During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

There is increasing interest in the use of adjuvant hormonal therapies, which are given after the resection or destruction of all gross disease, in early-stage prostate cancer, as a significant proportion of patients experience progression and/or die from the disease despite undergoing therapy with curative intent. Several retrospective studies suggest that adjuvant hormonal therapy may improve long-term outcome after radical surgery in men with positive lymph nodes, although this approach has yet to be studied in a prospective setting. No studies of adjuvant therapy for patients with extracapsular extension at surgery have been completed, but in an interim analysis of an open controlled trial, adjuvant flutamide significantly improved progression-free survival at 4 years. Three prospective studies in the radiotherapy setting have shown that adjuvant luteinizing hormone-releasing hormone (LH-RH) agonist therapy significantly improves progression-free and/or overall survival. Future studies need to define patient subgroups who will benefit most from adjuvant therapy. The side effects of the different therapeutic options also need to be compared. It is hoped that many of the outstanding questions concerning adjuvant hormonal therapy will be answered by the ongoing Bicalutamide Early Prostate Cancer Programme. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The majority of cancer research projects mainly focus on the epithelial cancer cell, while the role of the tumour stroma has been largely neglected. Conventional 2D techniques, such as well plates and other kinds of tissue culture plastic, and animal models are mainly used to broaden our understanding of how tumours arise, develop, and induce metastasis. However, there is accumulating evidence suggesting a tremendous impact of the non‐cancerous tumour stroma on carcinogenesis, while other publications illustrate the great importance of advanced 3D in vitro models for cancer research. The overall goal of this work was to investigate how cancer associated fibroblasts (CAFs; the most abundant component in the tumour stroma) and normal prostate fibroblasts (NPFs), isolated from patients diagnosed with aggressive forms of prostate cancer, contribute to angiogenesis, an important hallmark of cancer progression. For this purpose, a 3D in vitro angiogenesis co‐culture model was established. At first, two (semi‐) synthetic hydrogel platforms, gelatine methacrylate (GelMA) and star‐shaped (star)PEG‐heparin hydrogels were characterised and their physicochemical properties were compared with each other. Interestingly, GelMA gels shrank while starPEG‐heparin gels swelled in cell culture medium over the course of 24 hours. The cell concentration, in addition to the stiffness, was critical for the formation of endothelial networks, and the knowledge of swelling behaviour enabled the adjustment of initial cell density to ensure the density between both gel types was comparable. Moreover, preliminary tests with mesenchymal stem cells demonstrated that the hydrogel can be actively remodelled, as evaluated by stiffness parameters at day one and seven of incubation. Growth factors (GFs) affect cellular fate and behaviour, and storage, presentation and administration of such chemokines can be critical for certain cellular applications. Due to the high anionic charge density of heparin, starPEG‐heparin hydrogels are known to reversibly immobilise several GFs and thereby might mimic the GF reservoir of the extra cellular matrix. Thus, transport processes of GFs with low and high heparin affinity inside these hydrogels were analysed by fluorescence correlation spectroscopy and a bulk diffusion approach. Results indicated that diffusion constants were synergistically decreased with increasing size and heparin affinity of the diffusant. Next, the capability of endothelial cells (ECs) to self‐assemble and organise into 3D capillary networks was tested in GelMA, starPEG‐heparin and Matrigel hydrogels. Only starPEG‐heparin hydrogels allowed the formation of interconnected capillaries in macroscopic hydrogel samples. However, as it is widely used to test for pro‐ and anti‐angiogenic agents, the 2D Matrigel angiogenesis assay was included for subsequent co‐culture experiments of ECs and fibroblasts in order to investigate how the stromal cells influence the formation of endothelial networks. For a detailed characterisation of 3D structures, a conventionally applied 2D method (Maximum Intensity Projection for 3D reconstructed images, MIP) was compared to an optimised 3D analysing tool. As a result, it was discovered that MIP analysis did not allow for an accurate determination of 3D endothelial network parameters, and can result in misleading interpretations of the data set. Indirect co‐cultures of hydrogel‐embedded ECs with a 2D layer of fibroblasts showed that fibroblast‐derived soluble factors, including stromal cell‐derived factor 1 and interleukin 8, affected endothelial network properties. However, only co‐encapsulation of ECs and fibroblasts in starPEG‐heparin hydrogel discs revealed remarkable changes in endothelial network parameters between CAF and NPF samples. In detail, the total length and branching of the capillaries was increased. For two donor pairs, the diameter of capillaries was decreased in CAF samples compared to NPF samples, underlining the high physiological relevance of this model. In contrast, significant differences in 2D Matrigel assays were not detected between, CAF, NPF and control (ECs only) samples. In summary, a 3D angiogenesis co‐culture system was successfully developed and used to characterise stromal‐endothelial interactions in detail. The combination of advanced biomaterials (starPEG‐heparin) and 3D analysing techniques goes beyond conventional 2D in vitro cancer research, and opens new avenues for the development of more complex models to further improve the acquisition of more biologically relevant data.

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Les cellules tumorales circulantes (CTC) représentent une source de matériel tumoral accessible de manière non invasive, susceptible de fournir des informations cliniques et fondamentales. Ces cellules issues de tumeurs primitives ou métastatiques représentent une population hétérogène d’éléments très rares circulant dans le sang. La personnalisation des traitements en oncologie repose sur la caractérisation moléculaire de biopsies tumorales mais celles-ci peuvent être difficiles à réaliser ou peu informatives. De ce fait, la caractérisation moléculaire et fonctionnelle des CTC présente un double intérêt, clinique pour identifier des biomarqueurs de sensibilité à des traitements, et fondamental pour étudier les mécanismes qui sous-tendent leur potentiel à initier des tumeurs.Les objectifs de ma thèse ont été d’une part de caractériser par séquençage de l’exome (WES) les CTC à l’échelle de cellule unique de patients atteints de cancers de la prostate (PCa) métastatiques et d’autre part d’établir puis caractériser des modèles de xénogreffes dérivés de CTC (CDX) chez des patients atteints de cancers bronchiques non à petites cellules (CBNPC) ou de PCa.Pour répondre au premier objectif, nous avons développé une méthode expérimentale globale incluant trois approches technologiques permettant d’enrichir et d’isoler des CTC individuelles de différents phénotypes (épithélial, épithélio-mésenchymateux et mésenchymateux), d’amplifier la totalité du génome (WGA) et de le séquencer. Le WES a été réalisé pour 34 échantillons de CTC sélectionnés sur des critères de qualité du WGA, ainsi que pour les biopsies de métastases correspondantes chez sept patients. Deux patients présentant une hétérogénéité phénotypique de leurs CTC, ont été analysés en profondeur. Nous avons mis en évidence des mutations partagées entre les CTC et les biopsies tumorales correspondantes ainsi que des mutations uniquement retrouvées dans les CTC. Ces mutations spécifiques aux CTC sont présentes dans tous les phénotypes et affectent particulièrement les gènes impliqués dans le remodelage du cytosquelette, la réparation de l’ADN ou l’invasion. L’existence de mutations communes entre les CTC de différents phénotypes suggère une relation phylogénique entre ces cellules mais une évolution divergente pendant le processus métastatique. Ce travail est soumis pour publication.Dans la seconde partie de ma thèse, nous avons implantés les CTC de 67 patients atteints de CBNPC et 24 patients atteints de PCa chez des souris immunodéprimées. Nous avons établis quatre CDX de CBNPC et un CDX de PCa. La caractérisation de ces modèles, des biopsies tumorales, des CTC collectées au moment de la xénogreffe, des CDX et des lignées cellulaires établies à partir du CDX, ont révélé que les CTC, le CDX et les lignées cellulaires « miment » le phénotype et le profil mutationnel des biopsies tumorales. La caractérisation plus approfondie de l’une des lignées cellulaires montre la présence d’un stress réplicatif et d’une instabilité génomique élevée. Ce résultat nous oriente sur l’hypothèse d’un rôle éventuel de l’instabilité génomique dans la tumorigénicité des CTC.Dans ce travail, nous avons montré que le profil mutationnel des CTC présente de fortes similitudes avec les biopsies tumorales des patients dans les patients atteints de PCa étudiés. De plus, nous avons observé l’existence de mutations spécifiques aux CTC, non détectées dans les biopsies tumorales. Également, nous montrons que des CTC issues de CBNPC et de PCa sont tumorigéniques in vivo et qu’elles reflètent le profil mutationnel des biopsies tumorales des patients. Ces modèles constituent des outils originaux et intéressants pour identifier de nouvelles cibles thérapeutiques et stratégies anti-cancéreuses, et comprendre les mécanismes qui supportent le potentiel des CTC à initier des tumeurs. / Circulating tumor cells (CTCs) represents an non invasive source of tumor material which may provide clinical and basic information. These cells derived from primary or metastatic tumors represents an heterogeneous population of very rare events which circulates in the blood. Oncology personnalized medicine is based on biopsies molecular characterization but these are sometimes which difficult to realize and poorly informative. Thereby molecular and functional characterization of CTCs presents a double interest, clinical to identify treatments biomarkers sensitivity and basic to study mechanisms underlying their tumor inititiating cell (TIC) potential. The two goals of my thesis were on the one hand to characterize by whole-exome sequencing (WES) at the single level the CTCs from patients with metastatic prostate cancers (mPCa) and on the other hand to establish and characterize CTC-derived xenografts (CDX) from patients with non-small-cell lung cancer (NSCLC) or mPCa. For the first goal we developped a global workflow which include three technological approaches to enrich and isolate individual CTCs from different phenotype (epithelial, epithelial and mesenchymal, mesenchymal), to perform whole genome amplification (WGA) and to sequence them. WES was performed on 34 CTC samples selected according to WGA quality and on corresponding metastasis biopsies from seven patients. Two patients with phenotypic heterogeneity of CTCs were deeply analyzed. We highlighted shared mutations between CTCs and matched biopsies as well as mutations only detected in CTCs. These private CTC mutations are detected in all phenotype and particularly affect genes invlved in cytoskeleton remodeling, DNA repair or invasion. The existence of common mutations between CTCs from various phenotype suggests a phylogenic link between these cells but a divergent evolution during metastatic process. This work is submitted for publication. For the second goal, we implanted CTCs from 67 NSCLC patients and 28 mPCa patients in immunocompromised mice. We established four NSCLC CDX and one mPCa CDX. The characterization of tumor biopsies, CTCs collected at the time of xenograft, CDX and CDX-derived cell lines revealed that CTCs, CDX and cell lines miror the phenotype and mutational landscape of tumor biopsies. The more deeply characterization of one cell line show the presence of a high replicative stress and genomic instability. This result directs us to the hypothesis of a possible role of the genomic instability in CTC tumorigenicity.We demonstrated in this work that CTCs mutational landscape harbors high similairities with patients tumor biopsies in mPCa. Furthermore we observed CTC private mutations not detected in tumor biopsies. Also we showed that some CTCs from NSCLC and mPCa are tumorigenic in vivo and that these CTCs mirror mutational profile of patients tumor biopsies. These models are original and interesting tools to identify new therapeutic targets and anti-tumoral strategies and understand mechanisms underlying the TIC potential of CTCs.

Prostate cancer diagnostic algorithm Aim: The aim of the study is to implement the latest scientific knowledge in the diagnosis of prostate cancer (PC). We focused on tumor markers, imaging methods, prostate biopsy methodology and we created a diagnostic algorithm based on a review of current literature in combination with our own experience. Material and methods: The algorithm is divided into several branches, which have been individually subjected to clinical studies. Due to the low sensitivity and specificity of PSA, prostate health index (PHI) was added to the first line of patient stratification. 787 patients were primarily examined and these subsequently underwent radical prostatectomy. PHI levels were compared with definitive staging and grading. Cut-off values for PC detection and high-risk stratification, including locally advanced PC were determined. Next, 320 patients underwent prostate biopsy followed by radical prostatectomy. The cohort was further divided into two subgroups, patients with GS = 6 and patients with GS > 6. The ability of PHI to distinguish between insignificant and significant prostate cancer was evaluated. In a multicentric study with 395 patients, PHI with additional markers (tPSA, PSAD) and multiparametric magnetic resonance imaging of prostate (mpMRI) was assessed....

Bakgrund: Prostatacancer är en sjukdom som påverkar ett stort antal män världen över där behandlingsalternativen ofta följer med svåra biverkningar för patienten. Biverkningarna påverkar bland annat sexuell hälsa och urinvägar. Biverkningarna påverkar även männens identitet och manlighet.  Syfte: Syftet med litteraturöversikten var att beskriva patienters upplevelser av prostatacancer. Metod: En litteraturöversikt användes där författarna hittade 10 stycken kvalitativa vetenskapliga artiklar som sammanställts till resultatet i denna studie.  Resultat: Resultatet visar att männens upplevelser kring prostatacancer är ofta svåra för männen och att det finns många påverkande faktorer mot deras identitet och självkänsla.  Sammanfattning: Med denna studie ger vi en ökad förståelse för männens upplevelser under sin sjukdom med prostatacancer och ge kunskap till sjuksköterskor om männens psykiska tillstånd för att kunna utföra god omvårdnad. / Background: Prostate cancer is a disease that affects many men around the world where treatment options often come with severe side effects for the patient. The side effects affect their sexuality among other things, but there are many more serious side effects. The side effects also often hit hard on men's identity, which often has serious consequences on their life.  Aim: The aim of this literature overview was to describe patient’s experiences of prostate cancer.  Method: A literature review was performed where 10 articles was found for our result.  Results: The results showed that men's experiences of prostate cancer are often difficult for men and that there are many influencing factors towards their identity and self-esteem.  Conclusion: With this study we provided an increased understanding of men's experiences during their illness with prostate cancer and to provide nurses with knowledge about men's mental state in order to be able to perform good nursing.

Le cancer de la prostate est le cancer le plus fréquemment diagnostiqué chez les hommes canadiens. Aucun facteur de risque modifiable n’a été identifié, mais l’alimentation pourrait être impliquée. Les profils alimentaires, décrivant l’ensemble de l’apport alimentaire, constituent une approche de recherche prometteuse. L’objectif général de cette thèse était d’évaluer le rôle des profils alimentaires et du niveau de transformation des aliments sur le risque de cancer de la prostate. Les données colligées dans une vaste étude cas-témoins populationnelle menée chez les résidents montréalais ont été utilisées. Les 1919 cas incidents histologiquement confirmés étaient âgés de 75 ans ou moins et avaient été diagnostiqués entre 2005 et 2009. Les 1991 témoins ont été sélectionnés aléatoirement à partir de la liste électorale, puis appariés aux cas selon l’âge (± 5 ans). Les informations concernant l’alimentation ont été recueillies avec un questionnaire de fréquence alimentaire documentant la consommation deux ans avant le diagnostic ou l’entrevue. Le premier objectif visait à identifier des profils alimentaires parmi les témoins francophones ainsi que les caractéristiques associées à ces profils. Une analyse en composantes principales a permis d’identifier les profils alimentaires Santé, Occidental modifié - Salé et Occidental modifié - Sucré. Le profil Santé a été associé à des niveaux plus élevés de revenu et d’éducation, à un niveau modéré d’activité physique et à un faible niveau de tabagisme. Le profil Occidental modifié - Salé a été associé avec des ethnicités française, européenne (autre que française) ou latine, avec le fait d’être marié ou en union libre, et était inversement associé avec l’âge. Le profil Occidental modifié - Sucré était plus commun chez les hommes d’origine française et chez les consommateurs de suppléments de vitamines et minéraux. Le deuxième objectif visait à évaluer les associations entre les profils alimentaires et le cancer de la prostate. Les rapports de cotes (RC) et intervalles de confiance (IC) à 95% ont été obtenus par régression logistique non conditionnelle ajustée pour les facteurs de confusion. Le profil Santé était inversement associé au risque de cancer de la prostate (RC= 0,76 [IC 95% = 0,61-0,93], en comparant le quartile supérieur au quartile inférieur). Le profil Occidental - Sucré et Boissons était associé à une augmentation du risque de cancer de la prostate (RC= 1,35 [IC 95% =1,10-1,66], quartile supérieur vs inférieur). Ces résultats sont novateurs. Aucune association n’a été observée avec le profil Occidental - Salé et Alcool. Le troisième objectif visait à évaluer l’association entre le niveau de transformation des aliments et le cancer de la prostate. Les aliments transformés étaient associés à une augmentation du risque (RC= 1,32 [IC 95% =1,07-1,62], quartile supérieur vs inférieur) et l’association était légèrement plus prononcée pour les cancers agressifs. En conclusion, ces résultats suggèrent que les profils alimentaires et le niveau de transformation des aliments jouent un rôle dans le développement du cancer de la prostate. Il s’agit d’informations importantes pour soutenir la promotion de saines habitudes de vie et la prévention du cancer de la prostate. / Prostate cancer is the most commonly diagnosed cancer among men in Canada. No modifiable risk factor has been identified, but diet is suspected to play a role. Dietary patterns, which describe the overall dietary intake rather than the consumption of specific foods or nutrients, represent a promising research approach. The general objective of this thesis was to assess the role of dietary patterns and the level of food processing on the risk of prostate cancer. Data collected in a large population-based case-control study conducted among Montreal residents were used. The 1919 histologically confirmed incident cases were 75 years of age or younger and had been diagnosed between 2005 and 2009. Concurrently, the 1991 controls were randomly selected from the electoral list and frequency-matched to cases by age (± 5 years). Food consumption was assessed using a food frequency questionnaire focusing on the period two years before diagnosis or interview. The first objective was to identify dietary patterns among the French-speaking controlsas well as the characteristics associated with these patterns. Principal component analysis led to the identification of three dietary patterns: Healthy, Western modified - Salty and Western modified - Sweet. The Healthy pattern was associated with higher income, education, moderate levels of recreational physical activity and lower levels of smoking. The Western modified – Salty pattern was positively associated with French, other European (other than French), and Latino ancestries, and with married and common-law relationships, whereas it was inversely associated with age. Finally, the Modified Western – Sweet pattern was more common among men of French ancestry and users of vitamin/mineral supplements. The second objective was to assess associations between the different dietary patterns and prostate cancer. Odds ratios (OR) and 95% confidence interval (95% CI) were obtained by unconditional logistic regression adjusting for confounders. The Healthy dietary pattern was inversely associated with prostate cancer (OR = 0,76 [95% CI = 0,61-0,93], highest vs lowest quartile), whereas the Western - Sweet and beverages pattern increased the risk of this cancer (OR = 1,35 [95% CI = 1,10-1,66], highest vs lowest quartile). Both results are novel. The Western - Salty and alcohol pattern was not associated with prostate cancer risk. The third objective was to assess the association between the level of food processing and prostate cancer. The level of food processing in the diet was assigned using the NOVA food classification. Processed foods were associated with an increased risk (OR = 1,32 [95% CI] = 1,07-1,62], highest vs lowest quartile) of prostate cancer, and the association was slightly more pronounced for high-grade prostate cancers. In conclusion, these results suggest that dietary patterns and the level of food processing play a role on the risk of developing prostate cancer. This information is important for promoting a healthy lifestyle and for prostate cancer prevention.

Deregulation of gene expression caused by genetic or epigenetic changes plays an important role in pathogenesis of cancer. The thesis is a commented collection of ten publications dealing with the molecular biology of tumours. The author has significantly contributed to all of them. All the articles contained in the thesis are linked to the topic of assessment of molecules involved in gene expression regulation (microRNAs) or DNA alterations that affect gene expression (promoter methylation, presence of a fusion gene). MicroRNAs are short single-stranded RNA molecules involved in posttranscriptional regulation of gene expression by triggering mRNA degradation or inhibiting translation. It is a basic mechanism with an impact on all cellular processes including the pathogenesis of various diseases. MicroRNAs can either act as oncogenes by decreasing the expression of tumour-suppressor genes or as tumour-suppressor genes by decreasing the expression of oncogenes. However, the network of microRNA - RNA interactions is much more complex. Our published results that are part of this thesis are focused on colorectal carcinoma (CRC), prostate cancer, head and neck squamous cell carcinoma (HNSCC), gastric cancer and non-small cell lung cancer (NSCLC). In patients with CRC, we demonstrated the prognostic...

<p>Herein, the development, optimization, and evaluation of quantitative techniques are presented for dynamic PET studies in cancer imaging applications. Dynamic PET image analysis techniques are first applied to 18F-fluoroethyltyrosine (FET) PET imaging of glioma and brain metastasis patients. In a second application, dynamic PET image analysis techniques are applied to 68Ga-PSMA-11 PET imaging for primary prostate cancer patients. Overall, the application of dynamic PET imaging techniques supports improved clinical outcomes and enhanced clinician confidence for treatment modifications. </p>