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      The Many Faces of Neuroendocrine Differentiation in Prostate Cancer Progression


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          In normal prostate, neuroendocrine (NE) cells are rare and interspersed among the epithelium. These cells are believed to provide trophic signals to epithelial cell populations through the secretion of an abundance of neuropeptides that can diffuse to influence surrounding cells. In the setting of prostate cancer (PC), NE cells can also stimulate surrounding prostate adenocarcinoma cell growth, but in some cases adenocarcinoma cells themselves acquire NE characteristics. This epithelial plasticity is associated with decreased androgen receptor (AR) signaling and the accumulation of neuronal and stem cell characteristics. Transformation to an NE phenotype is one proposed mechanism of resistance to contemporary AR-targeted treatments, is associated with poor prognosis, and thought to represent up to 25% of lethal PCs. Importantly, the advent of high-throughput technologies has started to provide clues for understanding the complex molecular profiles of tumors exhibiting NE differentiation. Here, we discuss these recent advances, the multifaceted manner by which an NE-like state may arise during the different stages of disease progression, and the potential benefit of this knowledge for the management of patients with advanced PC.

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          Most cited references95

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          Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration.

          The human Y chromosome is intriguing not only because it harbours the master-switch gene that determines gender but also because of its unusual evolutionary history. The Y chromosome evolved from an autosome, and its evolution has been characterized by massive gene decay. Recent whole-genome and transcriptome analyses of Y chromosomes in humans and other primates, in Drosophila species and in plants have shed light on the current gene content of the Y chromosome, its origins and its long-term fate. Furthermore, comparative analysis of young and old Y chromosomes has given further insights into the evolutionary and molecular forces triggering Y-chromosome degeneration and into the evolutionary destiny of the Y chromosome.
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            Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.

            Embryonic signalling pathways regulate progenitor cell fates in mammalian epithelial development and cancer. Prompted by the requirement for sonic hedgehog (Shh) signalling in lung development, we investigated a role for this pathway in regeneration and carcinogenesis of airway epithelium. Here we demonstrate extensive activation of the hedgehog (Hh) pathway within the airway epithelium during repair of acute airway injury. This mode of Hh signalling is characterized by the elaboration and reception of the Shh signal within the epithelial compartment, and immediately precedes neuroendocrine differentiation. We reveal a similar pattern of Hh signalling in airway development during normal differentiation of pulmonary neuroendocrine precursor cells, and in a subset of small-cell lung cancer (SCLC), a highly aggressive and frequently lethal human tumour with primitive neuroendocrine features. These tumours maintain their malignant phenotype in vitro and in vivo through ligand-dependent Hh pathway activation. We propose that some types of SCLC might recapitulate a critical, Hh-regulated event in airway epithelial differentiation. This requirement for Hh pathway activation identifies a common lethal malignancy that may respond to pharmacological blockade of the Hh signalling pathway.
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              Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.

              In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. In a shRNA screen of genes that are highly expressed in MYCN-amplified tumors, we have identified AURKA as a gene that is required for the growth of MYCN-amplified neuroblastoma cells but largely dispensable for cells lacking amplified MYCN. Aurora A has a critical function in regulating turnover of the N-Myc protein. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and Gsk3. N-Myc is therefore degraded during mitosis in response to low levels of PI3-kinase activity. Aurora A interacts with both N-Myc and the SCF(Fbxw7) ubiquitin ligase that ubiquitinates N-Myc and counteracts degradation of N-Myc, thereby uncoupling N-Myc stability from growth factor-dependent signals.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                03 March 2014
                25 March 2014
                : 4
                [1] 1U955, Institut Mondor de Recherche Biomédicale, INSERM , Créteil, France
                [2] 2UMR 3244, Institut Curie , Paris, France
                [3] 3Division of Hematology and Medical Oncology, Weill Cornell Medical College , New York, NY, USA
                Author notes

                Edited by: Mercedes Salido, University of Cadiz, Spain

                Reviewed by: Fabio Calabrò, San Camillo and Forlanini Hospitals, Italy; Alan Dal Pra, Bern University Hospital, Switzerland

                *Correspondence: Stéphane Terry, Faculté de Médecine, INSERM U955 EQ7, 8 rue de Général Sarrail, Créteil 94000, France e-mail: stephane.terry@ 123456gmail.com ; Himisha Beltran, Division of Hematology and Oncology, Weill Cornell Medical College, 525 East 68th Street, Box 403, New York, NY 10021, USA e-mail: hip9004@ 123456med.cornell.edu

                This article was submitted to Genitourinary Oncology, a section of the journal Frontiers in Oncology.

                Copyright © 2014 Terry and Beltran.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 111, Pages: 9, Words: 8536
                Review Article

                Oncology & Radiotherapy
                prostate cancer,neuroendocrine differentiation,small-cell carcinoma,cancer biology,nrsf/rest,androgen receptor,aurora kinase a,protocadherin


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