Neuroendocrine differentiation in prostate cancer: Novel morphological insights and future therapeutic perspectives

Santoni, Matteo; Conti, Alessandro; Burattini, Luciano; Berardi, Rossana; Scarpelli, Marina; Liu, Cheng; López-Beltrán, Antonio; Cascinu, Stefano; Montironi, Rodolfo

doi:10.1016/j.bbcan.2014.10.008

Cited by 44 publications

(55 citation statements)

References 79 publications

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“…The mechanisms underlying androgen-independent proliferation of CRPC cells include amplification of the androgen receptor ( AR ) gene, mutations in the AR gene, deregulation of AR co-regulators, ligand-independent activation of AR with or without elevated androgen synthesis, and AR-independent signaling [2, 6]. Evidence is accumulating that neuroendocrine-like (NE-like) cells, which express neuronal genes such as chromogranin A ( CHGA ), enolase 2 ( ENO2 ) and synaptophysin ( SYP ), are present during PCa progression [7]. These cells can arise via neuroendocrine differentiation (NED), a process that can be induced by ADT and by the administration of therapeutic agents that target dividing cells, e.g.…”

Section: Introductionmentioning

confidence: 99%

c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

et al. 2016

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Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A. We also found that the c-MYC/miR-22/PHF8 axis is downstream of androgen receptor (AR) signaling in CRPC cells. The co-expression of PHF8 with AR in clinical CRPC samples, normal mouse prostate, and adenocarcinomas of the prostate during PCa progression in a transgenic (TRAMP) mouse model supports the connection between PHF8 and AR. Knockdown of PHF8 impedes cell cycle progression in CRPC cells and has more profound effects on their growth than on the parental LNCaP cell line. Furthermore, PHF8 knockdown sensitizes LNCaP-Abl cells to the AR antagonist enzalutamide. Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC.

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Section: Introductionmentioning

confidence: 99%

c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

et al. 2016

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“…One model suggests that NEPC could originate from luminal cells expressing NE genes, potentially due to input from surrounding NECs. NE transdifferentiation is primarily a mechanism of adaptive response/tumor resistance [10,25]. In vitro data demonstrate that LNCaP cells can be induced to trans-differentiate into NEPC cells by various stimuli such as androgen depletion, or supplementation with cAMP, cytokines, or growth factors [21].…”

Section: Neuroendocrine Prostate Cancer: Clinical and Molecular Featuresmentioning

confidence: 99%

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

et al. 2016

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Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm.NEPC is thought to originate from the trans-differentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/non-coding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drugresistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, microRNAs) play a key role in NEPC initiation and progression. Long non-coding RNAs (lncRNAs) represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively up-regulated in NEPCs and might interact with Polycomb genes. Our results indicate that lncRNAs can be exploited as new biomarkers and therapeutic targets for NEPC.Keywords: Neuroendocrine prostate cancer; MIAT; Long non-coding RNAs; Polycomb; Epigenetic/non-coding interactome; Trans-differentiation. Neuroendocrine Prostate Cancer: Clinical and Molecular FeaturesIn adult males, the prostate is a small acorn-shaped tissue with ductal-acinar histology surrounding the urethra at the base of the bladder. Its main function is to contribute secretory proteins to the seminal fluid [1]. The adult prostate is a pseudo-stratified epithelium composed of three main cell lineages (Fig.1, left panel): 1) secretory luminal cells are the predominant cell type; these cells express keratins (K8, K18), the androgen receptor (AR) and secretory proteins such as prostate-specific antigen (PSA) and prostatic specific acid phosphatase (PSAP);2) basal cells expressing K5 and K14 keratins and p63 are the second major cell type;3) neuroendocrine cells (NEC) expressing chromogranin A (CHGA), synaptophysin (SYP), and neuropeptides are scattered throughout the basal layer and comprise less than 1% of normal prostatic glandular epithelium [1][2][3].Prostate cancer (PCa) represents the second most frequently diagnosed neoplasm and is the sixth leading cause of cancer-related deaths in males worldwide [4,5]. In keeping with the composition of prostate epithelium, more than 95% of PCas are classified as adenocarcinomas, which show luminal phenotype and AR expression [6] (Fig.1, middle panel).Endogenous androgens, mainly produced by the testis, bind to the AR and fuel prostate adenocarcinoma proliferation [7]. For this reason, androgen-deprivation therapy (a.k.a. castration) is an effective therapeutic strategy for this disease. However, patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC) mainly via genetic and epigenetic alterations that facilitate ligand-independent AR activation, amplify the ARdependent signaling, or trigger different proliferative pathways [7]. CRPCs are characterized by substantially worse prognoses, but chemotherapeutics and newly approved hormonal treatments (e.g., Enzalutamide [8] and Abiraterone [9]) are still effective in p...

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“…Tomato feeding altered expression of more genes (steroid-5-alpha-reductase, alpha polypeptide 2; Srd5 α 2 , paxillin; Pxn , and sterol regulatory element binding transcription factor; Srebf) involved in androgen metabolism compared to lycopene ( Srd5 α 2 ), while lycopene demonstrated a specific inhibition of genes related to neuroendocrine differentiation ( Ngfr and Syp ) [17]. These findings suggest that lycopene maybe useful in aggressive disease especially with the emerging literature demonstrating an association of aggressive cancer with neuroendocrine phenotype [18]. On the other hand tomato powder may be useful in the setting of early stage localized disease.…”

Section: Whole Vs Isolated Compound Entitiesmentioning

confidence: 99%

Food-based natural products for cancer management: Is the whole greater than the sum of the parts?

Hussain

Kumar

Ghosh

2016

Seminars in Cancer Biology

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The rise in cancer incidence and mortality in developing countries together with the human and financial cost of current cancer therapy mandates a closer look at alternative ways to overcome this burgeoning global healthcare problem. Epidemiological evidence for the association between cancer and diet and the long latency of most cancer progression have led to active exploration of whole and isolated natural chemicals from different naturally occurring substances in various preclinical and clinical settings. In general the lack of systemic toxicities of most ‘whole’ and ‘isolated’ natural compounds, their potential to reduce toxic doses and potential to delay the development of drug-resistance makes them promising candidates for cancer management. This review article examines the suggested molecular mechanisms affected by these substances focusing to a large extent on prostate cancer and deliberates on the disparate results obtained from cell culture, preclinical and clinical studies in an effort to highlight the use of whole extracts and isolated constituents for intervention. As such these studies underscore the importance of factors such as treatment duration, bioavailability, route of administration, selection criteria, standardized formulation and clinical end points in clinical trial design with both entities. Overall lack of parallel comparison studies between the whole natural products and their isolated compounds limits decisive conclusions regarding the superior utility of one over the other. We suggest the critical need for rigorous comparative research to identify which one of the two or both entities from nature would be best qualified to take on the mantle of cancer management.

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Neuroendocrine differentiation in prostate cancer: Novel morphological insights and future therapeutic perspectives

Cited by 44 publications

References 79 publications

c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

c-MYC drives histone demethylase PHF8 during neuroendocrine differentiation and in castration-resistant prostate cancer

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

Food-based natural products for cancer management: Is the whole greater than the sum of the parts?

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