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Valerie Oderomarah - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3415 diverse roles for snail transcription factor in epithelial mesenchymal transition emt and Neuroendocrine Differentiation ned in human prostate cancer
    Cancer Research, 2011
    Co-Authors: Danielle Mckeithen, Leland W. K. Chung, Tisheeka Graham, Colm Morrissey, Xiaotun Zhang, Valerie Oderomarah
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Snail transcription factor induces epithelial-mesenchymal transition (EMT) via decreased cell adhesion-associated molecules like E-cadherin, and increased mesenchymal markers like vimentin. We previously established Snail-mediated EMT model utilizing androgen-dependent LNCaP cells. These cells express increased vimentin protein and relocalization of E-cadherin from the cell membrane to the cytosol. Interestingly, Snail transfection in LNCaP cells resulted in cells acquiring a Neuroendocrine-like morphology with long neurite-like processes. We tested for expression of Neuroendocrine markers neuron specific enolase (NSE) and chromogranin A (CgA) by Western blot analysis, and performed proliferation assays to test for paracrine cell proliferation. LNCaP cells transfected with Snail displayed increase in the Neuroendocrine markers, NSE and CgA as well as translocation of androgen receptor to the nucleus. We found that LNCaP C-33 cells that have been previously published as a Neuroendocrine Differentiation (NED) model exhibited increased expression levels of Snail protein as compared to LNCaP parental cells. Functionally, conditioned medium from the LNCaP-Snail transfected cells increased proliferation of parental LNCaP and PC-3 cells. In addition, NED in LNCaP-C33 cells or that induced in parental LNCaP cells by serum starvation could be inhibited by knockdown of Snail with siRNA. Knockdown of NSE and CgA with siRNA abrogated Snail induced paracrine cell proliferation in parental LNCaP and PC3 cells. Immunohistochemical staining of prostate cancer patient tissue revealed increased expression of Snail with prostate cancer progression and bone metastasis. Higher Snail staining was observed in primary prostate cancer tissue containing a Neuroendocrine component (identified by CgA staining) as compared to primary cancer with no Neuroendocrine Differentiation. However, in metastatic tissue, Snail was highly expressed in both Neuroendocrine and non-Neuroendocrine cancer tissue. Overall our data provide evidence that Snail transcription factor may promote tumor aggressiveness in the prostate cancer cells through multiple processes; induction of EMT may be required to promote migration, while NED may promote tumor proliferation by a paracrine mechanism. Therefore, therapeutic targeting of Snail may prove beneficial in not only abrogating EMT but also NED. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2011-3415

  • snail transcription factor regulates Neuroendocrine Differentiation in lncap prostate cancer cells
    The Prostate, 2010
    Co-Authors: Danielle Mckeithen, Tisheeka R Graham, Leland W. K. Chung, Valerie Oderomarah
    Abstract:

    BACKGROUND Snail transcription factor induces epithelial–mesenchymal transition (EMT) via decreased cell adhesion-associated molecules like E-cadherin, and increased mesenchymal markers like vimentin. We previously established Snail-mediated EMT model utilizing androgen-dependent LNCaP cells. These cells express increased vimentin protein and relocalization of E-cadherin from the cell membrane to the cytosol. Interestingly, Snail transfection in LNCaP cells resulted in cells acquiring a Neuroendocrine (NE)-like morphology with long neurite-like processes. METHODS We tested for expression of NE markers neuron-specific enolase (NSE) and chromogranin A (CgA) by Western blot analysis, and performed proliferation assays to test for paracrine cell proliferation. RESULTS LNCaP cells transfected with Snail displayed increase in the NE markers, NSE and CgA as well as translocation of androgen receptor (AR) to the nucleus. LNCaP C-33 cells that have been previously published as a Neuroendocrine Differentiation (NED) model exhibited increased expression levels of Snail protein as compared to LNCaP parental cells. Functionally, conditioned medium from the LNCaP-Snail transfected cells increased proliferation of parental LNCaP and PC-3 cells, which could be abrogated by NSE/CgA siRNA. Additionally, NED in LNCaP-C33 cells or that induced in parental LNCaP cells by serum starvation could be inhibited by knockdown of Snail with siRNA. CONCLUSION Overall our data provide evidence that Snail transcription factor may promote tumor aggressiveness in the LNCaP cells through multiple processes; induction of EMT may be required to promote migration, while NED may promote tumor proliferation by a paracrine mechanism. Therefore, therapeutic targeting of Snail may prove beneficial in not only abrogating EMT but also NED. Prostate 70: 982–992, 2010. © 2010 Wiley-Liss, Inc.

Keliang Wang - One of the best experts on this subject based on the ideXlab platform.

  • lncrna p21 alters the antiandrogen enzalutamide induced prostate cancer Neuroendocrine Differentiation via modulating the ezh2 stat3 signaling
    Nature Communications, 2019
    Co-Authors: Jie Luo, Shuyuan Yeh, Yuanjie Niu, Keliang Wang, Yin Sun, Liang Liang, Yao Xiao, Liang Cheng, Sankar N Maity
    Abstract:

    While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients’ survival an extra 4.8 months, it might also result in some adverse effects via inducing the Neuroendocrine Differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression. The induction of Neuroendocrine Differentiation occurs in enzalutamide treated castration resistant prostate cancer. Here, the authors show that lncRNA-21 mediates enzalutamide induced Neuroendocrine Differentiation through EZH2/STAT axis and EZH2 inhibition suppresses this Differentiation.

  • adt with antiandrogens in prostate cancer induces adverse effect of increasing resistance Neuroendocrine Differentiation and tumor metastasis
    Cancer Letters, 2018
    Co-Authors: Yuanjie Niu, Chawnshang Chang, Shuyuan Yeh, Changcheng Guo, Simeng Wen, Jing Tian, Jie Luo, Keliang Wang, Hao Tian
    Abstract:

    Prostate cancer (PCa) is the most common cancer and the 2nd leading cause of cancer-related deaths among men in the United States. Androgen-deprivation-therapy (ADT) with antiandrogens to target the androgens/androgen receptor (AR) signals remains the standard therapy for advanced PCa. However, most of the PCa patients who received ADT with antiandrogens, including the recently developed Enzalutamide (Enz) that might extend PCa patients survival an extra 4.8 months, will still develop the castration (or antiandrogen) resistance. Mechanism dissection studies suggest these antiandrogen resistances may involve the induction of AR splicing variants and/or AR mutants. Further preclinical in vitro/in vivo studies suggest ADT-antiandrogens may also enhance the Neuroendocrine Differentiation (NED) and PCa cell invasion, and these unwanted side-effects may function through various mechanisms including altering the infiltrating inflammatory cells within the prostate tumor microenvironment. This review summarizes these unwanted ADT-induced side-effects and discusses multiple approaches to overcome these side-effects to better suppress the PCa at the castration resistant stage.

Liliana Al De Angelo Andrade - One of the best experts on this subject based on the ideXlab platform.

  • malignant mixed mullerian tumor of the uterine cervix with Neuroendocrine Differentiation
    International Journal of Gynecological Cancer, 2002
    Co-Authors: A Ribeirosilva, A Novellovilar, A M Cunhamercante, Liliana Al De Angelo Andrade
    Abstract:

    . Ribeiro-Silva A, Novello-Vilar A, Cunha-Mercante AM, De Angelo Andrade LAL. Malignant mixed Mullerian tumor of the uterine cervix with Neuroendocrine Differentiation. Malignant mixed Mullerian tumors (MMMTs) are rare neoplasms. We report the clinical, pathologic, and immunohistochemical features of an MMMT primary of uterine cervix. This lesion was composed of a poorly differentiated epithelial component (cytokeratin positive) and a spindle cell component (vimentin positive) with heterologous (myoblastic) Differentiation (focal 1A4 positive). There were also cells with Neuroendocrine features that expressed S-100 and chromogranin A. Along with a brief review of this amazing neoplasm, some histogenetic concepts relevant to this case are discussed. To our knowledge this is the first report of a malignant mixed Mullerian tumor of the uterine cervix with Neuroendocrine Differentiation.

Zhonghua Chu - One of the best experts on this subject based on the ideXlab platform.

Ka Mun Nip - One of the best experts on this subject based on the ideXlab platform.

  • abstract 3189 neuronal transcription factor brn2 is an androgen suppressed driver of Neuroendocrine Differentiation in prostate cancer
    Cancer Research, 2017
    Co-Authors: Jennifer L Bishop, Daksh Thaper, Sepideh Vahid, Alastair H Davies, Kirsi Ketola, Ka Mun Nip, Ravi Shashi Nayana Munuganti, Paul Ahn, Dong Lin, Yuzhuo Wang
    Abstract:

    Neuroendocrine prostate cancer (NEPC) is an incurable, rapidly progressing and lethal disease. NEPC is increasingly recognized as a highly therapy resistant tumor variant that evolves from castration-resistant prostate cancer (CRPC) in a subset of patients treated with potent androgen receptor (AR) pathway inhibitors like enzalutamide (ENZ). Importantly, mechanisms by which the AR directly controls the emergence of NEPC from CRPC under the selective pressure of ENZ remain elusive. As the AR is the cornerstone therapeutic target in men with CRPC, understanding its contribution to the development of NEPC is critical to better implement current standard-of-care therapies such as ENZ, and to identify novel therapeutic targets for this incurable disease. Hallmarks of NEPC are resistance to ENZ and the loss or reduced activity of the AR. Thus, we hypothesized that a consequence of ENZ treatment and resistance in CRPC is relief of AR-mediated suppression of factors that drive NEPC. To investigate this, we developed a model of prostate cancer that mimics clinical progression to CRPC and ENZ resistance (ENZR CPRC). Mirroring what is observed in some patients who progress on ENZ, 25% of our ENZR CRPC tumors and derived cell lines showed strong reduction in classic activity of the AR and a NEPC phenotype. By interrogating NEPC-like ENZR CRPC and ENZ-treated CRPC tumors and cell lines with RNA-Seq and mechanistic in vitro and in vivo studies, as well as human tumors with RNA-Seq and IHC, we identified the master neural transcription factor BRN2 as a central and clinically relevant driver of NEPC Differentiation. Specifically, we found AR binding in the BRN2 enhancer directly represses BRN2 transcription and this release drives NEPC marker expression and aggressive growth of ENZR CRPC. Our data also reveal a striking overlap of AR and SOX binding motifs in the enhancer region of BRN2 creating a competitive binding scenario between AR and SOX2, another cell-fate determining transcription factor associated with NEPC. We discovered that upregulation of BRN2 further enhances SOX2 expression and that a BRN2-SOX2 interaction contributes to NEPC Differentiation. Importantly, we found BRN2 is highly expressed in human NEPC and metastatic CRPC, especially in patients with low AR activity, highlighting its clinical relevance to disease that is difficult to treat with mainstay therapies. These data underscore the consequences of potent AR inhibition in CRPC, revealing a novel mechanism of AR-dependent control of NEPC via direct suppression of BRN2. This work uncovers BRN2 as a clinically relevant potential therapeutic target to prevent emergence of NEPC from ENZR CRPC. Citation Format: Jennifer L. Bishop, Daksh Thaper, Sepideh Vahid, Ravi S. Munuganti, Paul Ahn, Alastair Davies, Kirsi Ketola, Ka Mun Nip, Dong Lin, Yuzhuo Wang, Himisha Beltran, Amina Zoubeidi. Neuronal transcription factor BRN2 is an androgen suppressed driver of Neuroendocrine Differentiation in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3189. doi:10.1158/1538-7445.AM2017-3189

  • the master neural transcription factor brn2 is an androgen receptor suppressed driver of Neuroendocrine Differentiation in prostate cancer
    Cancer Discovery, 2017
    Co-Authors: Jennifer L Bishop, Daksh Thaper, Sepideh Vahid, Alastair H Davies, Kirsi Ketola, Hidetoshi Kuruma, Randy Jama, Ka Mun Nip
    Abstract:

    Mechanisms controlling emergence of lethal Neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor-resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo. Mechanistic studies showed the AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker, SOX2. Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in CRPC compared to adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest targeting BRN2 is a strategy to treat or prevent Neuroendocrine Differentiation in prostate tumors.