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Neuroendocrine Differentiation in Prostate Cancer: Emerging Biology, Models, and Therapies

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Neuroendocrine Differentiation in Prostate Cancer: Emerging Biology, Models, and Therapies Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Neuroendocrine Differentiation in Prostate Cancer: Emerging Biology, Models, and Therapies Loredana Puca,1,2 Panagiotis J. Vlachostergios,2 and Himisha Beltran1,2 1Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, New York 10021 2Division of Medical Oncology, Weill Cornell Medicine, New York, New York 10021 Correspondence: [email protected] Although a de novo clinical presentation of small cell neuroendocrine carcinoma of the prostate is rare, a subset of patients previously diagnosed with prostate adenocarcinoma may develop neuroendocrine features in later stages of castration-resistant prostate cancer (CRPC) progression as a result of treatment resistance. Despite sharing clinical, histologic, and some molecular features with other neuroendocrine carcinomas, including small cell lung cancer, castration-resistant neuroendocrine prostate cancer (CRPC-NE) is clonally derived from prostate adenocarcinoma. CRPC-NE therefore retains early prostate cancer genomic alterations and acquires new molecular changes making them resistant to traditional CRPC therapies. This review focuses on recent advances in our understanding of CRPC-NE biology, the transdifferentiation/plasticity process, and development and characterization of relevant CRPC-NE preclinical models. ellular plasticity plays a pivotal role in carcinoma cells in this setting typically show Cdriving treatment resistance in cancer. In low or absent androgen receptor (AR) expres- prostate cancer, a subset of patients initially sion, express classical neuroendocrine markers, diagnosed with prostate adenocarcinoma may and may harbor genomic features common in acquire histologic features of small cell neuroen- other small cell carcinomas such as TP53 and www.perspectivesinmedicine.org docrine carcinoma on metastatic biopsy during RB1 loss (Beltran et al. 2016a). Clinically, cas- later stages of disease progression after develop- tration-resistant neuroendocrine prostate can- ing resistance to traditional systemic therapies cer (CRPC-NE) is associated with aggressive (Bluemn et al. 2017). These may encompass a disease, relative resistance to AR-directed ther- spectrum ranging from adenocarcinoma with apeutics, and sensitivity to platinum-based che- neuroendocrine differentiation, mixed histolo- motherapy. Recent advances in the molecular gies, and in extreme cases complete transforma- characterization of CRPC-NE combined with tion to small cell carcinoma, which is morpho- preclinical observations have provided biologic logically indistinguishable from other small cell insights into the evolutionary process and have cancers (Epstein et al. 2014). Neuroendocrine informed the development of new therapeutics Editors: Michael M. Shen and Mark A. Rubin Additional Perspectives on Prostate Cancer available at www.perspectivesinmedicine.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a030593 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press L. Puca et al. targets for this aggressive subset of advanced INDUCERS OF THE NEUROENDOCRINE prostate cancer. PHENOTYPE IN PROSTATE CANCER A number of signaling molecules have been NEUROENDOCRINE CELLS IN BENIGN shown to trigger the development of neuroen- PROSTATE AND PROSTATE CANCER docrine features in prostate adenocarcinoma Neuroendocrine cells (NEs) in the normal pros- cells in vitro. Androgen-deprivation therapy tate gland were first described by Pretl in 1944 as (ADT) affects the expression of epithelial mark- the argentaffin basal cells (Kazzaz 1974). They ers with a decrease in E-cadherin and gain of exist among the prostate-specific antigen (PSA) mesenchymal markers, such as N-cadherin, vi- producing luminal cells and the prostate basal mentin, Zeb1, Twist1, and Snail2 (Sun et al. cells, representing only a minor fraction of the 2012), toward an epithelial-mesenchymal tran- epithelial compartment (<1%) (Parimi et al. sition (EMT)-like state. LNCaP cells transfected 2014). The exact function of these normal pros- with Snail undergo neuroendocrine differentia- tatic NEs is not well understood, but they may tion with neurite-like morphologic characteris- play a role in supporting the growth of sur- tics and increased levels of classical NE markers rounding basal and luminal cells through the such as neuron specific enolase (NSE) and secretion of neuropeptides (e.g., calcitonin, chromogranin A; subsequent knockdown of serotonin, adrenomedullin, bombesin, and oth- Snail in these cells can revert this phenotype ers). In the normal prostate gland, NEs lack the (McKeithen et al. 2010). Similar to ADT, loss proliferation marker Ki67, appear to be postmi- or silencing of the AR itself with small interfer- totic, and express antiapoptotic protein Bcl-2 ing RNA (siRNA) may also trigger NE proper- (Bonkhoff et al. 1991, 1995; Nakada et al. 1993). ties to LNCaP cells (Wright et al. 2003). De novo small cell neuroendocrine carcino- Hypoxia is a characteristic feature of ad- ma of the prostate is rare, and these cases are vanced solid tumors and strongly associates hypothesized to arise from these normal NEs with malignant tumor progression and resis- or a multipotent stem cell located within the tance to chemotherapy. Studies have suggested prostate gland based on the high expression of that hypoxia facilitates the malignancy of pros- CD44 (Simon et al. 2009) and other genes related tate adenocarcinoma cells by increasing andro- to stemness such as OCT-3/4 and Bmi (Patra- gen-independence (Yamasaki et al. 2013). Other wala et al. 2006). Several studies have suggested reports show that hypoxia can induce neuroen- that NEs can help sustain surrounding prostate docrine programs through down-regulation adenocarcinoma cellular growth through a para- of Notch signaling (Danza et al. 2012). Hypoxia www.perspectivesinmedicine.org crine mechanism via their secretory products down-regulates both PTEN and REST in pros- (i.e., bombesin, serotonin [5-HT], neuron-spe- tate cancer epithelia inducing expression of neu- cific enolase [NSE], a thyroid-stimulating-like ronal genes and microRNAs (miRNAs) associ- peptide [thyroid-stimulating hormone, TSH], ated with neuroendocrine reprogramming somatostatin [SST], parathyroid hormone-relat- (Liang et al. 2014). ed protein [PTHrP]). For instance, bombesin The Wnt pathway may also play a role in has been shown to increase prostate cancer pro- neuroendocrine transformation of prostate can- liferation (Jongsma et al. 2000) and prevent ap- cer cells through activation of the Wnt pathway optosis of prostate cancer cells in vitro (Salido effector ß-catenin. ß-catenin induces neuroen- et al. 2000). Receptors for various NE products docrine features in LNCaP cells (Ciarlo et al. such as serotonin (5HT1a) (Abdul et al. 1994), 2012). LNCaP cells transfected with Wnt-11 re- bombesin/gastrin-releasing peptide (GRP), gas- semble LNCaP cells grown in an androgen-de- trin-releasing peptide receptor (GRPR) (Mark- pleted environment. Cells with Wnt-11 overex- walder and Reubi 1999), and somatostatin pression display high levels of the NE markers (SSTR1-5) (Dizeyi et al. 2002) are present in NSE and ASCL1. LNCaP cells in androgen-free both benign prostate and prostate tumors. medium and LNCaP cells transfected with Pro- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a030593 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Castration-Resistant Neuroendocrine Prostate Cancer tocadherin-PC (PCDH-PC) show higher levels cursors derived from neuronal progenitor cells. of luciferase ß-catenin and expression of Wnt Overexpression and amplification of N-MYC target genes (Uysal-Onganer et al. 2010). have been implicated in driving a subset of neu- Other inducers of the neuroendocrine roblastoma, small cell lung cancer, central ner- phenotype in vitro include MnSOD (Quiros- vous system (CNS) tumors (Brodeur et al. 1984; Gonzalez et al. 2011; Courel et al. 2014), Knoepfler et al. 2002), and more recently neuro- hASH-1 (Rapa et al. 2013), HB-EGF (Adam endocrine prostate cancer. In prostate cancer, N- et al. 2002), RPTPα (Zhang et al. 2003), and MYC suppresses AR signaling and regulates the cAMP (Cox et al. 1999). Overall these studies CRPC-NE program through transcriptional reg- provided early insights into the appearance of ulation and cooperation with Aurora kinase A neuroendocrine characteristics from adenocar- (AURKA), EZH2, and other cofactors (Beltran cinoma cells. et al. 2011; Dardenne et al. 2016, Lee et al. 2016). The repressor element-1 silencing transcrip- tion factor (REST), also known as neuron REACTIVATION OF STEM CELL, restrictive silencing factor (NRSF), silences the DIFFERENTIATION AND NEURONAL expression of neuron-specific protein coding PATHWAYS IN CRPC-NE genes and miRNAs in nonneuronal cells (Ballas During progression toward the neuroendocrine et al. 2005). REST down-regulation is observed state, multiple molecular programs are activated in up to 50% of CRPC-NE tumors (Lapuk et al. conferring neuronal and stem-like characteris- 2012). LNCAP cells transfected with si-REST tics as shown by the CD49f High
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