Im Rahmen einer prospektiven Studie wurden zwischen Juli 2007 und Oktober 2008 Patienten mit Prostatakarzinom in der Klinik für Urologie des Universitätsklinikums Leipzig befragt. Die Lebensqualität und Lebenszufriedenheit wurden mit Hilfe von Selbstbeurteilungsfragebögen (EORTC QLQ-C30, SF-8 und FLZM) erfasst. Insgesamt lagen Daten von 276 Patienten vor. Ziel der Arbeit war es, den Verlauf von Lebensqualität und Lebenszufriedenheit über drei Monate nach dem Klinikaufenthalt zu beobachten, sowie diese Daten mit denen der Allgemeinbevölkerung zu vergleichen. Weiterhin wurden verschiedene Einflussfaktoren auf Lebensqualität und Lebenszufriedenheit bewertet. Prostatakarzinompatienten gaben die schlechteste Lebensqualität zum Zeitpunkt vierzehn Tage nach Entlassung aus der Klinik an. Innerhalb von drei Monaten erreichten sie wieder das Ausgangsniveau an Lebensqualität. Insgesamt zeigten sich kaum klinisch bedeutsame Unterschiede in der Lebensqualität zwischen Patienten und Allgemeinbevölkerung. Die Lebenszufriedenheit nahm im Verlauf zwar ab, jedoch gaben die Prostatakrebspatienten zu fast allen Zeitpunkten eine ähnliche oder sogar höhere Lebenszufriedenheit als die Vergleichsgruppe an. Die einzige, aber wichtige Ausnahme hiervon bildete der Bereich Sexualität, hier waren die Patienten nach 3 Monaten deutlich unzufriedener als die Männer der Allgemeinbevölkerung. Alter, Bildungsgrad und die seit Diagnosestellung vergangene Zeit stellten sich im Gegensatz zum Tumorstadium als Einflussfaktoren für die Beurteilung der Lebensqualität dar. Alle diese Faktoren zeigten jedoch keinen signifikanten Einfluss auf deren Lebenszufriedenheit. Die Korrelationen zwischen den drei eingesetzten Fragebögen waren fast ausnahmslos positiv, entsprechend einer gleichsinnigen Variabilität. Eine generelle psychoonkologische Betreuung aller Patienten scheint nicht notwendig, jedoch sollten Ärzte für die Probleme des Einzelnen sensibilisiert sein um rechtzeitig Hilfe anbieten zu können.

<p>Abstract</p><p>The trefoil factor family of secreted proteins contains three members; trefoil factor 1 or TFF1, trefoil factor 2 or TFF2, and trefoil factor 3 or TFF3. These three proteins share a conserved 42-43 amino acid domain containing 6 cysteine residues resulting in three disulfide bonds that holds the protein in a characteristic three-loop or "trefoil structure" known as the P domain. TFF1 is primarily localized to the stomach and secreted by the gastric mucosa while TFF2 and TFF3 are primarily localized to the colon and duodenum and secreted by the goblet cells. All three of these proteins play a protective role in the gastrointestinal tract where they are normally localized and have been identified as possible tumor suppressors, however, these proteins are also upregulated in cancer within tissues where they are not normally expressed including the breast, pancreas, prostate, and liver. The mechanisms by which two of these factors, TFF1 and TFF3, promote tumorigenesis remain largely undefined. In this dissertation we will attempt to elucidate these mechanisms as well as the regulation of these two proteins in both pancreatic and prostate cancer. Many of the underlying genetic and molecular mechanisms involved in the development of both pancreatic and prostate cancer remain largely unknown and as a result, therapeutic and diagnostic tools for treating these diseases are not as effective as they could be. By deciphering the role of TFF1 and TFF3 in these cancers, they could potentially serve as new therapeutic targets or biomarkers for treating both diseases.</p><p>Chapter 2 of this dissertation will examine the functional role of TFF1 promoting tumorigenesis in pancreatic and prostate cancer. We will show that TFF1 expression is critical for the viability of both pancreatic and prostate cancer cells and that reduction of TFF1 expression in these cells results in decreased tumorigenicity when implanted in immunocompromised mice. It will also be demonstrated that TFF1's function in promoting tumorigenicity is its ability to assist tumor cells overcome the tumor suppressive barrier of senescence. Thirdly, we show that the form of senescence that TFF1 assists in allowing the cells overcome is oncogene-induced senescence (OIS). Lastly, a cell cycle array identifies the potential downstream target p21CIP, a cyclin-dependent kinase inhibitor and OIS marker, whose expression is induced by loss of TFF1 expression.</p><p>In Chapter 3 of this work, we examine the role of another trefoil factor family member, TFF3, and its role in promoting prostate tumorigenesis. Just as with TFF1, it appears that TFF3 3 expression is critical for prostate cancer cell viability and tumorigenicity using the same experimental techniques used in Chapter 2. Using a genetically defined model of prostate cancer, a PI3-kinase-dependent regulatory mechanism of TFF3 emerges in this prostate cancer context. Using this system we begin to see a divergence in both regulation and function of TFF1 and TFF3 in prostate cancer. Finally, a mouse model expressing TFF3 was developed to monitor the histopthological changes associated with expression of this protein. Initial characterization of this model suggests a hyperplastic phenotype coinciding with TFF3 expression in the prostate.</p><p>The two studies in this dissertation establish a role of TFF1 and TFF3 in both prostate and pancreatic tumorigenesis and demonstrate that ablation of expression of both proteins is a potent inhibitor of tumorigenesis. With this knowledge, it is possible that TFF1 and TFF3 may become a potential therapeutic target or diagnostic marker for better treatment of prostate and pancreatic cancer.</p> / Dissertation

<p>Glucose metabolism remains an intensely explored topic of cancer biology since the initial discoveries of Otto Warburg nearly 80 years ago. Many solid tumors metabolize glucose primarily to lactate despite the availability of oxygen, revealing a dependence on glycolysis that may serve as a basis for targeted therapy. In particular, a diet devoid of carbohydrate may minimize the growth capabilities of glucose-dependent cancers. As our interests lie in prostate cancer, we examined whether a ketogenic diet devoid of carbohydrate (NCKD) would reduce the growth rate of tumors derived from human prostate cancer cell lines in a murine xenograft model.</p> <p>Our initial experiments utilized the LAPC-4 cell line, a human androgen-sensitive prostate cancer cell line, in a SCID-mouse xenograft model to determine the effects of an NCKD on tumor growth and animal survival relative to two other diets: (1.) a Western-type diet (WD) reflecting consumptions patterns of men diagnosed with prostate-cancer in the Western world and (2.) a low-fat diet (LFD) representing the present standard of care. Following this study, we conducted a second study utilizing a different human prostate cancer cell line (LNCaP) in order to assess whether our initial observations were robust across multiple prostate cancer tumor models and to also further explore the molecular underpinnings of our observations. Both studies revealed the NCKD leads to a reduction in tumor growth rate and greater overall mouse survival relative to the WD. In addition, the NCKD was equivalent in these parameters to the LFD. We also observed key associations between survival and extent of urinary ketosis as well as favorable changes in insulin and insulin-like growth factor-1 (IGF-1) and gene expression that would be predictive of prolonged survival in mice consuming the NCKD.</p> <p>We believe these data provide compelling evidence to consider a potential therapeutic role for dietary carbohydrate restriction in prostate cancer. We hope these results ultimately serve as a basis to conduct future clinical trials assessing whether dietary carbohydrate restriction, either alone or in combination with more conventional therapies, provides clinicians with an additional weapon against prostate cancer.</p> / Dissertation

Title from title page of PDF (University of Missouri--St. Louis, viewed February 9, 2010). Includes bibliographical reference (p. 165-182).

p38 mitogen-activated protein kinases (MAPKs) control the endocytic trafficking of various growth-related cell surface receptors and transporters. Herein, I demonstrate that p38 MAPKs also regulate autophagy, or the process of self-cannibalism. In my studies, inhibition of p38 MAPKs triggered rapid formation of autophagosomes in prostate cancer cells, even under nutrient-rich conditions, and remarkably, the autophagosomal membranes emanated from endoplasmic reticulum exit sites via the concerted actions of the small GTPases, ARF1 and SAR1. Once formed, the autophagosomes fused with late endosomes and/or lysosomes, in a Rab7-dependent manner, to form “hybrid organelles” that were co-labeled with ER, autophagic, late endosomal, and lysosomal markers. Unlike other inducers of autophagy, however, inhibition of p38 MAPKs suppressed the fission of hybrid organelles, resulting in a profound but reversible accumulation of large cytoplasmic vacuoles. Thus, in addition to their previously reported roles in endocytosis, p38 MAPKs appear to coordinately regulate autophagy and the downstream biogenesis and fission of hybrid organelles. / text

Prostate cancer (PCa) is heterogeneous containing phenotypically diverse cells. It is unclear whether these phenotypically different PCa cells are functionally distinct and possess divergent tumorigenic potential. Androgen signaling plays important roles in differentiation and survival of malignant PCa cells, and prostate specific antigen (PSA) as one of the androgen signaling target genes is used as a biomarker of AR signaling to assess tumor progression and evaluate therapeutic efficiency in clinic. Here we present evidence for discordant AR and PSA expression resulting in AR⁺/PSA⁺, AR⁺/PSA⁻, AR⁻/PSA⁻, and AR⁻/PSA⁺ PCa cells in human tumors. We also show that prostate tumor PSA mRNA levels inversely correlate with poor clinical outcomes and patient survival. By employing a lentiviral reporter system, we have fractionated bulk PCa cells into PSA⁺ and PSA⁻[superscript '/lo'] cell populations, with the former being AR⁺/PSA⁺ and the latter containing both AR⁺/PSA⁻ and AR⁻/PSA⁻ cells. The PSA⁺ and PSA⁻[superscript '/lo'] PCa cells demonstrate distinct molecular, cellular, and tumor-propagating properties. PSA⁻[superscript '/lo'] PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division to generate PSA⁺ cells. Of great clinical interest, PSA⁻[superscript '/lo'] PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and they harbor highly tumorigenic castration resistant PCa cells. In contrast, PSA⁺ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division, and are sensitive to castration. Systemic androgen levels dynamically regulate the relative abundance of PSA⁺/PSA⁻[superscript '/lo'] PCa cells in the tumors, which in turn impact the kinetics of tumor growth. Further studies reveal that the PSA⁻[superscript '/lo'] PCa cell population harbors several overlapping but nonidentical tumorigenic subsets including ALDH⁺, CD44⁺, and [alpha]2[beta]1⁺ cells and ALDH⁺CD44⁺[alpha]2[beta]1⁺ can further enrich castration resistant PCa cells. These observations together suggest that heterogeneous PCa cells are organized as a tumorigenic hierarchy. Our results have important implications in understanding how different subpopulations of PCa cells manifest differential responses to current androgen deprivation therapy (ADT). / text

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Bakgrund: Prostatacancer är den vanligaste typen av cancer i världen och antalet drabbade ökar för varje år i Sverige. Diagnosticeringsprocessen av cancer är ett känsligt ämne för männen då det väcker existentiella frågor som leder till en förändrad kroppsuppfattning. Cancer kan också innebära en störning av hälsan och leda till ett lidande. Syfte: Syftet med studien var att belysa mäns erfarenheter av att diagnosticeras med prostatacancer. Metod: Litteraturbaserad studie baserad på tolv vetenskapliga artiklar med kvalitativ ansats. Resultat: Ur analysen framkom tre kategorier; diagnosen ett livsomvälvande besked, hantera sjukdomen är en krävande process samt kunskapsbrist skapar otrygghet med nio underkategorier. Diskussion: Det är viktigt att sjuksköterskan har kunskap om de känslor och informationsbehov männen upplever i samband med diagnosen och hur de kan möta detta genom en god kommunikation och stöd. Sjuksköterskan blir medveten om dessa erfarenheter och kan då främja hälsa och lindra lidande för männen. Slutsats: Männen upplever en omvälvande period fram tills ett behandlingsbeslut ska tas. De behöver egentid för initial hantering av diagnos följt av information och stöd. De upplever också en bristfällig sjukvårdspersonal under denna period. / Background: Prostate cancer is the most common form of cancer in the world and the amount of people affected in Sweden increasing every year. The diagnosing process of cancer is a sensitive subject and it leads to existential questions followed by a perceived change in the body image. Cancer could also lead to a disturbance in health and lead to suffering. Aim: The aim of this study was to illuminate men’s experiences of being diagnosed with prostate cancer. Method: A qualitative literature study based on twelve research articles with a qualitative approach. Results: Three categories emerged from the analysis; diagnosis a life-changing result, handle the disease is a demanding period and lack of knowledge creates insecurity followed by nine subcategories. Discussion: It is important that the nurse has knowledge about the emotions and informational needs the men experience associated to the diagnosis and how they can meet these needs through good communication and support. The nurse becomes aware of these experiences and can then promote health and ease suffering for the men. Conclusion: Men experience a life-changing period from diagnosis to the treatment decision. They need time alone in order to cope with the diagnosis followed by information and support. They also experience a deficient medical staff during this period.

Prostate cancer is the second leading cause of cancer deaths among men. Targeted analyses of DNA from prostate cancers have identified recurrent somatic alterations that promote tumor growth and survival. Only recently, however, has the comprehensive analysis of cancer genomes become possible due to rapid advances in DNA sequencing technology.

The recently resurrected cancer stem cell (CSC) theory sheds new light on understanding tumor biology. Most solid tumors have now been shown to contain CSCs, i.e., stem cell-like cancer cells. These cells, although generally rare, appear to be highly tumorigenic and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. In order to test whether any given human tumor cell population has CSC properties, the relatively enriched single tumor cells have to be put into a foreign microenvironment in a recipient animal to test their tumorigenic potential. Furthermore, various in vitro assays can be performed to demonstrate that the presumed CSCs have certain biological properties normally associated with the stem cells (SCs). Herein, I first present a comprehensive review of the experimental methodologies that our lab has been using in assaying putative prostate cancer (PCa) SCs in culture, xenograft tumors, and primary tumor samples. Clonal morphology is one of the critical properties of cultured cancer cells that has been largely ignored. Interestingly, long term-cultured human epithelial cancer cells form holoclones, meroclones, and paraclones, and tumor cell holoclones have been hypothesized to harbor stem-like cells. Using PC3 human prostate carcinoma cells as a model, we provide direct experimental evidence that tumor cell holoclones contain stem-like cells that can initiate serially transplantable tumors. Importantly, holoclones derived from either cultured PC3 cells or holoclone-initiated tumors can be serially passaged and regenerate all three types of clones. In contrast, meroclones and paraclones cannot be continuously propagated and fail to initiate tumor development. Phenotypic characterizations reveal high levels of CD44, [alpha]2[beta]1 integrin, and [beta]-catenin expression in holoclones, whereas meroclones and paraclones show markedly reduced expression of these markers. These observations have important implications in understanding morphologic heterogeneities and tumorigenic hierarchies in human epithelial cancer cells. PCa metastasis represents the worst outcome, and, if unchecked, will eventually kill the patient. Although many PCa cell-intrinsic molecules and end-organ factors have been implicated in the metastatic dissemination of PCa cells, the role of primary tumor microenvironment and the nature of the metastatic PCa cells remain poorly defined. By establishing a reliable and quantifiable experimental PCa metastasis model in NOD/SCID mice, we show that PCa cells implanted orthotopically (i.e., in the prostate) metastasize much more extensively and widely than those implanted ectopically (i.e., subcutaneously or s.c). Microarray-based gene expression profiling reveals that the orthotopically implanted human PCa cells prominently overexpress not only several classes of molecules involved in proteolysis/invasion/angiogenesis and inflammation, but also numerous developmental and SC regulating genes. These latter observations suggest that the orthotopic microenvironment (i.e. mouse prostate) appears to be promoting the manifestation of CSC phenotypes and these CSCs might be involved in enhanced metastasis in the orthotopic microenvironment and later distant organ metastasis. In support, shRNA-mediated knockdown in many metastatic and CSC genes greatly inhibits PCa cell metastasis. Importantly, PCa cells that express high levels of osteopontin (OPN) or CD24, when prospectively purified out and used in spontaneous metastasis assays, demonstrate high metastatic capacities characteristic of metastatic CSCs. In sharp contrast, PCa cells negative for OPN and CD24 expression show little metastatic property. Finally, we provide multiple pieces of additional evidence that metastatic/metastasizing PCa cells possess CSC properties. / text