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[This corrects the article DOI: 10.18632/oncotarget.16055.].
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Castration resistant-prostate cancer is largely impervious to feather hormonal therapy and hence the outlook for patients is grim. Here we use an approach to attach the recently discovered Achilles heel. The experimental treatment established in this study is based on the recent discovery that it is the FABP5-PPARγ-VEGF signalling axis, rather than the androgen receptor pathway, played a dominant role in promoting the malignant progression of castration resistant prostate cancer cells. Treatments have been established in mice by suppressing the biological activity of FABP5 using a chemical inhibitor SBFI26. The inhibitor significantly suppressed the proliferation, migration, invasiveness and colony formation of PC3-M cells in vitro. It also produced a highly significant suppression of both the metastases and the primary tumours developed from cancer cells implanted orthotopically into the prostate glands of the mice. The inhibitor SBFI26 interferes with the FABP5-PPARγ- signalling pathway at the initial stage of the signal transduction by binding competitively to FABP5 to inhibit cellular fatty acid uptake. This avoids the fatty-acid stimulation of PPARγ and prevents it activating the down-stream regulated cancer-promoting genes. This entirely novel experimental approach to treating castration- resistant prostate cancer is completely different from current treatments that are based on androgen-blockade therapy.
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Antineoplásicos/farmacologia , Ciclobutanos/farmacologia , Ácidos Dicarboxílicos/farmacologia , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Metástase Neoplásica , PPAR gama/agonistas , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Ligação Proteica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In contrast to numerous studies conducted to investigate the crucial role of fatty acid binding protein 5 (FABP5) in prostate cancer, investigations on the possible involvement of other FABPs are rare. Here we first measured the mRNA levels of 10 FABPs in benign and malignant prostate cell lines and identified the differentially expressed FABP6 and FABP9 mRNAs whose levels in all malignant cell lines were higher than those in the benign cells. Thereafter we assessed the expression status of FABP6 and FABP9 in both prostate cell lines and in human tissues. FABP6 protein was overexpressed only in 1 of the 5 malignant cell lines and its immunostaining intensities were not significantly different between benign and malignant prostate tissues. In contrast, FABP9 protein was highly expressed in highly malignant cell lines PC-3 and PC3-M, but its level in the benign PNT-2 and other malignant cell lines was not detectable. When analysed in an archival set of human prostate tissues, immunohistochemical staining intensity for FABP9 was significantly higher in carcinomas than in benign cases and the increase in FABP9 was significantly correlated with reduced patient survival times. Moreover, the increased level of staining for FABP9 was significantly associated with the increased joint Gleason scores (GS) and androgen receptor index (AR). Suppression of FABP9 expression in highly malignant PC3-M cells inhibited their invasive potential. Our results suggest that FABP9 is a valuable prognostic marker to predict the outcomes of prostate cancer patients, perhaps by playing an important role in prostate cancer cell invasion.
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Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias da Próstata/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Ligação a Ácido Graxo/genética , Hormônios Gastrointestinais/genética , Hormônios Gastrointestinais/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Invasividade Neoplásica , Valor Preditivo dos Testes , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Interferência de RNA , RNA Mensageiro/genética , Receptores Androgênicos/metabolismo , Fatores de Tempo , Regulação para CimaRESUMO
PURPOSE: To assess the role and implications of MRI in the management of patients with stage T(1c) prostate cancer. PATIENTS AND METHODS: Data were collected from our oncology database, where all new prostate cancers are recorded, for a period of 3 years ending December 2005. A total of 915 patients were found to have prostate cancer. Of the 204 patients with stage T(1c) disease, 144 were considered eligible for radical treatment and underwent cross-sectional imaging in the form of an MRI scan. Gleason grade, clinical stage, cross-sectional imaging results, and subsequent treatment were recorded. The results were analyzed to see whether the MRI findings altered the modality of treatment offered to the patient. RESULTS: Of the 144 patients, 137 had scans that showed no extracapsular invasion, while five scans were equivocal. All five patients had further investigation, either by CT scanning or targeted biopsies, which confirmed the cancer to be localized. In the remaining two cases, the MRI findings upstaged T(1c) disease to T(3) disease, as there was evidence of extracapsular involvement. The imaging result therefore affected treatment choice in only two patients in that radical surgery was not offered because of the scan findings. CONCLUSIONS: The role of MRI in the management of clinical stage T(1c) prostate cancer is limited, as it altered the management of only 1.3% of our patients. The cost v the value of this study should be discussed with the patient before MRI is prescribed.
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Pesquisa sobre Serviços de Saúde , Imageamento por Ressonância Magnética , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
BACKGROUND: The association of testicular microlithiasis with testicular tumour and the need for follow-up remain largely unclear. METHODS: We conducted a national questionnaire survey involving consultant BAUS members (BAUS is the official national organisation (like the AUA in USA) of the practising urologists in the UK and Ireland), to provide a snapshot of current attitudes towards investigation and surveillance of patients with testicular microlithiasis. RESULTS: Of the 464 questionnaires sent to the BAUS membership, 263(57%) were returned. 251 returns (12 were incomplete) were analysed, of whom 173(69%) do and 78(31%) do not follow-up testicular microlithiasis. Of the 173 who do follow-up, 119(69%) follow-up all patients while 54(31%) follow-up only a selected group of patients. 172 of 173 use ultra sound scan while 27(16%) check tumour makers. 10(6%) arrange ultrasound scan every six months, 151(88%) annually while 10(6%) at longer intervals. 66(38%) intend to follow-up these patients for life while, 80(47%) until 55 years of age and 26(15%) for up to 5 years. 173(68.9%) believe testicular microlithiasis is associated with CIS in < 1%, 53(21%) think it is between 1&10% while 7(3%) believe it is > 10%. 109(43%) believe those patients who develop a tumour, will have survival benefit with follow-up while 142(57%) do not. Interestingly, 66(38%) who follow-up these patients do not think there is a survival benefit. CONCLUSION: There is significant variability in how patients with testicular microlithiasis are followed-up. However a majority of consultant urologists nationally, believe surveillance of this patient group confers no survival benefit. There is a clear need to clarify this issue in order to recommend a coherent surveillance policy.
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Cálculos/complicações , Vigilância da População , Inquéritos e Questionários , Doenças Testiculares/complicações , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Reino UnidoRESUMO
We immunohistochemically identified protein kinase C (PKC) isoenzymes and the receptor for activated C-kinase (RACK-1) in normal, chronically inflamed, and malignant pancreas specimens. Expression patterns were specific and consistent for each microanatomic structure. In chronic pancreatitis, the expression patterns by epithelial cells were indistinguishable from those in normal pancreas. In the stroma, there was a gain of PKC-delta (P < .05) and loss of PKC-mu (P < .0001). Expression in pancreatic duct carcinomas, compared with control normal minor ductular epithelial cells, revealed relative loss of PKC-epsilon (P < .0001), PKC-iota (P = .005), and PKC-theta (P < .0001) but no gain in any isoenzyme. Compared with control normal major duct epithelial cells, the principal differences were a relative loss in PKC-gamma (P < .05) and a relative gain in PKC-beta (P < .05), PKC-iota (P < .05), and PKC-zeta (P < .005). The stroma adjacent to ductal carcinomas was characterized by prominent expression of PKC-mu and a gain in PKC-delta (P < .0001) and PKC-zeta (P > .005). Ampullary carcinomas revealed a relative gain of PKC-iota (P < .05) and RACK-1 (P < .05). In the adjacent stroma was enhanced expression of PKC-delta (P < .005) and PKC-gamma (P < .001) and loss of PKC-mu (P < .05). Specific changes in isoenzyme expression in stroma of chronic pancreatitis and in epithelial cells and stroma of ductal and ampullary pancreatic adenocarcinomas reflect specific modulation of intracellular signaling pathways that control critical homeostatic mechanisms.