| 1. |
- Barbieri, Christopher E., et al.
(författare)
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The Mutational Landscape of Prostate Cancer
- 2013
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 64:4, s. 567-576
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Forskningsöversikt (refereegranskat)abstract
- Context: Prostate cancer (PCa) is a clinically heterogeneous disease with marked variability in patient outcomes. Molecular characterization has revealed striking mutational heterogeneity that may underlie the variable clinical course of the disease. Objective: In this review, we discuss the common genomic alterations that form the molecular basis of PCa, their functional significance, and the potential to translate this knowledge into patient care. Evidence acquisition: We reviewed the relevant literature, with a particular focus on recent studies on somatic alterations in PCa. Evidence synthesis: Advances in sequencing technology have resulted in an explosion of data regarding the mutational events underlying the development and progression of PCa. Heterogeneity is the norm; few abnormalities in specific genes are highly recurrent, but alterations in certain signaling pathways do predominate. These alterations include those in pathways known to affect tumorigenesis in a wide spectrum of tissues, such as the phosphoinositide 3-kinase/phosphatase and tensin homolog/Akt pathway, cell cycle regulation, and chromatin regulation. Alterations more specific to PCa are also observed, particularly gene fusions of ETS transcription factors and alterations in androgen signaling. Mounting data suggest that PCa can be subdivided based on a molecular profile of genetic alterations. Conclusions: Major advances have been made in cataloging the genomic alterations in PCa and understanding the molecular mechanisms underlying the disease. These findings raise the possibility that PCa could soon transition from being a poorly understood, heterogeneous disease with a variable clinical course to being a collection of homogenous subtypes identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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| 2. |
- Ceder, Yvonne, et al.
(författare)
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The Molecular Evolution of Castration-resistant Prostate Cancer
- 2016
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Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 2:5, s. 506-513
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Forskningsöversikt (refereegranskat)abstract
- CONTEXT: Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. However, castration-resistant prostate cancer (CRPC) nearly invariably develops through a range of different molecular mechanisms accompanied by progression to a more aggressive phenotype.OBJECTIVE: To understand the key molecular mechanisms leading to CRPC and the functional implications of this progression. Understanding molecular evolutionary mechanisms in CRPC is essential for the development of novel curative therapeutic approaches.EVIDENCE ACQUISITION: A systematic literature search to identify relevant original articles was conducted using PubMed. Findings verified in independent studies and supported by in vivo data were prioritised. From the eligible collection, 50 papers were selected.EVIDENCE SYNTHESIS: The majority of CRPC tumours harbour alterations in the androgen receptor (AR) at the DNA, RNA, and/or protein level, and/or other alterations involving the AR signalling pathway, so this central molecule is the focus of this review. To survive and resume growth despite low levels of circulating androgens, prostate cancer cells can also adapt androgen synthesis or induce alternative pathways.CONCLUSIONS: Despite more efficient ADT strategies, most evidence points to persistent AR signalling as a major mechanism of progression to CRPC. Resistance due to transdifferentiation or AR independence is also emerging as a mechanism of resistance. The diversity of potential resistance mechanisms supports the need for combination treatment and serial monitoring for adaptive treatment strategies.PATIENT SUMMARY: In this review, we summarise how prostate cancer cells evade androgen deprivation therapy and become more aggressive. Defining the molecular mechanisms will be critical for the development of new treatment approaches and hence improved survival.
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| 3. |
- Cuzick, Jack, et al.
(författare)
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Prevention and early detection of prostate cancer.
- 2014
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 15:11, s. e484-92
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.
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| 4. |
- Tassidis, Helena, et al.
(författare)
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Role of the protein tyrosine phosphatase SHP-1 in Interleukin-6 regulation of prostate cancer cells
- 2010
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Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 70:14, s. 1491-1500
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine that has been implicated in the modulation of growth and progression of prostate cancer. Decreased expression of the tyrosine phosphatase SHP-1, involved in regulation of cytokine and tyrosine kinase receptor signaling, has been shown to be associated with less favorable outcome among prostate cancer patients.METHODS: Parental LNCaP cells and an LNCaP-IL6+ subline, derived from parental LNCaP cells by continuous culture of the cells in the presence of recombinant IL-6 were used in the study. Expression of STAT3, pSTAT3, ERK, pERK, AKT, pAKT, PTEN, and SHP-1 was analyzed by immunohistochemistry, Western blots, cDNA microarray, quantitative PCRs, and reverse transcriptase PCRs. Proliferation and apoptosis of transfected cells were analyzed by caspase3/7 assay and flow cytometry.RESULTS: Phosphorylation of ERK and STAT3 was increased in the LNCaP-IL6+ subline compared with LNCaP cells, whereas pAKT was decreased. Overexpression and inhibition experiments with SHP-1 siRNA showed that SHP-1 reduced proliferation and increased apoptosis in both cell lines. Microarray analysis revealed 80 up-regulated and 87 down-regulated SHP-1-related genes in the LNCaP-IL6+ cell line compared with LNCaP cells.CONCLUSIONS: SHP-1 suppresses growth and increases apoptosis in both LNCaP and LNCaP-IL6+ cells, which suggests that SHP-1 could be a therapeutic target in prostate cancer, even when there is an IL-6-related growth advantage.
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| 5. |
- Tassidis, Helena, et al.
(författare)
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Role of the ProteinTyrosine Phosphatase SHP-I in Interleukin-6 Regulation of Prostate Cancer Cells
- 2010
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 70:14, s. 1491-1500
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Interleukin-6 (IL-6) is a multifunctional cytokine that has been implicated in the modulation of growth and progression of prostate cancer. Decreased expression of the tyrosine phosphatase SHP-1, involved in regulation of cytokine and tyrosine kinase receptor signaling, has been shown to be associated with less favorable outcome among prostate cancer patients. METHODS. Parental LNCaP cells and an LNCaP-IL6+subline, derived from parental LNCaP cells by continuous culture of the cells in the presence of recombinant IL-6 were used in the study. Expression of STAT3, pSTAT3, ERK, pERK, AKT, pAKT, PTEN, and SHP-1 was analyzed by immunohistochemistry, Western blots, cDNA microarray, quantitative PCRs, and reverse transcriptase PCRs. Proliferation and apoptosis of transfected cells were analyzed by caspase3/7 assay and flow cytometry. RESULTS. Phosphorylation of ERK and STAT3 was increased in the LNCaP-IL6+ subline compared with LNCaP cells, whereas pAKT was decreased. Overexpression and inhibition experiments with SHP-1 siRNA showed that SHP-1 reduced proliferation and increased apoptosis in both cell lines. Microarray analysis revealed 80 up-regulated and 87 down-regulated SHP-1-related genes in the LNCaP-IL6+ cell line compared with LNCaP cells. CONCLUSIONS. SHP-1 suppresses growth and increases apoptosis in both LNCaP and LNCaP-IL6+ cells, which suggests that SHP-1 could be a therapeutic target in prostate cancer, even when there is an IL-6-related growth advantage. Prostate 70: 1491-1500, 2010. (C) 2010 Wiley-Liss, Inc.
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