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c-myc ewing sarcoma

Hemant K Bid, Doris A Phelps, Linlin Xaio, Denis C Guttridge, Jiayuh Lin, Cheryl London, Laurence H Baker, Xiaokui Mo, Peter J Houghton
The bromodomain and extra-terminal domain inhibitor JQ1 has marked antitumor activity against several hematologic malignancies as well as solid tumor models. Here, we investigated its activity in vitro and in vivo against models of childhood rhabdomyosarcoma and Ewing sarcoma. In vitro, JQ1 (but not the inactive enantiomer JQ1R) inhibited cell proliferation and increased G1 fraction of cells, although there was no correlation between cell line sensitivity and suppression of c-MYC or MYCN. In vivo, xenografts showed significant inhibition of growth during the period of treatment, and rapid regrowth after treatment was stopped, activity typical of antiangiogenic agents...
May 2016: Molecular Cancer Therapeutics
Piotr Czapiewski, Marzena Wełnicka-Jaśkiewicz, Barbara Seroczyńska, Jarosław Skokowski, Aleksandra Sejda, Jolanta Szade, Claudia Wiewiora, Wojciech Biernat, Anna Żaczek
CD99 is a protein initially described in the Ewing sarcoma family of tumors, but growing evidence has shown its expression in other tumors of mesenchymal, hematopoietic and even epithelial origin. Some articles report CD99 in metaplastic carcinoma of the breast, a subtype of breast carcinoma (BC) with pronounced epithelial to mesenchymal (EMT) phenotype. Our aim was to analyse the potential relationship between CD99 and selected EMT (vimentin, E-cadherin, Twist) and proliferation markers (Ki-67, c-myc, cyclin D1, topoisomerase 2), molecular subtypes of BC, as well as overall survival (OS) and progression-free survival (PFS)...
September 2015: Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists
Steven Christopher Smith, Darya Buehler, Eun-Young Karen Choi, Jonathan B McHugh, Brian P Rubin, Steven D Billings, Bonnie Balzer, Dafydd G Thomas, David R Lucas, John R Goldblum, Rajiv M Patel
Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases...
January 2015: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Srikanth R Ambati, Eloisi Caldas Lopes, Kohji Kosugi, Ullas Mony, Ahmet Zehir, Smit K Shah, Tony Taldone, Andre L Moreira, Paul A Meyers, Gabriela Chiosis, Malcolm A S Moore
Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and in vivo experiments in NSG and nude mice using the A673 cell line...
March 2014: Molecular Oncology
Shuang Yan, Zhijie Li, Carol J Thiele
The IL-6/JAK/STAT pathway is a key signal transduction pathway implicated in the pathogenesis of many human cancers, suggesting that kinase inhibitors targeting JAK/STAT3 may have a broad spectrum of antitumor activity. AZD1480, a pharmacological JAK1/2 inhibitor, exhibits anti-tumor potency in multiple adult malignancies. To evaluate the efficacy of inhibition of JAK/STAT3 signal transduction pathway we assessed the activity of AZD1480 in pediatric malignancies using preclinical models of three highly malignant pediatric solid tumors: neuroblastoma (NB), rhabdomyosarcoma (RMS) and the Ewing Sarcoma Family Tumors (ESFT)...
March 2013: Oncotarget
Babu Jully, Ramshankar Vijayalakshmi, Gopisetty Gopal, Kesavan Sabitha, Thangarajan Rajkumar
BACKGROUND: Ewing's sarcoma is a malignancy characterized by a specific 11:22 chromosomal translocation which generates a novel EWS-FLI1 fusion protein functioning as an aberrant transcription factor. In the present study, we have further characterized the junction region of the EWS-FLI1 fusion protein. METHODS: In-silico model of EWS-FLI1 fusion protein was analysed for ligand binding sites, and a putative region (amino acid (aa) 251-343 of the type 1 fusion protein) in the vicinity of the fusion junction was cloned and expressed using bacterial expression...
2012: BMC Cancer
Emmanuelle David, Franck Tirode, Marc Baud'huin, Pierre Guihard, Karine Laud, Olivier Delattre, Marie F Heymann, Dominique Heymann, Françoise Redini, Frédéric Blanchard
Primary bone tumors, osteosarcomas and chondrosarcomas, derive from mesenchymal stem cells committed into osteoblasts and chondrocytes; in Ewing sarcomas (ESs), the oncogenic fusion protein EWS-FLI1 prevents mesenchymal differentiation and induces neuroectodermic features. Oncostatin M (OSM) is a cytokine from the IL-6 family that modulates proliferation and differentiation in numerous cells. The basis for inhibition versus induction of proliferation by this cytokine is obscure, although MYC was described as a potent molecular switch in OSM signaling...
November 2012: American Journal of Pathology
Iori Takigami, Takatoshi Ohno, Yukio Kitade, Akira Hara, Akihito Nagano, Gou Kawai, Mitsuru Saitou, Aya Matsuhashi, Kazunari Yamada, Katsuji Shimizu
The EWS/Fli-1 fusion gene, a product of the translocation t(11;22, q24;q12), is detected in 85% of Ewing sarcomas and primitive neuroectodermal tumors. It is thought to be a transcriptional activator that plays a significant role in tumorigenesis. In this study, we developed a novel EWS/Fli-1 blockade system using RNA interference and tested its application for inhibiting the proliferation of Ewing sarcoma cells in vitro and the treatment of mouse tumor xenografts in vivo. We designed and synthesized a small interfering RNA (siRNA) possessing an aromatic compound at the 3'-end targeting the breakpoint of EWS/Fli-1...
January 1, 2011: International Journal of Cancer. Journal International du Cancer
Diana Zambelli, Monia Zuntini, Filippo Nardi, Maria Cristina Manara, Massimo Serra, Lorena Landuzzi, Pier-Luigi Lollini, Stefano Ferrari, Marco Alberghini, Antonio Llombart-Bosch, Enza Piccolo, Stefano Iacobelli, Piero Picci, Katia Scotlandi
Starting from an experimental model that accounts for the 2 most important adverse processes to successful therapy of Ewing's sarcoma (EWS), chemoresistance and the presence of metastasis at the time of diagnosis, we defined a molecular signature of potential prognostic value. Functional annotation of differentially regulated genes revealed 3 major networks related to cell cycle, cell-to-cell interactions and cellular development. The prognostic impact of 8 genes, representative of these 3 networks, was validated in 56 EWS patients...
January 1, 2010: International Journal of Cancer. Journal International du Cancer
Mattias K Andersson, Pierre Aman
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR) and vandetanib selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2) with additional activity against VEGFR-3, EGFR and RET kinase receptors...
2008: Cancer Cell International
J P Zwerner, J Joo, K L Warner, L Christensen, S Hu-Lieskovan, T J Triche, W A May
Ewing family tumors (EFT), classically Ewing's sarcoma and peripheral primitive neuroectodermal tumor, share a common class of tumor-specific fusion genes thought to be key mediators of tumor biology. Here we demonstrate that the most common Ewing's fusion, EWS/FLI1, produces transcriptional upregulation of GLI1 and its direct transcriptional target PATCHED1 in a model transformation system. This deregulation of GLI1 is common to other EWS/ets chimera and depends on the functional transcriptional regulatory domains...
May 22, 2008: Oncogene
Min-Suk Kim, Chong Jai Kim, Hyun Sook Jung, Mi Ran Seo, Yong-Sung Juhnn, Hee Young Shin, Hyo Seop Ahn, Carol J Thiele, Je G Chi
Peripheral primitive neuroectodermal tumour (PNET)/Ewing's sarcoma (ES) and neuroblastoma (NB) are related tumours of neural crest origin with primitive neural characteristics. Fibroblast growth factor 2 (FGF2) is a critical signalling molecule for primitive neural crest cells. The treatment of NB cells with FGF2 variably affects biological characteristics such as growth and differentiation, while in PNET/ES, FGF2 predominantly induces apoptosis. The JK-GMS Askin tumour cell line can be induced to differentiate upon treatment with nerve growth factor (NGF), indicating the integrity of the cellular machinery necessary for differentiation...
January 2004: Journal of Pathology
Hiroshi Moritake, Tohru Sugimoto, Hiroshi Kuroda, Fumio Hidaka, Yukiko Takahashi, Masazumi Tsuneyoshi, Mitsuaki A Yoshida, Qingping Cui, Kensuke Akiyoshi, Tatsuro Izumi, Hiroyuki Nunoi
Askin tumor is a malignant small round cell tumor that originates from the thoracopulmonary region and is a member of Ewing sarcoma family of tumors (ESFT). Only a few Askin tumor cell lines have been established. An Askin tumor cell line, designated MP-ASKIN-SA, was established from the left thoracic tumor of a 13-year-old Japanese boy. ESFT is known to have a high rate of distant metastases at diagnosis. The genes controlling the spread of ESFT cells, however, have not been elucidated. G-banding chromosome analysis revealed that the MP-ASKIN-SA cell line has complex chromosomal abnormalities including trisomy 8...
October 15, 2003: Cancer Genetics and Cytogenetics
D Chan, T J Wilson, D Xu, H E Cowdery, E Sanij, P J Hertzog, I Kola
Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS/FLI-1. To elucidate the mechanisms by which EWS/FLI-1 mediates transformation in mouse models, we have generated a murine Ews/Fli-1 fusion protein. We demonstrate that this protein transforms fibroblast cells in vitro similar to human EWS/FLI-1 as demonstrated by serum and anchorage-independent growth, the formation of tumours in nude mice and elevation of the oncogenic marker c-myc...
January 13, 2003: British Journal of Cancer
Mariko Fukuma, Hajime Okita, Jun-Ichi Hata, Akihiro Umezawa
The chromosomal translocation specifically linked to the Ewing sarcoma family results in the generation of fusion proteins comprising the amino terminal portion of EWS and the DNA-binding domain of ets transcription factors. The EWS/ets chimeric proteins act as aberrant transcription factors leading to tumorigenic processes. We searched for genes specifically activated in Ewing sarcoma cells but not in other tumor cell lines using the gene array technique, and found significantly enhanced expression of the Id2 gene...
January 9, 2003: Oncogene
Hiroyuki Nishimori, Yasushi Sasaki, Koichi Yoshida, Hideto Irifune, Hitoshi Zembutsu, Toshihiro Tanaka, Tomoki Aoyama, Taisuke Hosaka, Satoshi Kawaguchi, Takuro Wada, Jun-Ichi Hata, Junya Toguchida, Yusuke Nakamura, Takashi Tokino
We report here that the Id2 (inhibitor of DNA binding 2) gene is a novel target of transcriptional activation by EWS-FLI1 and EWS-ERG, two fusion proteins that characterize Ewing family tumors (EFTs). To identify downstream targets of these EWS-ETS fusion proteins, we introduced EWS-ETS fusion constructs into a human fibrosarcoma cell line by retroviral transduction. cDNA microarray analysis revealed that Id2 expression was up-regulated by introducing the EWS-ETS fusion gene but not by the normal full-length ETS gene...
November 28, 2002: Oncogene
Gi-Jin Kim, Chong Jai Kim, So Young Cho, In Pyung Chung, Sun-Hwa Park, Min Jung Lee, Je G Chi
Peripheral primitive neuroectodermal tumor (PNET) and Ewing's sarcoma (ES) constitute a unique group of small round cell tumors in childhood and young adults that are characterized by the same chromosomal translocation t(11;22)(q24;q12). Recently, the expression of neurotrophin receptors has been found in various human tumors including PNET/ES, but the functional significance of these receptor expressions has not been documented in PNET/ES. In the present study, we investigated the biologic effects of trkA neurotrophin receptor activation by nerve growth factor (NGF) in a newly established Askin tumor cell line, JK-GMS, which constitutively expresses a high level of trkA...
February 2002: Laboratory Investigation; a Journal of Technical Methods and Pathology
P Ioannidis, T Trangas, E Dimitriadis, M Samiotaki, I Kyriazoglou, C M Tsiapalis, C Kittas, N Agnantis, F C Nielsen, J Nielsen, J Christiansen, N Pandis
Mouse coding region determinant-binding (mCRD-BP) and human IGF-II mRNA-binding 1 (hIMP-1) proteins are orthologous mRNA-binding proteins that recognize c-myc and IGF-II mRNA, respectively, and regulate their expression posttranscriptionally. Here, we confirm that human CRD-BP/IMP-1 binds to c-myc mRNA and that it is predominantly expressed in fetal tissues. Moreover, hCRD-BP/IMP-1 expression was detected in cell lines of neoplastic origin and in selected primary tumors. In a series of 33 malignant and 10 benign mesenchymal tumors, 73% and 40%, respectively, were found to express hCRD-BP/IMP-1...
November 2001: International Journal of Cancer. Journal International du Cancer
L Dauphinot, C De Oliveira, T Melot, N Sevenet, V Thomas, B E Weissman, O Delattre
Ewing tumour is characterized by specific chromosome translocations which fuse EWS to a subset of genes encoding ETS transcription factors, most frequently FLI-1. We report the analysis of the expression of various cell cycle regulators both in Ewing tumour derived cell lines and in different cellular models with either inducible or constitutive EWS-FLI-1 cDNA expression. In Ewing cell lines, cyclin D1, CDK4, Rb, p27KIP1 and c-Myc were consistently highly expressed whereas p57KIP2, p15INK4B and p14ARF demonstrated undetectable or low expression levels...
May 31, 2001: Oncogene
M R Sollazzo, M S Benassi, G Magagnoli, G Gamberi, L Molendini, P Ragazzini, M Merli, C Ferrari, A Balladelli, P Picci
AIMS AND BACKGROUND: Ewing's sarcoma is a highly malignant musculoskeletal tumor composed of small round cells. Although important results have been achieved with surgery associated with chemotherapy, recurrent disease is still a major problem. In order to define new prognostic factors useful for therapeutic decision-making, we conducted a study on 38 Ewing's sarcoma samples in which c-myc oncogene expression and Ki67 proliferation index were correlated with clinical outcome. METHODS AND STUDY DESIGN: Nineteen patients developed metastases during follow-up and 10 of these patients died...
May 1999: Tumori
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