scholarly journals Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

2016 ◽  
Vol 113 (42) ◽  
pp. E6457-E6466 ◽  
Author(s):  
Tanya Stoyanova ◽  
Mireille Riedinger ◽  
Shu Lin ◽  
Claire M. Faltermeier ◽  
Bryan A. Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Castration Resistant Prostate Cancer ◽  
Intracellular Domain ◽  
Mesenchymal Transition ◽  
Alternative Pathways ◽  
High Risk Prostate Cancer ◽  
Castration Resistant ◽  
Oncogenic Pathways ◽  
Risk Prostate Cancer

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

scholarly journals ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (11) ◽  
pp. 2802 ◽  
Author(s):  
AbdulFattah Salah Fararjeh ◽  
Yen-Nien Liu
Keyword(s):  
Prostate Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitor ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Castration Resistant ◽  
Therapeutic Regime ◽  
Potential Biomarkers

Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers (ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa.

Aldo-keto-reductase 1C3 expression as an independent risk factor for occurrence of castration resistant prostate cancer in high risk prostate cancer treated with neoadjuvant therapy and prostatectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 172-172
Author(s):  
Yasuhiro Hashimoto ◽  
Toshikazu Tanaka ◽  
Atsushi Imai ◽  
Shingo Hatakeyama ◽  
Takahiro Yoneyama ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factor ◽  
High Risk ◽  
Independent Risk Factor ◽  
Multivariable Analysis ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
High Risk Prostate Cancer ◽  
Castration Resistant ◽  
Risk Prostate Cancer

172 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) is a key steroidogenic enzyme that is implicated in the development of castration-resistant prostate cancer (CRPC). In this study, we examined AKR1C3 expression in surgical specimens of high risk prostate cancer treated with neoadjuvant LHRH + EMP, and we investigate the correlation between the expression level of AKR1C3 and the occurrence of CRPC. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone ( < 50 ng/dL). Along with the routine pathological assessment, AKR1C3 expression was evaluated in tissue microarray analysis (TMA) in all patients. A multivariable Cox proportional hazards model was used to evaluate the association between CRPC and clinical data. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). At a median follow-up period of 79.5 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). In TMA, overexpression of AKR1C3 was seemed in 14 patients (13.6%). 5-year CRPC free survival rate of AKR1C3(+) patients (64.2%) was significantly lower than that of AKR1C3(-) patients (97.6%). (Log-rank test: p < 0.001) On multivariable analysis, AKR1C3 expression is an independent risk factor for occurrence of CRPC in this study. (p = 0.044). Conclusions: Although the present study was small and preliminary, overexpression of AKR1C3 is an independent risk factor for occurrence of CRPC in the high risk prostate cancer treated with neoadjuvant LHRH + EMP and prostatectomy. Further study is warranted to elucidate its clinical significance.

scholarly journals Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2947
Author(s):  
Fanny Bery ◽  
Mathilde Cancel ◽  
Maxime Guéguinou ◽  
Marie Potier-Cartereau ◽  
Christophe Vandier ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Epithelial To Mesenchymal Transition ◽  
Neuroendocrine Differentiation ◽  
Calcium Signal ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Castration Resistant

Therapeutic strategies for metastatic castration-resistant prostate cancer aim to target androgen receptor signaling. Despite initial survival benefits, treatment resistance invariably occurs, leading to lethal disease. Therapies targeting the androgen receptor can induce the emergence of a neuroendocrine phenotype and reactivate embryonic programs associated with epithelial to mesenchymal transition. We recently reported that dysregulation of the calcium signal can induce the transcription factor Zeb1, a key determinant of cell plasticity during tumor progression. The aim of this study was to determine whether the androgen receptor-targeted treatment Enzalutamide could induce dysregulation of the calcium signal involved in the progression toward epithelial to mesenchymal transition and neuroendocrine differentiation, contributing to therapeutic escape. Our results show that Zeb1 and the SK3 potassium channel are overexpressed in vivo in neuroendocrine castration-resistant prostate cancer and in vitro in LNCaP cells neurodifferentiated after Enzalutamide treatment. Moreover, the neuroendocrine phenotype is associated with a deregulation of the expression of Orai calcium channels. We showed that Zeb1 and SK3 are critical drivers of neuroendocrine differentiation. Interestingly, Ohmline, an SK3 inhibitor, can prevent the expression of Zeb1 and neuroendocrine markers induced by Enzalutamide. This study offers new perspectives to increase hormone therapy efficacy and improve clinical outcomes.

Are patients with Gleason 6 pathology safe from developing metastatic castration-resistant prostate cancer (mCRPC)?

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 110-110
Author(s):  
Christoph A. J. von Klot ◽  
Alena Boeker ◽  
Thomas R. W. Herrmann ◽  
Mario W. Kramer ◽  
Markus A. Kuczyk ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Gleason Score ◽  
Initial Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Biopsies ◽  
Castration Resistant ◽  
Risk Prostate Cancer ◽  
Low Risk Prostate Cancer

110 Background: Prostate cancer may remain clinical unapparent for decades, however at the stage of metastatic castration resistant prostate cancer (mCRPC), patients have only limited survival even with new therapeutic options. Recent evidence from histology studies regarding random prostate biopsies hint toward a relationship between higher biopsy Gleason score and the development of mCRPC. A few patients with initial low risk prostate cancer also seem to develop mCRPC. However, prostate biopsy underestimates final pathology in about one third of patients. We therefore evaluated the final whole gland pathology from radical prostatectomy to better assess the risk of progressing to mCRPC for patients with Gleason 6 prostate cancer in particular. Methods: Clinical data was assessed for patients with confirmed mCRPC between 3/2007 and 10/2014. Whole gland pathology workup was not available for patients with either metastatic disease on diagnosis, external radiation therapy or no curatively intended initial therapy. Results: Out of 605 screened patients we identified a total of 77 patients with confirmed mCRPC. Mean PSA at initial diagnosis was 29.5 ng/mL (range 1 - 58 ng/mL ). Mean PSA at the end of follow up was 34.1 ng/mL (range 1 - 71 ng/mL ). A total of 30 patients died during follow up. Distribution of Gleason scores for gleason 6, 7, 8, 9 and 10 were 2, 24, 28, 18, 5 patients respectively. Pathological evaluation obtained from laparoscopic or retropubic radical prostatectomy was available in 43 of 77 cases. cases. Interestingly, out of the only two patients with a documented gleason score of 6, one had radiation/I125 brachytherapy while the other had primary anti hormonal therapy. Therefore an understaging may be possible. Out of the confirmed final pathologies, non of the patients had a Gleason score below 7. Conclusions: Our observations suggest a non significant occurrence of mCRPC during the development of prostate cancer for patients with Gleason pathology of less than 7. Our results may potentially help better counseling for patients and need further validation in a larger series.

scholarly journals Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 135
Author(s):  
Panagiotis J. Vlachostergios ◽  
Athanasios Karathanasis ◽  
Vassilios Tzortzis
Keyword(s):  
Prostate Cancer ◽  
Mrna Expression ◽  
Epithelial To Mesenchymal Transition ◽  
Fibroblast Activation Protein ◽  
Castration Resistant Prostate Cancer ◽  
Sequencing Data ◽  
Clinical Value ◽  
Mesenchymal Transition ◽  
Fibroblast Activation ◽  
Neuroendocrine Prostate Cancer

Background: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. Methods: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. Results: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). Conclusions: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

scholarly journals Identification of Key Genes and Molecular Mechanisms Associated With Docetaxel Resistance in Castration Resistant Prostate Cancer Based on Bioinformatics Analysis

2020 ◽  
Author(s):  
Yu Liu ◽  
Changpeng Hu ◽  
Qian Zhang ◽  
Wuyi Liu ◽  
Guobing Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
Docetaxel Resistance ◽  
Castration Resistant ◽  
E2f Transcription Factor ◽  
Key Genes

Abstract BackgroundCastration resistant prostate cancer (CRPC) is one of the most common solid tumor with high mortality and limited therapeutic options, and docetaxel is the first-line chemotherapy for patients. However, the long-term use of docetaxel has limited its clinical applications. The aim of this study was to identify docetaxel-resistant key genes and molecular mechanisms. ResultsTUBB4A (Class IVa beta-tubulin), SRPX (Sushi repeat containing protein, X chromosome) and CSRP2 (Cysteine and glycine rich protein 2) were finally identified as the key genes tightly related to docetaxel resistance. TUBB4A and CSRP2 may participate in docetaxel resistance by E2F transcription factor and MYC proto-Oncogene in the process of cell cycle, and SRPX may participate in docetaxel resistance by epithelial–mesenchymal transition (EMT) and P53 pathway. ConclusionTUBB4A, SRPX and CSRP2 may be the key genes associated with docetaxel resistance, which could be prognostic biomarkers for docetaxel resistance in CRPC.

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