| 1. |
- Rueenauver, K., et al.
(författare)
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Prognostic significance of YWHAZ expression in localized prostate cancer
- 2014
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608. ; 17:4, s. 310-314
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer (PCa) patients are often over-treated because of the lack of biomarkers needed to distinguish the lethal from the indolent form of PCa. YWHAZ was recently identified as a potential therapeutic target in castration-resistant PCa (CRPC). Therefore, this study focused on determining the prognostic significance of YWHAZ in localized PCa.METHODS: YWHAZ expression was assessed by immunohistochemistry on formalin-fixed paraffin-embedded tissue from 213 men who underwent radical prostatectomy. Kaplan-Meier analysis and Cox proportional-hazards models were, used to assess the prognostic value of YWHAZ intensity.RESULTS: High YWHAZ expression was strongly associated with high Gleason score at the time of diagnosis (P<0.001) and PSA relapse (P=0.001). Importantly, patients with high expression of YWHAZ had a higher risk of CRPC development (P=0.002) and reduced survival time (P=0.002).CONCLUSIONS: Our findings indicate that YWHAZ could serve as a promising prognostic biomarker in localized PCa to predict poor prognosis and to identify a subgroup of tumors, which might benefit from earlier adjuvant or YWHAZ-targeted therapy.
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| 2. |
- Brady, Lauren, et al.
(författare)
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Correlation of integrated ERG/PTEN assessment with biochemical recurrence in prostate cancer
- 2021
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Ingår i: Cancer Treatment and Research Communications. - : Elsevier. - 2468-2942. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Prostate cancer is a heterogeneous disease, with a complex molecular landscape that evolves throughout disease progression. Common alterations in genes such as ERG and PTEN have been attributed to worse prognosis. This study aimed to further examine the clinical relevance of PTEN and ERG expression in a cohort of patients with prostate cancer post radical prostatectomy.METHODS: Tissue microarrays were constructed from 132 patients with prostate cancer from the Irish Prostate Cancer Research Consortium and University Hospital of Orebro, Sweden. Patients were divided into three groups - Group 1: biochemical recurrence, Group 2: no biochemical recurrence and Group 3: immediate progression after surgery. PTEN and ERG immunohistochemical analysis was performed and the association between expression levels and clinical parameters were compared.RESULTS: Pathological stage pT3 tumours were more common at borderline significantly higher levels amongst patients who biochemically recurred when compared to patients who did not recur after radical prostatectomy (p = 0.05). ERG and PTEN expression levels were compared separately and concurrently across all three patient groups. Lack of ERG expression was strongly associated with immediate progression after surgery (p = 0.029). Loss of/low PTEN trended towards an association with immediate progression, however this was not statistically significant (p = 0.066).CONCLUSION: In this study, negative ERG expression was strongly associated with immediate biochemical progression after radical prostatectomy. Moreover, a trend towards a relationship between aberrant PTEN expression and progression was observed. Additional studies with long-term follow up data may provide further clinical insight into the genomic heterogeneity in this population.
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| 3. |
- Braegelmann, Johannes, et al.
(författare)
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Pan-Cancer Analysis of the Mediator Complex Transcriptome Identifies CDK19 and CDK8 as Therapeutic Targets in Advanced Prostate Cancer
- 2017
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 23:7, s. 1829-1840
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches.Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer-specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq.Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type-specific Mediator complex compositions. Only prostate cancerwasmarked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8were present inmetastases. In vitro, inhibition ofCDK19 and CDK8 by knockdown or treatment with a selective CDK8/ CDK19 inhibitor significantly decreased migration and invasion.Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer.
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| 4. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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A miRNA expression signature that separates between normal and malignant prostate tissues
- 2011
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; :11, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.ResultsNine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.ConclusionsWe found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.
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| 5. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
- 2013
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Ingår i: BMC Cancer. - London, United Kingdom : BioMed Central (BMC). - 1471-2407. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate. Methods: Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student's t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers. Results: The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified. Conclusions: The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the different zones. MicroRNA signatures that are specific for PZ and TZ tumors could also lead to more accurate prognoses, since tumors arising in the PZ tend to be more aggressive than tumors arising in the TZ.
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| 6. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ) and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation to the difference in propensity of tumors in the zones of the prostate.Methods:The expression of 667 unique miRNAs was investigated in normal and malignant transition zone and peripheral zone prostate tissues using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs and hierarchical clustering and principal component analyses were used to note the separation of the tissues. A cross-validation test using the ADtree algorithm was used to test the generality of the identified miRNA signatures.Results:The Student’s t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentiallyexpressed miRNAs between normal and malignant tissues showed a perfect separation between samples while analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmedt hese results and several potential miRNA markers were identified.Conclusions:The results of this study indicate that the major differences in the transcription programme are those arising during tumor development, rather than during normal tissue development. In conclusion, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ, indicating that the PZ are more prone to tumor development than the TZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the transition- or peripheral zone.
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| 7. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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Quantity and quality of nucleic acids extracted from archival formalin fixed paraffin embedded prostate biopsies
- 2018
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Ingår i: BMC Medical Research Methodology. - : BioMed Central. - 1471-2288. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In Sweden, human tissue samples obtained from diagnostic and surgical procedures have for decades been routinely stored in a formalin-fixed, paraffin-embedded, form. Through linkage with nationwide registers, these samples are available for molecular studies to identify biomarkers predicting mortality even in slow-progressing prostate cancer. However, tissue fixation causes modifications of nucleic acids, making it challenging to extract high-quality nucleic acids from formalin fixated tissues.METHODS: In this study, the efficiency of five commercial nucleic acid extraction kits was compared on 30 prostate biopsies with normal histology, and the quantity and quality of the products were compared using spectrophotometry and Agilent's BioAnalyzer. Student's t-test's and Bland-Altman analyses were performed in order to investigate differences in nucleic acid quantity and quality between the five kits. The best performing extraction kits were subsequently tested on an additional 84 prostate tumor tissues. A Spearman's correlation test and linear regression analyses were performed in order to investigate the impact of tissue age and amount of tissue on nucleic acid quantity and quality.RESULTS: Nucleic acids extracted with RNeasy® FFPE and QIAamp® DNA FFPE Tissue kit had the highest quantity and quality, and was used for extraction from 84 tumor tissues. Nucleic acids were successfully extracted from all biopsies, and the amount of tumor (in millimeter) was found to have the strongest association with quantity and quality of nucleic acids.CONCLUSIONS: To conclude, this study shows that the choice of nucleic acid extraction kit affects the quantity and quality of extracted products. Furthermore, we show that extraction of nucleic acids from archival formalin-fixed prostate biopsies is possible, allowing molecular studies to be performed on this valuable sample collection.
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| 8. |
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| 9. |
- Davidsson, Sabina, 1972-, et al.
(författare)
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FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer
- 2018
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Ingår i: The Prostate. - Hoboken, USA : John Wiley & Sons. - 0270-4137 .- 1097-0045. ; 78:1, s. 40-47
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart.CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.
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| 10. |
- Davidsson, Sabina, 1972-, et al.
(författare)
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Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer
- 2016
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Ingår i: Infectious Agents and Cancer. - London, United Kingdom : BioMed Central (BMC). - 1750-9378. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acnes has been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease.Methods: We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient's prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes.Results: The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93-11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed.Conclusion: The present study provides further evidence for a role of P. acnes in prostate cancer development.
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