Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Kenneth R. Diller. Vita. Includes bibliographical references.

Th.--Méd.--Reims, 1980. N°: 62.

Prostate cancer is one of the most common cancers affecting one of every six men in United States. It is increasingly appreciated that tumor or cancer stem cells are the cells responsible for initiating tumor formation and therefore should be targeted for eradication in cancer treatment. But the mechanism involved in the acquisition of unlimited self-renewal and tumor initiation by cancer stem cells is unknown. Nanog, along with Oct3/4 and Sox-2, constitute the core transcriptional circuitry for the maintenance of stemness in embryonic stem cells. Herein we report that Nanog expression was detected at mRNA and protein levels in prostate cancer cells. The Nanog-expressing LNCaP-T and DU145 cells were enriched by infection with lentiviruses expressing GFP under the control of Nanog promoter. The Nanog-enriched prostate cancer cells had stronger expressions of stem and progenitor cell surface markers, including CD44 and CD133, when compared with those in the control group. Colony formation assay found that the Nanog-enriched LNCaP-T and DU145 cells formed more holoclones and prosta-spheres, which contained more self-renewing cells, than the control cells did. On the other hand, knockdown of Nanog in DU145 or LNCaP-T cells, via shRNAs, reduced their ability to form holoclones. Instead, most clones derived were meroclone and paraclones as result of increased differentiation and senescence due to knockdown of Nanog. When injected into mice, Nanog-enriched DU145 cells were found to possess increased tumorigenic potentials when compared to the vector controls. On the other hand, LNCaP-T cells with Nanog knocked down did not form tumors, while the vector controls readily formed tumors. Taken together, our data suggest an essential role for Nanog in the self-renewal and tumor initiation of prostate cancer cells. Chemotherapy is the major salvage therapeutic modality available for the patients with advanced cancers. However, drug resistance by some prostate cancer cells is a major barrier to efficacious chemotherapy. It has been increasingly appreciated that cancer stem cells are responsible for resistance to chemo- or radio-therapy, in addition to tumor initiation. However, the mechanisms involved remain unknown. In this study, we examined whether Nanog plays an essential role of Nanog in resistance to chemotherapy. In the surviving fractions of prostate cancer cells, we found increased levels of Nanog protein when compared to the cells treated with solvent control. To determine the role of Nanog in resistance of prostate cancer cells, we marked and enriched Nanog-expressing prostate cancer DU145 and LNCaP-T cells using a reporter gene under control of 2.5 kb hNanog1 promoter. When compared to the control, the prospectively enriched Nanog-expressing cells presented increased resistance to Taxol, vinblastine, and doxorubicin. Profiling of genes in drug resistance and metabolism revealed a marked increase in the mRNA level of ATP-binding cassette (ABC) efflux transporters B1 and G2 in tumor cells enriched with endogenous Nanog expression. The increased expression of ABCB1 and ABCG2 at protein levels in Nanog expressing cells was confirmed by Western blot and immunocytochemistry. Inhibition of ABCB1 activities sensitized Nanog expressing cells toward Taxol and vinblastine, and to less extent, doxorubicin. Blocking of ABCG2 activity sensitized Nanog expressing cells toward doxorubicin, but not Taxol and vinblastine. In addition, the tumor cells enriched with Nanog expression showed reduced apoptosis in response to Taxol treatment. Interestingly, Nanog-enriched prostate carcinoma cells displayed aberrantly activated â-catenin signaling, which is potentially associated with their increased chemo-resistant ability as well as the increased acquisition of epithelial to mesenchymal transition. In summary, Nanog is expressed in prostate cancer cells, especially in those positive for stem/progenitor markers. Enrichment of Nanog expressing cells led to enrichment of tumor cells with increased tumor initiating ability and increased resistance toward chemotherapy. Knockdown of Nanog reduces tumor initiating ability of prostate cancer cells and further sensitizes them toward chemotherapy. The gain-of-function and loss-of-function studies suggest an essential role of Nanog for prostate cancer cells to initiate tumor formation and resist chemotherapy.

Made available in DSpace on 2014-06-11T19:32:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-01Bitstream added on 2014-06-13T19:02:40Z : No. of bitstreams: 1 paiva_ghrg_dr_botib.pdf: 1701322 bytes, checksum: d1fa5b5c562a2a6ce8ad0d14ab948d4a (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer de próstata (CaP) é a neoplasia mais comumente diagnosticada entre homens no ocidente. Embora tratamentos efetivos para a doença localizada estejam disponíveis atualmente, não há terapia curativa para tumores metastáticos. Além disso, os marcadores diagnósticos utilizados na clínica não conseguem discriminar totalmente a evolução diferencial da doença. Desta forma, o conhecimento das diferenças biológicas entre tumores primários confinados ao órgão e metástases é essencial para o desenvolvimento de novos marcadores e identificação de alvos terapêuticos. Neste estudo a análise baseada na metodologia de HR-CGH cromossômico foi realizada para identificar alterações de ganhos e perdas genômicas em três grupos de amostras: o grupo I, que compreende amostras pareadas de tumor primário e respectivas metástases (11 casos); o grupo II, constituído de pacientes que apresentaram seguimento clínico favorável por mais de 10 anos (5 casos); e o grupo III, constituído por diferentes biópsias do mesmo paciente (5 pacientes com 2 biópsias cada). As amostras foram microdissecadas (amostras a fresco: a partir de lâminas de referência; em blocos de parafina: a laser) e após a obtenção de DNA foram amplificadas (amostras de arquivo: PCR-SCOMP) ou marcadas por nick-translation para a realização de HR-CGH. Os resultados de HR-CGH foram comparados com os dados obtidos da análise de CGH-array num subgrupo de amostras e revelaram concordâncias significativas. Os resultados obtidos na presente investigação revelaram perdas dos cromossomos 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q e 22q em 80% dos casos avaliados. Além disso, perdas em 17q11.2-25, por exemplo, foram detectadas exclusivamente nos tumores do grupo I e nas suas metástases, e não nos tumores do grupo II, sugerindo que esta alteração deve ser importante... / Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer mortality in men from Occident. Although effective treatments for the localized disease are available, there is no efficient therapy for metastatic tumors. Additionally, clinical diagnostic markers are not able to completely discriminate the differential evolution of the disease. The knowledge of biological differences between localized primary tumors and metastasis can establish new molecular markers and therapeutic targets. In this study, an analysis based on HR-CGH methodology was performed to identify imbalances genomic in three groups of samples: group I, paired samples of primary tumors and its metastasis (11 cases); group II, patients that exhibited favorable follow-up over 10 years (5 cases); and group III, different biopsies from the same patient (5 patients with 2 biopsies each). The tumor samples were submitted to microdissection procedures (fresh samples: from reference slides; paraffin embedded samples: laser), DNA extracted and amplified (archive sample: PCR-SCOMP) or labeled by nick-translation to HR-CGH. The HRCGH results were compared with data obtained from CGH-array analysis of a subgroup of samples and revealed significant concordances. In the present investigation, there were observed losses on chromosomes 1p, 2, 3q, 4p, 5q, 7, 8, 9q, 10q, 11q, 12q, 14q, 15q, 16q, 17q, 18q, 19, 20q and 22q in 80% of the cases. Losses in 17q11.2-25, for instance, were detected exclusively in tumor from group I and its metastasis, but were not found in tumors from group II, suggesting that this alteration must be important in the progression of the disease. Five genes were selected after the comparison between the HR-CGH and CGH-array data. The tumor suppressor genes ARID1A, MTSS1, NME1 and S100A4 and TOP2A (oncogenes) were evaluated by quantitative real time... (Complete abstract click electronic access below)

Purpose: To assess (1) the potential benefit that MRI may bring to prostate radiotherapy planning and delivery; (2) a method of improving registration of MRI and CT imaging to aid the RT planning workflow; (3) the role of in-bore MRI guided biopsy in informing management; (4) dosimetric outcome and toxicity of an integrated High Dose Rate (HDR-B) or Volumetric Modulated Arc Therapy (VMAT-IB) boost to the area of dominant disease within the prostate; (5) whether a predictive response can be identified measuring changes in Diffusion Weighted Imaging (DWI) and Dynamic Contrast Enhancement (DCE) during prostate RT after neo-adjuvant HT (NA-HT); (6) the necessity of hormone therapy (HT) with dose escalated radiotherapy (DE-RT) for intermediate risk prostate cancer. Methods: (1) Perform a systematic review of literature pertaining to MRI and image guided radiotherapy; (2) compare registration accuracy, based on displacement of fiducial markers or degree of overlap of segmented prostate measured by Dice Similarity Coefficient (DSC), of MRI and CT for 14 patients after conventional operator driven visual matching and then an additional registration step using interstitial points identified on high quality volumetric CT (HQVCT); (3) assess the predictive power of in-bore MRI guided biopsy of areas with suspicious appearance on multi-parametric MRI by comparing biopsy accuracy to histological findings and repeat biopsy results for 42 PIRADS 4-5 lesions in 31 men; (4) analyse patients treated in a prospective study receiving standard radiotherapy to the prostate plus a HDR-B (20 patients) or VMAT-IB (26) to a total dose of 250 Gy BED to assess acute and late toxicity and dosimetric variation between the two methods; (5) prospectively recruit 15 patient who have received NA-HT and perform DWI and DCE before, during and after completion of radiotherapy to look for significant changes in values in normal and malignant tissue which may predict for ultimate outcome; (6) Assess clinical outcome for patients receiving 75.6 – 78 Gy +/- bicalutamide. Results: (1) The review has quantified uncertainties in treatment delivery and the degree that the addition of MRI may mitigate this; (2) point based registration of CT and MRI imaging after visual registration achieved a significant reduction in fiducial marker displacement and a significant increase in DSC; (3) seven lesions targeted by in-bore MR guided biopsy had non-significant or negative results, most with biopsy needle deflected to the target periphery with four confirmed false negative on repeat biopsy; (4) with a median follow up of 12 months acute and late toxicity was similar after either treatment with HDR-B delivering a significantly higher dose to a proportion of the gross tumour volume (GTV) but with significantly lower minimum dose to the planned target volume (PTV); (5) tumour DWI values during RT after NA-HT were not found to significantly alter, DCE was found to vary significantly during treatment and initial changes correlated with changes in DWI; (6) the addition of bicalutamide did not significantly improve biochemical control or overall survival. Conclusions: (1) Routine use of MRI will to improve radiotherapy planning and delivery; (2) repeat point based registration using interstitial points has the potential to improve visual CT and MRI registration; (3) an in-bore MRI guided biopsy has little value in informing a decision to offer focal therapy to an MRI identified PIRADS 4-5 lesion due to its high false negative rate; (4) with limited follow up HDR-B and VMAT-IB appear safe methods of focal dose escalation although with significant dosimetric variations;(5) early changes in DWI and DCE during RT after NA-HT appear to correlate, longer follow up will assess their prognostic value; (6) A benefit of HT combined with DE-RT was not shown in this study.

Evidence from international comparisons and migrant studies suggest that environmental factors, such as a Western diet, may be important in prostate cancer development, possibly through effects on hormone and growth factor secretion and metabolism. However, despite considerable research, convincing associations between diet and risk for prostate cancer have not been established. Random and systematic measurement error in dietary assessment using traditional survey methods may contribute to inconsistent findings, particularly as they may not capture adequately specific nutritional constituents of the diet that may be associated with risk, such as fatty acids or vitamins. Validated biomarkers of nutritional factors and hormonal activity, as used in this thesis, provide more precise, objective and integrated measures of exposure, with the capacity to clarify potential mechanisms in the causal pathway of prostate cancer development. Nutritional and hormonal biomarkers investigated for their potential role in the development of prostate cancer include: folate and vitamin B₁₂, which are essential for DNA methylation, repair and synthesis; phytanic acid, obtained predominantly from ruminant fat intake and associated with an enzyme (α-Methylacyl-Coenzyme A Racemase (AMACR)) that is consistently over-expressed in prostate cancer tissue; and insulin-like growth factor (IGF-I), a growth factor influenced by diet and involved in the regulation of cell proliferation, differentiation, and apoptosis. All work presented in this thesis is from the European Prospective Investigation into Cancer and Nutrition (EPIC) study of 500,000 European men and women, using prospectively collected diet and lifestyle data and biological samples. The large number of prostate cancer cases diagnosed during long-term follow-up of EPIC participants enabled investigation of heterogeneity in risk for prostate cancer by time from recruitment to diagnosis (of particular importance for a disease with a long pre-clinical phase) and cancer characteristics such as disease grade and stage. Plasma phytanic acid concentration was highly correlated with dietary intake of fat from dairy products (r = 0.46) and beef (r = 0.30); capturing differences between countries in consumption of fat from these foods. Although phytanic acid is a useful biomarker of ruminant fat consumption, there was little evidence to support the hypothesis that the association between dairy products and prostate cancer risk (as suggested by previous work in EPIC and other studies) is mediated by phytanic acid (OR for doubling in concentration 1.05; 95%CI 0.91 – 1.21; P _trend = 0.53). There was strong evidence for an association between higher circulating IGF-I concentration and risk for prostate cancer (OR for highest versus lowest fourth 1.69; 95% CI: 1.35, 2.13; P _trend = 0.0002). Furthermore, the positive association observed among men diagnosed with advanced stage disease and among men diagnosed more than seven years after blood collection, supports the hypothesis that high IGF-I concentration is associated with clinically significant prostate cancer many years before diagnosis. There was no evidence of an association between prostate cancer risk and dietary folate or vitamin B₁₂ intake, or between circulating levels of folate (OR for doubling in concentration 1.05; 95%CI 0.95 – 1.15; <en>P _trend = 0.33) or vitamin B₁₂ (1.05; 95%CI 0.92 – 1.21; P _trend = 0.47) and only limited evidence for an increased risk associated with elevated vitamin B₁₂ in a meta-analysis of six prospective studies, that included the present study. All of these analyses were based on a blood sample taken at one point in time, with the assumption that this reflects the ‘true’ underlying concentration over the long-term. The poor to modest reliability estimates (intra-class correlation coefficients ranging from 0.18 to 0.48) for circulating concentrations of folate, IGF-I, phytanic acid and vitamin B₁₂ taken in samples approximately six years apart in a sub-sample of participants from EPIC Oxford, show that estimates of usual concentrations based on a single blood measurement weaken the ability to detect associations with disease risk. Where small effect sizes are anticipated, this may bias associations toward the null. In conclusion, there is convincing evidence that IGF-I is an important and potentially modifiable risk factor for prostate cancer many years before diagnosis. However, there is little evidence for an association between biomarkers of folate, vitamin B₁₂ and phytanic acid concentrations and risk for prostate cancer. Future studies should, where possible, incorporate multiple blood samples taken several years apart to better characterise long term relationships between biomarkers of nutritional and hormonal exposure and disease risk and pool individual participant data from multiple prospective studies to strengthen the power to detect modest associations.

No description available.

Prostate cancer (CaP) is the most common cancer in men in the UK and its incidence is increasing. The natural history of the disease is very variable, in some men progressing rapidly while in others It will run a more indolent course, in early disease localised to the prostate, radical treatment options offer potential cure however these come with considerable potential morbidity and a significant proportion of patients will relapse despite such interventions. This suggests the presence of microscopic disease beyond the prostate, not clinically detectable using current staging modalities.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22115号 / 医博第4528号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 道行, 教授 武藤 学, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Danial Alaei Faradonbeh, Natural drugs in the treatment and prevention of prostate diseases, Charles University in Prague, faculty of pharmacy in Hradec Králové, 2015, 86 pages. "Natural drugs in the treatment and prevention of prostate diseases" deals with prostate diseases which are some of the common ailments affecting men in different parts of the world. The etiology of prostate diseases has been identified but little progress has been witnessed as far as treatment is concerned. Of all prostate diseases identified so far, prostate cancer is the most common and affect me aged 40 and above. Prostate cancer affects the prostate gland and affects the normal function of other genitourinary tissues. Conventional prostate disease therapies have yielded minimal results, leading to increased calls for further research. Successful application of plants in the management of other conditions has attracted the interests of cancer researchers. Focus on a number of plants can provide the much needed reprieve and therapy against prostate cancer. Previous studies have identified a number of plants whose active component can act against cancer cells. Ficus pseudopalma, Nelumbo nuficera, Camptotheca acuminata, Rauvolfa vomitoria and Viscum album are some of the plants which have been identified to act against...