Activation of TGF-β - SMAD2 signaling by IL-6 drives neuroendocrine differentiation of prostate cancer through p38MAPK

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.

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Personalizing Therapy for Metastatic Prostate Cancer: The Role of Solid and Liquid Tumor Biopsies

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175510 ◽

2017 ◽

pp. 358-369 ◽

Cited By ~ 1

Author(s):

Terence W. Friedlander ◽

Colin C. Pritchard ◽

Himisha Beltran

Keyword(s):

Prostate Cancer ◽

Metastatic Prostate Cancer ◽

Tumor Tissue ◽

Neuroendocrine Differentiation ◽

Metastatic Tumor ◽

Metastatic Lesion ◽

Phenotypic Changes ◽

Tumor Biopsies ◽

Bioinformatic Approach

Although biopsies of metastatic prostate cancer are rarely undertaken in the clinical setting, there is increasing interest in developing personalized approaches to therapy by taking into account the genetic and phenotypic changes in an individual tumor. Indeed, analysis of metastatic prostate tumors can predict sensitivity to agents that inhibit DNA repair and resistance to novel hormonal agents, such as abiraterone and enzalutamide, and identify phenotypic changes, such as neuroendocrine differentiation, that have important clinical implications. Although obtaining metastatic tumor tissue is necessary for this genomic and molecular profiling, knowing when to biopsy, selecting the appropriate metastatic lesion, and interpreting the results are major challenges facing clinicians today. In this article, we discuss the rationale for obtaining metastatic tumor tissue, review the bioinformatic approach to analyzing these specimens, discuss the timing and approach to solid and liquid tumor biopsies, review the challenges associated with obtaining and acting on clinically relevant results, and discuss opportunities for the future.

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N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

Endocrine Related Cancer ◽

10.1677/erc-10-0015 ◽

2010 ◽

Vol 17 (2) ◽

pp. 469-479 ◽

Cited By ~ 79

Author(s):

Karin Jennbacken ◽

Tajana Tešan ◽

Wanzhong Wang ◽

Heléne Gustavsson ◽

Jan-Erik Damber ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Mesenchymal Transition ◽

Neuroendocrine Differentiation ◽

Hormonal Treatment ◽

Androgen Deprivation ◽

Prostate Tumors ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Molecular Alterations

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelial–mesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

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The Many Faces of Neuroendocrine Differentiation in Prostate Cancer Progression

Frontiers in Oncology ◽

10.3389/fonc.2014.00060 ◽

2014 ◽

Vol 4 ◽

Cited By ~ 117

Author(s):

StÃ©phane Terry ◽

Himisha Beltran

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Neuroendocrine Differentiation ◽

Prostate Cancer Progression ◽

The Many

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Neuroendocrine differentiation in prostate cancer

Vojnosanitetski pregled ◽

10.2298/vsp0405513c ◽

2004 ◽

Vol 61 (5) ◽

pp. 513-518 ◽

Cited By ~ 4

Author(s):

Snezana Cerovic ◽

Goran Brajuskovic ◽

Vinka Maletic-Vukotic ◽

Sava Micic

Keyword(s):

Prostate Cancer ◽

Clinical Stage ◽

Prognostic Significance ◽

Specific Antigen ◽

Neuron Specific Enolase ◽

Neuroendocrine Differentiation ◽

Current Evidence ◽

Gleason Grade ◽

Preoperative Serum ◽

Significant Expression

Background. In numerous recent studies attention has been focused to neuroendocrine differentiation (NED) in prostate cancer (PC). Focal NED is present in almost all PCs, but it is prominent in only 5-10% of the carcinomas. The prognostic significance of focal NED in PC is controversial, but current evidence suggests its influence on the onset and/or conversion of hormon resistant tumor phenotype. The aim of this study was to evaluate the relationship between NED status, based only on immunohistochemical use of neuroendocrine (NE) markers, with PC grade and stage, and preoperative serum levels of prostate-specific antigen (PSA). Methods. The study included the biopsy material of 73 untreated PC patients (pts.) obtained by transurethral resection (TUR) (37 pts.), and radical retropubic prostatectomy (RRP) (36 pts.). Two representative tissue samples (tipically the block containing the largest amount of neoplasm) were selected for immunohistochemical (IMM) staining. NE cells were identified using a panel of IMM markers: chromogranin A, neuron-specific enolase, and serotonin. The level of PC exocrine differentiation was detected by monoclonal antibodies against PSA. Results. Significant expression of NE cells was demonstrated in 26 (70.2%) pts. with PC after TUR. In this group, serum preoperative PSA values ranged from 0.1 to 9.6 ng/ml. The majority of pts. with NED had low differentiated PC with Gleason grade score (GGS) >7, and normal PSA values below 4 ng/ml (77%), in clinical stage D (54%). Statistically significant correlation (p<0.01) of positive NED with higher stage and grade and low PSA values was established. Among the pts. with localized PC in whom RRP was performed (n=36), significant expression of NE cells was found in 15 pts. (41.7%), 8 (53.3%) in pT2 stage, and 7 (46.7%) in pT3 stage. Significant correlation between NED with preoperative PSA values and stage of PC in pts. with RRP was not found. Conclusion. We demonstrated the significant NED in poorly differentiated PC in patients in the advanced stage of the disease. The expression of NED in organ-confined PC did not correlate with tumor stage, but it correlated with tumor grade (GGS?7).

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MicroRNA-1205 Regulation of FRYL in Prostate Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.647485 ◽

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.

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