scholarly journals TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer

Oncogenesis ◽  
2021 ◽  
Vol 10 (11) ◽  
Author(s):  
Yu-Ching Wen ◽  
Yen-Nien Liu ◽  
Hsiu-Lien Yeh ◽  
Wei-Hao Chen ◽  
Kuo-Ching Jiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Wnt Signaling ◽  
Neuroendocrine Differentiation ◽  
Cytokine Response ◽  
Cytokine Signaling ◽  
Regulatory Sequence ◽  
Castration Resistant Prostate Cancer ◽  
Tissue Samples ◽  
Neuroendocrine Prostate Cancer ◽  
Signaling Activation

AbstractNeuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.

scholarly journals Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Divya Bhagirath ◽  
Michael Liston ◽  
Theresa Akoto ◽  
Byron Lui ◽  
Barbara A. Bensing ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Neuroendocrine Differentiation ◽  
Extracellular Vesicle ◽  
Machine Learning Algorithms ◽  
Castration Resistant Prostate Cancer ◽  
Cellular Models ◽  
Non Invasive ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer

AbstractNeuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.

scholarly journals The Correlation between PSCA Expression and Neuroendocrine Differentiation in Prostate Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Qian Xiang ◽  
Zhiguo Zhu ◽  
Lianmin Luo ◽  
Jiamin Wang ◽  
Yangzhou Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Specific Antigen ◽  
Neuroendocrine Differentiation ◽  
Positive Association ◽  
Tumor Stage ◽  
Clinicopathological Parameters ◽  
Specific Marker ◽  
Castration Resistant Prostate Cancer ◽  
Neuroendocrine Prostate Cancer

The prostate stem cell antigen (PSCA), as a predominantly prostate-specific marker, is overexpressed in most prostate cancer specimens, is positively correlated with prostate cancer androgen independence, and has the potential to be treated with castration-resistant prostate cancer (CRPC) as a gene therapy target. Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients’ age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

scholarly journals Sympathetic signaling facilitates progression of neuroendocrine prostate cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shubham Dwivedi ◽  
Maricris Bautista ◽  
Sanskriti Shrestha ◽  
Hussain Elhasasna ◽  
Tanaya Chaphekar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Intervention Point ◽  
High Concentrations ◽  
Potential Therapeutic Intervention

AbstractThe progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC.

scholarly journals Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhi Long ◽  
Liang Deng ◽  
Chao Li ◽  
Qiangrong He ◽  
Yao He ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcriptional Repression ◽  
Critical Role ◽  
Histone H3 ◽  
Neuroendocrine Differentiation ◽  
Cell Models ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Aggressive Subtype

AbstractThe rising of a highly aggressive subtype of castration-resistant prostate cancer (CRPC) named treatment-induced neuroendocrine prostate cancer (t-NEPC) after androgen deprivation therapy (ADT) is well known for its features of the neuroendocrine differentiation (NED) and androgen receptor (AR) independence. However, t-NEPC is still largely unknown. Here, we found that EHF is notably depressed in t-NEPC tumors, patient-derived xenografts, transgenic mice, and cell models. Results from cell lines uncovered that ADT represses EHF expression, which is required for the ADT-induced NED. Mechanism dissection revealed that ADT decreases the EHF transcription via relieving the AR binding to different androgen-responsive elements, which then promotes the expression and enzymatic activity of enhancer of zeste homolog 2 (EZH2), consequently catalyzing tri-methylation lysine 27 of histone H3 for transcriptional repression of its downstream genes to promote the NED. Furthermore, preclinical studies from cell and mice models proved that recovery of EHF expression or using EZH2 inhibitor can attenuate aggressive properties of CRPC cells, hinder the progression of t-NEPC, and promote the response of CPRC cells to enzalutamide. Together, we elucidate that the ADT/AR/EHF/EZH2 signaling is required for the ADT-enhanced NED and plays a critical role in the progression of t-NEPC.

scholarly journals Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Wei-Yu Chen ◽  
Yu-Ching Wen ◽  
Shian-Ren Lin ◽  
Hsiu-Lien Yeh ◽  
Kuo-Ching Jiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Neuroendocrine Differentiation ◽  
Cholinergic Receptor ◽  
Castration Resistance ◽  
Nerve Growth ◽  
Neuroendocrine Prostate Cancer ◽  
Signaling Activation

AbstractNerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.

Clinical investigation of neuroendocrine differentiation in prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 138-138
Author(s):  
Tatsuya Shimomura ◽  
Takashi Kurauchi ◽  
Keigo Sakanaka ◽  
Takahiro Kimura ◽  
Shin Egawa
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Neuroendocrine Markers ◽  
Neuroendocrine Prostate Cancer ◽  
Positive Rate

138 Background: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection. The treatment strategy against NEPC is not yet established and some clinical trials are ongoing now. Recently, clinical trial (RADIIANT4) showed that treatment with everolimus was associated with significant improvement in survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. In this study we evaluated the neuroendocrine differentiation of prostate cancer and we tried to introduce everolimus against pathologically proven NEPC and investigated the clinical outcomes of this agent. Methods: Total of 193 prostate cancer cases were included in this study. We tested serum neuroendocrine markers, including (NSE and pro-GRP). And we evaluated positive rate of these markers. Eleven cases were pathologically proven neuroendocrine prostate cancer (NEPC) in this cohort. Seven out of eleven NEPC cases were introduced everolimus 10mg daily. We investigated the change of serum neuroendocrine markers (NSE and pro-GRP), radiologic examination and survival. Results: The positive rate of serum neuroendocrine markers (at least one of the markers increasing above normal limit) were 23.5% in hormone sensitive prostate cancer (HSPC), 59.5% in castration resistant prostate cancer (CRPC), and 100% in neuroendocrine prostate cancer (NEPC). There were significant differences in each other (HSPC vs. CRPC: p=0.0001, CRPC vs. NEPC: p=0.0109). We introduced everolimus in seven cases out of eleven NEPC cases. The median follow up period was 18 months. Neuroendocrine markers decreased in five of seven (71.4%) cases after introduction of everolimus. Median decreasing rate were 67.1% in NSE and 65.5% in pro GRP. 24M progression free survival rate was 57.1% and 24M overall survival rate was 57.1%. Conclusions: There is a possibility that the incidence of NEPC is higher than expected, and treatment against prostate adenocarcinoma accelerate neuroendocrine differentiation. Everolimus showed efficacy against NEPC. Although this study was retrospective and number of cases was limited, everolimus would be a one of the treatment options against NEPC.

scholarly journals The Crosstalk of Long Non-Coding RNA and MicroRNA in Castration-Resistant and Neuroendocrine Prostate Cancer: Their Interaction and Clinical Importance

2021 ◽  
Vol 23 (1) ◽  
pp. 392
Author(s):  
Che-Yuan Hu ◽  
Kuan-Yu Wu ◽  
Tsung-Yen Lin ◽  
Chien-Chin Chen
Keyword(s):  
Prostate Cancer ◽  
Median Survival ◽  
De Novo ◽  
Neuroendocrine Differentiation ◽  
Cancer Development ◽  
Current Evidence ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Neuroendocrine Prostate Cancer ◽  
Epigenetic Regulators

Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant that arises from de novo presentation of small cell carcinoma or treatment-related transformation with a median survival of 1–2 years from the time of diagnosis. The epigenetic regulators, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been proven involved in multiple pathologic mechanisms of CRPC and NEPC. LncRNAs can act as competing endogenous RNAs to sponge miRNAs that would inhibit the expression of their targets. After that, miRNAs interact with the 3’ untranslated region (UTR) of target mRNAs to repress the step of translation. These interactions may modulate gene expression and influence cancer development and progression. Otherwise, epigenetic regulators and genetic mutation also promote neuroendocrine differentiation and cancer stem-like cell formation. This step may induce neuroendocrine prostate cancer development. This review aims to provide an integrated, synthesized overview under current evidence to elucidate the crosstalk of lncRNAs with miRNAs and their influence on castration resistance or neuroendocrine differentiation of prostate cancer. Notably, we also discuss the mechanisms of lncRNA–miRNA interaction in androgen receptor-independent prostate cancer, such as growth factors, oncogenic signaling pathways, cell cycle dysregulation, and cytokines or other transmembrane proteins. Conclusively, we underscore the potential of these communications as potential therapeutic targets in the future.

scholarly journals Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 578
Author(s):  
Marc Wiesehöfer ◽  
Elena Dilara Czyrnik ◽  
Martin Spahn ◽  
Saskia Ting ◽  
Henning Reis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Neuroendocrine Differentiation ◽  
Marker Genes ◽  
Castration Resistant Prostate Cancer ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Neuroendocrine Prostate Cancer ◽  
Long Term Treatment

Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, −20b and −106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA–miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer.

scholarly journals Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 692
Author(s):  
Roosa Kaarijärvi ◽  
Heidi Kaljunen ◽  
Kirsi Ketola
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Treatment Resistance ◽  
Research Field ◽  
Phenotypic Change ◽  
Prostate Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Treatment Resistant ◽  
Molecular Features ◽  
Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

scholarly journals MicroRNA-1205 Regulation of FRYL in Prostate Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Michelle Naidoo ◽  
Fayola Levine ◽  
Tamara Gillot ◽  
Akintunde T. Orunmuyi ◽  
E. Oluwabunmi Olapade-Olaopa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Neuroendocrine Differentiation ◽  
Castration Resistant Prostate Cancer ◽  
Chromosomal Locus ◽  
Protein Coding ◽  
Castration Resistant ◽  
Dendritic Branching ◽  
Very High

High mortality rates of prostate cancer (PCa) are associated with metastatic castration-resistant prostate cancer (CRPC) due to the maintenance of androgen receptor (AR) signaling despite androgen deprivation therapies (ADTs). The 8q24 chromosomal locus is a region of very high PCa susceptibility that carries genetic variants associated with high risk of PCa incidence. This region also carries frequent amplifications of the PVT1 gene, a non-protein coding gene that encodes a cluster of microRNAs including, microRNA-1205 (miR-1205), which are largely understudied. Herein, we demonstrate that miR-1205 is underexpressed in PCa cells and tissues and suppresses CRPC tumors in vivo. To characterize the molecular pathway, we identified and validated fry-like (FRYL) as a direct molecular target of miR-1205 and observed its overexpression in PCa cells and tissues. FRYL is predicted to regulate dendritic branching, which led to the investigation of FRYL in neuroendocrine PCa (NEPC). Resistance toward ADT leads to the progression of treatment related NEPC often characterized by PCa neuroendocrine differentiation (NED), however, this mechanism is poorly understood. Underexpression of miR-1205 is observed when NED is induced in vitro and inhibition of miR-1205 leads to increased expression of NED markers. However, while FRYL is overexpressed during NED, FRYL knockdown did not reduce NED, therefore revealing that miR-1205 induces NED independently of FRYL.

Sign in / Sign up

Export Citation Format

Share Document