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Bladder cancer (BICa) is the second most common genitourinary cancer, affecting both men and women. Most (70%) cases present at the superficial stage; 20% of these recur with muscle-invasive disease. Major genetic alterations associated with BICa include: loss/gain in expression or mutations in Retinoblastoma (RB) gene, human epidermal growth factor receptors (HERs), H-ras, p53 and FGFR3. Only p53 mutations are well correlated with invasive BICa; other changes show variable correlations with disease status. To understand the progression of BICa, a model of nine human BICa cell sublines derived from a single parent but differing in in vivo characteristics, has been developed previously. These cells represent a heterogenous population from a single tumour and a model of different stages of BICa progression, from non-tumourigenic to invasive. Two sublines were selected for further investigation: C3 (non-tumourigenic) and B8 (invasive). These were transfected with green (C3-GSP-2) and red fluorescent reporters (B8-RSP-gck) respectively to investigate the effects of their co-injection in vivo, specifically, promotion of C3 tumour growth by B8 cells. Surprisingly, B8 tumour growth was inhibited by C3 cells in vivo at different cell numbers and proportions of cells injected. Microarray analysis of C3 and B8 cells revealed differential expression of 1367 genes with dramatic differences in the transforming growth factor- ?? and integrin-mediated pathways. Gene expression of BMP2,INHBB, FST, NOG, ID4 and TGF- ??1, in the TGF- ?? pathway was further analysed with qRT-PCR in all nine sublines. Expression of BMP2 was significantly related to tumourigenic potential (p=0.0238, Mann-Whitney) and INHBB to invasive ability (p=0.0476, Mann-Whitney). The BICa model did not include a metastatic component. To broaden the model, cell lines were established from an invaded lymph-node (B8-RSP-LN) and a bonemetastasis (B8-RSP-BN) after subcutaneous and intra-cardiac injection of B8- RSP-gck cells. No significant differences were observed in the migratory capability and anchorage-independent colony formation of these metastatic cells compared with B8 cells. Evaluation of expression of the panel of TGF-beta genes (BMP2, INHBB, FST, NOG, /04 and TGF- (31) and metastasis-related genes (MMP9, MMP2 and KAI1) indicated that expression of BMP2, FST, /04 and MMP9 was decreased or lost in the metastatic sublines.

Bladder cancer is one of the commoner malignancies in humans and current treatments for invasive disease typically give a five year survival rate of around fifty percent. Current chemotherapeutic agents increase survival by a small amount; clearly there is the need for improved treatments and for this, novel targets need to be identified. One putative target is the Fos family member Fos-related antigen-1 (Fra-1), which form part of the AP-1 transcription factor complex. Fra-1 is elevated in numerous human malignancies and regulates the transcription of genes involved in many aspects of the malignant process, such as migration and invasion. Regulatory control of Fra-1 has been incompletely studied to date; it is known that MAP Kinase dependent signalling can influence Fra-1 accumulation but other aspects of control are only now being elucidated. This thesis demonstrates that Fra-1 is present in the majority of bladder cancers, that it is regulated by the structure of the C-terminus and MAP Kinase dependent phosphorylation of the amino acids Ser[superscript 252] and Ser[superscript 265], and undergoes proteasomal degradation. This highlights the potential role of Fra-1 as a novel therapeutic target and provides more information on the regulation of Fra-1 which may be targeted with novel agents.

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Disease-specific (e.g. urinary) and generic problems (e.g. fatigue) impact health-related quality of life (HRQOL) of patients with bladder cancer (BC). A questionnaire addressing both sets of problems and generating utilities, a measure of overall HRQOL, is needed for this population. In consultation with 47 BC patients and 12 BC experts we created a novel HRQOL questionnaire for BC in a stepwise, iterative fashion with conceptual framework development, item generation, item reduction, question design and pilot testing. Patients and experts identified urinary problems, bowel problems, sexual problems, body image, pain, and decreased vigor as domains, which impact daily activities and impair HRQOL. Support from patients’ family and friends and their medical team were also paramount to HRQOL. The Bladder Utility Symptom Scale is a comprehensible instrument that was created to facilitate patient-oriented care and guide clinical policy by grounding guidelines, health resource allocation, and policy decisions in the expressed preferences of BC patients.

Disease-specific (e.g. urinary) and generic problems (e.g. fatigue) impact health-related quality of life (HRQOL) of patients with bladder cancer (BC). A questionnaire addressing both sets of problems and generating utilities, a measure of overall HRQOL, is needed for this population. In consultation with 47 BC patients and 12 BC experts we created a novel HRQOL questionnaire for BC in a stepwise, iterative fashion with conceptual framework development, item generation, item reduction, question design and pilot testing. Patients and experts identified urinary problems, bowel problems, sexual problems, body image, pain, and decreased vigor as domains, which impact daily activities and impair HRQOL. Support from patients’ family and friends and their medical team were also paramount to HRQOL. The Bladder Utility Symptom Scale is a comprehensible instrument that was created to facilitate patient-oriented care and guide clinical policy by grounding guidelines, health resource allocation, and policy decisions in the expressed preferences of BC patients.

No description available.

Introduction: The outcomes following radical treatment for bladder cancer (BC) remain poor, with 5 year overall survival (OS) rates of approximately 50% and over 5000 deaths per year in the U.K. There has been paucity of significant therapeutic developments since the introduction of cisplatinum based chemotherapy in the 1970’s. The aim of this study was to identify putative drug targets for the treatment of this aggressive form of cancer. Methods: A tissue microarray (TMA) was constructed from the cystectomy specimens of 497 BC patients and 70 controls, linked to a clinical database with extended follow up. The online database Oncomine® was interrogated to identify putative treatment targets which were subsequently evaluated using in-vitro models of high grade invasive bladder cancer (using the J82 and T24 cell lines). In-vitro modelling was conducted using siRNA target knockdown during proliferation, chemo-sensitivity, migration and Matrigel™ invasion assays. Expression of the putative targets was then correlated with tumour characteristics and patient outcomes, by IHC and automated image analysis of the TMA. Results: The proteins CYR61 and CTGF were selected from Oncomine® and studied in conjunction with the HGF/MET axis, on the basis of known interactions in other cancer types. siRNA knockdown of both proteins abrogated HGF induced Matrigel™ invasion in both cell lines. CYR61 knockdown significantly reduced HGF induced cell migration and foetal calf serum (FCS) induced Matrigel™ invasion in both cell lines. Knockdown of both proteins also significantly increased the sensitivity of both cell lines to cisplatinum. CYR61 expression was significantly increased in BC samples compared to normal controls and an independent predictor of OS at 6 years (HR 1.493, p=0.030). In contrast, loss of CTGF expression was significantly associated with increasing tumour stage and worse OS. MET expression was reduced in BC compared to controls and not predictive of survival following cystectomy. Conclusions: The in-vitro findings for CTGF as a treatment target were encouraging, although these findings were not supported by the TMA data. CYR61 promotes an aggressive bladder cancer phenotype and knockdown reverses features of EMT and increases chemo-sensitivity. Clinical cohort correlation confirms CYR61 to be a promising treatment target in bladder cancer.

Yes / Context: Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of de novo and recurrent bladder cancer. Objective: To identify a highly sensitive and specific biomarker candidate set with potential clinical utility in bladder cancer. Materials and methods: Urinary biomarkers concentrations were determined by ELISA. The performance of individual markers and marker combinations was assessed using ROC analysis. Results: A 5-biomarker panel (IL8, MMP9, VEGFA, PTGS2 and EN2) was defined from the candidate set. Discussion and conclusion: This panel showed a better overall performance than the best individual marker. Further validation studies are needed to evaluate its clinical utility in bladder cancer. / This work has been supported in part by the European Commission Program DIPROMON - HEALTH-F5-2012-306157-2: Development of an integrated protein- and cell-based device for non-invasive diagnostics in the urogenital tract.

published_or_final_version / Pathology / Master / Master of Medical Sciences