if differences in behavior between transition zone and peripheral zone tumors are reflected in miRNA expression. One of the major findings is anexpression signature based on nine miRNAs that with high accuracy (85%) could classify normal and malignant tissues from the transition zone of the prostate. The results furthermore show that the major differences in miRNA expression are found between normal and malignant tissues, rather than between the different zones. In addition, tumors arising in the peripheral zone have fewer changes in miRNA expression compared to tumors in the transition zone, indicating that the peripheral zone is more prone to tumor development compared to the transition zone of the prostate. A crucial step in pre-processing of expression data, in order to differentiate true biological changes, is the normalization step. Therefore, an additional aim of this thesis was to compare different normalization methods for qPCR array data in miRNA expression experiments. The results show that data-driven methods based on quantile normalization performs the best. The results also show that in smaller miRNA expression studies, only investigating a few miRNAs, RNU24 is the most suitable endogenous control gene for normalization. Taken together, the results in this thesis show the importance of miRNAs and the possibility of their future use as biomarkers in the field of prostate cancer.

Introduction: Cancer-related fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after activity. Etiologic mechanisms underlying CRF are not well understood. Methods: A literature review was conducted to examine studies that had investigated the association of mitochondrial dysfunction with fatigue. The major conclusion from this review was that alterations in energy metabolism may contribute to fatigue. Therefore, the dissertation study focused on laboratory techniques for measuring mitochondrial oxidative phosphorylation enzymes (complexes I-V) and a mitochondrial-specific oxidative stress marker (superoxide dismutase 2 [SOD2]). The primary aim of the dissertation research was to describe levels of biomarkers of mitochondrial function, fatigue, and health-related quality of life (HRQOL) before and at the completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (NM-PC). To achieve this aim a secondary analysis of a descriptive, longitudinal study was conducted (#10-NR-0128). Results: A total of n = 22 men with NM-PC were included in this study. There were significant increases in fatigue and a significant decrease HRQOL from baseline to the completion of EBRT. However, there was no significant change in the biomarkers of mitochondrial function from baseline to EBRT completion. Given the exploratory nature of the study, it was decided to further investigate the patient sample to understand the relationship of fatigue and mitochondrial function in a well-characterized fatigue phenotype. There was preliminary evidence to support the possibility of distinct patterns of mitochondrial enzyme levels between those with a high intensification of fatigue and those with a low intensification of fatigue during EBRT; however, these differences were not statistically significant. Discussion: To our knowledge, this is the first study to describe the relationship between mitochondrial enzymes and fatigue before and during EBRT in men with NM-PC. The most important preliminary finding from this study is the possibility that mitochondrial enzymes might be related to fatigue intensification during EBRT. Future studies will be critical to determine if these preliminary findings are replicable, and if so, whether there are potential therapeutic targets in individuals at highest risk for fatigue intensification during EBRT.

The chemokine receptor CCR5 has been implicated in the pathogenesis of prostate cancer. A novel natural product, anibamine, was isolated and found to be a micromolar inhibitor of the receptor. Anibamine was used as a new anti-prostate cancer lead compound. To discover the pharmacophore, analogs of anibamine were designed using the “deconstruction-reconstruction-elaboration” approach and synthesized. The establishment of a stereoselective route to only one isomer was explored, to increase yield and eliminate elaborate purification procedures. Analogs were found to have anti-prostate cancer activity at levels higher than the parent compound. The molecular modeling studies of the deconstructed analogs indicate that due to the psuedo-symmetry of the parent compound, the binding conformation of the deconstructed analogs may not be very different from each other. All this information together may help identify a next generation lead compound for anti-prostate cancer treatment.

<p>The androgen receptor (AR) signaling axis is a well-established therapeutic target in prostate cancer, due to its central role in tumor maintenance and progression. Although patients respond initially to androgen deprivation therapies and AR antagonists, they invariably progress to a castration-resistant state. Consequently, there is an unmet need for agents that target the AR signaling axis in a unique manner. </p><p>Histone deacetylase (HDAC) inhibitors repress AR signaling and prostate cancer growth in cellular and xenograft models. However, HDAC inhibitors also induce epithelial to mesenchymal (EMT) and neuroendocrine differentiation, both of which are associated with prostate cancer progression and aggressiveness. Given that 18 different HDAC isoforms have been identified in humans, and non-selective or Class I (HDAC1, 2, 3, and 8) HDAC inhibitors have been used in most of these studies, the relative contribution of individual HDAC isoforms to AR transcriptional activity and prostate cancer pathophysiology remains to be elucidated. The overarching goals of this study were to (1) determine the role of individual Class I HDACs in AR transcriptional activity and prostate cancer growth, (2) identify selective HDAC inhibitors that have reduced adverse profiles to the treatment of prostate cancer, and (3) identify potential HDAC-interacting proteins that regulate AR target gene transcription and prostate cancer growth. </p><p>Using genetic knockdown studies and pharmacological inhibitors with isoform selectivity, we identified that HDAC3 was required for AR transcriptional activity and proliferation in cellular models of androgen-sensitive and castration-resistant prostate cancer (CRPC). Additionally, we found that RGFP966, an HDAC3-selective inhibitor, attenuated the growth of a xenograft model of CRPC. Furthermore, non-selective HDAC inhibitors induced EMT and neuroendocrine markers in prostate cancer cells, but RGFP966 treatment did not. These studies provide rationale for selective inhibition of HDAC3 for the treatment of CRPC, and could provide an explanation for the lack of success using non-selective HDAC inhibitors in clinical trials for prostate cancer.</p><p>We also assessed the role of REV-ERB alpha, an HDAC3-interacting protein, in the regulation of AR transcriptional activity and prostate cancer growth. Using siRNA knockdown studies, REV-ERB inhibitors, and overexpression studies, we concluded that REV-ERB alpha; was required for AR target gene induction and prostate cancer growth, including models of CRPC. These studies also provide rational for targeting REV-ERB alpha; for the treatment of CRPC.</p><p>Taken together, these studies identify two novel targets in the HDAC signaling axis for the treatment of prostate cancer: HDAC3 and REV-ERB alpha. Our studies provide greater insight into AR transcriptional regulation and prostate cancer pathophysiology.</p> / Dissertation

Background: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. Methods: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. Results: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile (1 vs. Quartile) (4) = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile (4) = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m(2)), but not among men with high BMI (>= 27.8 kg/m(2)). Interactions of race and BMI with vitamin D intake were significant (P-Interaction < 0.05). Conclusion: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Upplevelsen av livskvalitet hos män med prostatacancer – en litteraturstudie                                         Abstrakt Bakgrund: Prostatacancer är den vanligast förekommande cancerformen bland män i Sverige. Många män lever med biverkningar efter behandlingen, vilket kan påverka deras liv negativt och hur de upplever sin livskvalitet. Syfte: Syftet var att belysa upplevelsen av livskvalitet hos män med prostatacancer. Metod: En litteraturstudie där åtta vetenskapliga artiklar med kvalitativ ansats har granskats, sammanställts och analyserats. Resultat: Tre huvudkategorier med sex kategorier identifierades: Bemästrande av situationen – Strävan efter väbefinnande genom kontroll, Insikt i sjukdomens påverkan. Adaption till livssituation – En förändringsprocess i livet, En kamp för sinnesro. Manlig identitet – Den förändrade sexualiteten påverkar identiteten, Relationer som stöd.   Konklusion: Upplevelsen av livskvalitet varierar från individ till individ och påverkas av bl.a. biverkningar efter behandling och synen på sin livssituation. Författarna tror att litteraturstudien kan medvetandegöra sjuksköterskor om vilken påverkan prostatacancer har på männens livskvalitet. Genom att ställa personliga frågor kan sjuksköterskan ge god vård utifrån varje persons individuella behov.   Nyckelord: Prostatacancer, livskvalitet, män, anpassning / The experience of quality of life in men with prostate cancer – A literature study   Abstract Background: Prostate cancer is the most common cancer among men in Sweden. Many men live with treatment related side effects which can cause a negative effect on their lives and the experience of their quality of life. Aim: The aim was to illuminate the experience of the quality of life in men with prostate cancer. Method: A literature study of eight articles with qualitative approach. The articles result have been reviewed, compiled and analyzed. Results: Three main categories and six categories were identified: Control of the situation – quest for wellbeing through control, insight in the impact of the disease. Adaptation to life situation – a reconstruction of life, a struggle for peace of mind. Male identity – the altered sexuality affects the identity, the support of relationships. Conclusion: The experience of quality of life varies between individuals and is affected by side effects after treatment and the way they are looking at their life situation. The authors believe that this literature study can raise awareness among nurses regarding the impact prostate cancer has on men’s quality of life. By asking personal questions the nurse can provide good nursing care based on each person’s individual need.   Keywords: Prostate cancer, quality of life, men, adaptation

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Les pathologies du vieillissement prostatique (cancer de la prostate, hyperplasie bénigne de la prostate, déficit androgénique lié à l'âge) sont fréquentes, représentant un problème de santé publique. Leur prévalence s'accroit au gré du vieillissement de la population. Si leur coïncidence épidémiologique est claire, les liens physiopathologiques les unissant restent mal connus. Grâce aux progrès de la génétique, et notamment les associations d'étude du génome entier, la quantification du risque génétique du cancer de la prostate sporadique a été documentée par la découverte de loci de susceptibilité. Néanmoins, l'utilisation de ces marqueurs en pratique courante n'a pas fait la preuve de sa rentabilité, dans le complexe débat du dépistage du cancer de la prostate. La prédisposition génétique au vieillissement pathologique bénin de la prostate, en particulier vers l'HBP, est encore très peu étudiée. De plus amples travaux sont nécessaires pour caractériser la genèse et l'évolution du vieillissement prostatique. Du point de vue du traitement, la prise en charge diagnostique du vieillissement prostatique évolue avec de nouveaux biomarqueurs. Le poids respectif de ces outils diagnostiques multiples reste à déterminer avec un triple objectif : (i) mettre en place des arbres de décision permettent de cibler les biopsies prostatiques, (ii) intégrer à la prise en charge diagnostique les pathologies bénignes comme l'HBP dont le bilan, le traitement et le suivi sont connexes à la problématique du CaP et (iii) considérer tout au long de la prise en charge les pathologies associées tel le syndrome métabolique, dans l'objectif d'une démarche multidisciplinaire. / Prostatic diseases due to ageing of the prostate gland (prostate cancer, benign prostatic hyperplasia, late onset hypogonadism) are frequent, and represent a major public health issue. Their prevalence gets higher along the ageing of the population in western countries. If an epidemiological link can be stated between these three diseases, the underlying pathophysiology remains unclear. With recent innovation in human genetics, notably genome wide association studies, the risk of non hereditary prostate cancer has been documented by the identification of susceptibility loci. However, the utility of these genetic markers in a clinical practice environment has not been yet established regarding the complex issue of prostate cancer screening. Genetic predisposition to benign prostate ageing, particularly BPH, has not been extensively studied. Additional investigations are necessary to adequately document the initial phase and evolution of the ageing prostate. From the therapeutic point of view, new biomarkers are about to modify the diagnosis of prostatic ageing. The respective role of each of these new diagnostic tools should be determined with a triple goal. First, improve decision making leading to prostatic biopsies. Then, proceed to integrative therapy of prostatic diseases (prostate cancer but also benign prostatic hyperplasia), and finally consider associated conditions, such as metabolic syndrome, to improve the level of care of the ageing male via a multidisciplinary approach.

Resistance of various cancers to conventional therapies including radio- and chemo- therapy is one of the most investigated phenomena in the molecular and clinical oncology. Recurrent disease is characterized by the presence of metastases, which are responsible for 90% of cancer-related mortality. Fractionated ionizing radiation (fIR) combined with surgery or hormone therapy represent the first-choice treatment for medium to high risk localized prostate carcinoma (PCa). In PCa, the failure of radiotherapy (RT) is often caused by radioresistance and further dissemination of escaping (surviving) cells. To investigate the radioresistance-associated phenotype, we exposed four metastasis- derived human PCa cell lines (DU145, PC-3, LNCaP, and 22RV1) to clinically relevant daily fractions of ionizing radiation (fIR; 35 doses of 2 Gy) resulting in generation of two surviving populations: adherent senescent-like cells expressing common senescence-associated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2, and Nanog. While the radioresistant adherent cells were capable to resume proliferation shortly after the end of irradiation, the non- adherent cells started to proliferate only after their reattachment...