The Heterogeneity of Prostate Cancer: A Practical Approach

Tolkach, Yuri; Kristiansen, Glen

doi:10.1159/000477852

Cited by 102 publications

(83 citation statements)

References 77 publications

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“…If detected early, the chances of curing PCa are high, but more advanced PCa develops resistance to androgen deprivation therapies [7,8]. These tumors are referred to as "castration-resistant PCa," are highly heterogeneous in their molecular alterations [9][10][11], and are resistant to available therapies [12][13][14]. It is therefore crucial to identify new therapeutic targets and additional approaches to cure or at least increase the survival of patients with advanced PCa [15,16].…”

Section: Introductionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

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et al. 2020

Oxidative Medicine and Cellular Longevity

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The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

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Section: Introductionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

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Santos

Monção

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…PCa with high-levels of molecular and morphological diversity is an extremely heterogeneous neoplasm, ranging from clinically indolent to metastatic and life-threatening disease [2]. Therefore, For patients with and without PCa upgrading mean CSS was 11.9 (95% CI: 11.3-12.5) and 11.9 (95% CI: 11.7-12.0) years.…”

Section: Discussionmentioning

confidence: 99%

“…PCa with high-levels of molecular and morphological diversity is an extremely heterogeneous neoplasm, ranging from clinically indolent to metastatic and life-threatening disease [2]. Therefore, accurate assessment of tumour characteristics at diagnosis is essential for optimal disease management.…”

Section: Discussionmentioning

confidence: 99%

“…Globally, prostate cancer (PCa) is the second most common cancer in men, with 1.3 million incident cases and 416 000 deaths per year [1]. PCa is a heterogeneous disease in various aspects, including morphological manifestation, clinical course, and molecular features [2]. Usually, approximately three separate tumours arise in the gland [3], and several grading systems have been proposed for morphological evaluation of the disease [4].…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Prostate Cancer Upgrading and Upstaging on Biochemical Recurrence and Cancer-Specific Survival

et al. 2020

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Background and Objectives: Significant numbers of prostate cancer (PCa) patients experience tumour upgrading and upstaging between prostate biopsy and radical prostatectomy (RP) specimens. The aim of our study was to investigate the role of grade and stage increase on surgical and oncological outcomes. Materials and Methods: Upgrading and upstaging rates were analysed in 676 treatment-naïve PCa patients who underwent RP with subsequent follow-up. Positive surgical margin (PSM), biochemical recurrence (BCR), metastasis-free survival (MFS), overall (OS) and cancer specific survival (CSS) were analysed according to upgrading and upstaging. Results: Upgrading was observed in 29% and upstaging in 22% of PCa patients. Patients undergoing upgrading or upstaging were 1.5 times more likely to have a PSM on RP pathology. Both upgrading and upstaging were associated with increased risk for BCR: 1.8 and 2.1 times, respectively. Mean time to BCR after RP was 2.1 years in upgraded cases and 2.7 years in patients with no upgrading (p < 0.001), while mean time to BCR was 1.9 years in upstaged and 2.8 years in non-upstaged cases (p < 0.001). Grade and stage increase after RP were associated with inferior MFS rates and ten-year CSS: 89% vs. 98% for upgrading (p = 0.039) and 87% vs. 98% for upstaging (p = 0.008). Conclusions: Currently used risk stratification models are associated with substantial misdiagnosis. Pathological upgrading and upstaging have been associated with inferior surgical results, substantial higher risk of BCR and inferior rates of important oncological outcomes, which should be considered when counselling PCa patients at the time of diagnosis or after definitive therapy.

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“…Although this does not completely corroborate with cell line data, it is well known that in vitro cell lines do not necessarily reflect what happens in vivo. PC is well known for its tumour heterogeneity, which is reflected by diverse morphological manifestations and various molecular alterations associated with different tumour phenotypes [20]. …”

Section: Discussionmentioning

confidence: 99%

Expression, localisation and potential significance of aquaporins in benign and malignant human prostate tissue

et al. 2018

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BackgroundTo study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate tissue.MethodsThe AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-ΔCT method and correlated to clinicopathological parameters.ResultsTranscripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (ρ = − 0.354; p = 0.013), D’Amico risk stratification (ρ = − 0.336; p = 0.012), ISUP grade (ρ = − 0.321; p = 0.017) and Gleason score (ρ = − 0.342; p = 0.011).ConclusionsThis is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.Electronic supplementary materialThe online version of this article (10.1186/s12894-018-0391-y) contains supplementary material, which is available to authorized users.

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The Heterogeneity of Prostate Cancer: A Practical Approach

Cited by 102 publications

References 77 publications

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

The Impact of Prostate Cancer Upgrading and Upstaging on Biochemical Recurrence and Cancer-Specific Survival

Expression, localisation and potential significance of aquaporins in benign and malignant human prostate tissue

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