Twenty years on: What do we really know about ewing sarcoma and what is the path forward?

Critical Reviews in Oncogenesis

Volumn 20, Issue 3-4, 2015, Pages 155-171

  Lawlor, Elizabeth R ^a   Sorensen, Poul H ^b,c  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b BRITISH COLUMBIA CANCER RESEARCH CENTRE   (Canada)

^c UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Epigenetics; Ewing sarcoma; Genetics; Metastasis

Indexed keywords

CHEMOKINE RECEPTOR CXCR4; CYTOCHROME P450; CYTOKERATIN 15; HISTONE H2A; HISTONE H3; INHIBITOR OF DIFFERENTIATION 2; MICRORNA; OCTAMER TRANSCRIPTION FACTOR 4; POTASSIUM CHANNEL KCNE2; STROMAL CELL DERIVED FACTOR 1; STROMELYSIN; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR NKX2.2; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR SOX2; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA1; URIDINE PHOSPHORYLASE; EWS-FLI FUSION PROTEIN; ONCOPROTEIN; RNA BINDING PROTEIN EWS; TRANSCRIPTION FACTOR FLI 1;

APOPTOSIS; ARTICLE; BONE MARROW DERIVED MESENCHYMAL STEM CELL; CANCER GENETICS; CANCER GROWTH; CELL HETEROGENEITY; CELL PROLIFERATION; CELL SURVIVAL; CHROMATIN STRUCTURE; CHROMOSOME 12; CHROMOSOME 20; CHROMOSOME 8; CHROMOSOME TRANSLOCATION; CIRCULATING TUMOR CELL; CONSENSUS SEQUENCE; DOWN REGULATION; EWING SARCOMA; GENE EXPRESSION; GENE FUSION; GENOMICS; HUMAN; MESODERM; METASTASIS; NEURAL CREST; NEXT GENERATION SEQUENCING; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; QUALITY OF LIFE; RNA INTERFERENCE; TRANSCRIPTION INITIATION; ANIMAL; GENETIC EPIGENESIS; GENETICS; PATHOLOGY; SARCOMA, EWING; TUMOR EMBOLISM;

ANIMALS; EPIGENESIS, GENETIC; HUMANS; NEOPLASTIC CELLS, CIRCULATING; ONCOGENE PROTEINS, FUSION; PROTO-ONCOGENE PROTEIN C-FLI-1; RNA-BINDING PROTEIN EWS; SARCOMA, EWING;

EID: 84938097398     PISSN: 08939675     EISSN: 21626448     Source Type: Journal    
DOI: 10.1615/CritRevOncog.2015013553     Document Type: Article

References (152)

1. Karski EE, Matthay KK, Neuhaus JM, Goldsby RE, Dubois SG. Characteristics and outcomes of patients with Ewing sarcoma over 40 years of age at diagnosis. Cancer Epidemiol. 2013;37:29-33.
2. Balamuth NJ, Womer RB. Ewing's sarcoma. Lancet Oncol. 2010;11:184-92.
3. Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR. Randomized controlled trial of intervalcompressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012;30:4148-54.
4. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694-701.
5. Arnaldez FI, Helman LJ. New strategies in ewing sarcoma: lost in translation? Clin Cancer Res. 2014;20:3050-6.
6. Kelleher FC, Thomas DM. Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours. Clin Sarcoma Res. 2012;2(1):6.
7. Armstrong GT, Kawashima T, Leisenring W, Stratton K, Stovall M, Hudson MM, Sklar CA, Robison LL, Oeffinger KC. Aging and risk of severe, disabling, lifethreatening, and fatal events in the childhood cancer survivor study. J Clin Oncol. 2014;32:1218-27.
8. Ginsberg JP, Goodman P, Leisenring W, Ness KK, Meyers PA, Wolden SL, Smith SM, Stovall M, Hammond S, Robison LL, Oeffinger KC. Long-term survivors of childhood Ewing sarcoma: report from the childhood cancer survivor study. J Natl Cancer Inst. 2010;102:1272-83.
9. Meltzer PS. Is Ewing's sarcoma a stem cell tumor? Cell Stem Cell. 2007;1:13-5.
10. Riggi N, Suva ML, Stamenkovic I. Ewing's sarcoma origin: from duel to duality. Expert Rev Anticancer Ther. 2009;9:1025-30.
11. Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, Hoffmann F, Trumpp A, Stamenkovic I. Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459-68.
12. Riggi N, Suva ML, De Vito C, Provero P, Stehle JC, Baumer K, Cironi L, Janiszewska M, Petricevic T, Suva D, Tercier S, Joseph JM, Guillou L, Stamenkovic I. EWSFLI- 1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes Dev. 2010;24:916- 32.
13. von Levetzow C, Jiang X, Gwye Y, von Levetzow G, Hung L, Cooper A, Hsu JH, Lawlor ER. Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS One. 2011;6:e19305.
14. Castillero-Trejo Y, Eliazer S, Xiang L, Richardson JA, Ilaria RL Jr. Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells Results in EWS/FLI- 1-dependent, ewing sarcoma-like tumors. Cancer Res. 2005;65:8698-705.
15. Tanaka M, Yamazaki Y, Kanno Y, Igarashi K, Aisaki K, Kanno J, Nakamura T. Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors. J Clin Invest. 2014;124:3061-74.
16. Sankar S, Lessnick SL. Promiscuous partnerships in Ewing's sarcoma. Cancer Genet. 2011;204:351-65.
17. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, Aurias A, Thomas G. Gene fusion with an ETS DNAbinding domain caused by chromosome translocation in human tumours. Nature. 1992;359:162-65.
18. May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC, Delattre O, Zucman J, Thomas G, Denny CT. Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. Proc Natl Acad Sci U S A. 1993;90:5752-56.
19. Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, Lessnick SL. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma. Cancer Cell. 2006;9:405-16.
20. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004;24:7275-83.
21. Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETSfamily transcription factor, ERG. Nat Genet. 1994;6:146- 51.
22. Jeon IS, Davis JN, Braun BS, Sublett JE, Roussel MF, Denny CT, Shapiro DN. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995;10:1229-34.
23. Kaneko Y, Yoshida K, Handa M, Toyoda Y, Nishihira H, Tanaka Y, Sasaki Y, Ishida S, Higashino F, Fujinaga K. Fusion of an ETS-family gene, EIAF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. Genes Chromosomes Cancer. 1996;15:115-21.
24. Peter M, Couturier J, Pacquement H, Michon J, Thomas G, Magdelenat H, Delattre O. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene. 1997;14:1159-64.
25. Urano F, Umezawa A, Hong W, Kikuchi H, Hata J. A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma. Biochem Biophys Res Commun. 1996;219:608-12.
26. Tan AY, Manley JL. The TET family of proteins: functions and roles in disease. J Mol Cell Biol. 2009;1:82-92.
27. Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. FUS/ERG gene fusions in Ewing's tumors. Cancer Res. 2003;63:4568-76.
28. Ng TL, O'Sullivan MJ, Pallen CJ, Hayes M, Clarkson PW, Winstanley M, Sorensen PH, Nielsen TO, Horsman DE. Ewing sarcoma with novel translocation t(2;16) producing an in-frame fusion of FUS and FEV. J Mol Diagn. 2007;9:459-63.
29. Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, Gotoh T, Motoi T, Fukayama M, Aburatani H, Takizawa T, Nakamura T. Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet. 2006;15:2125-37.
30. Szuhai K, Ijszenga M, de Jong D, Karseladze A, Tanke HJ, Hogendoorn PC. The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res. 2009;15:2259-68.
31. Yamaguchi S, Yamazaki Y, Ishikawa Y, Kawaguchi N, Mukai H, Nakamura T. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12). Genes Chromosomes Cancer. 2005;43:217-22.
32. Sumegi J, Nishio J, Nelson M, Frayer RW, Perry D, Bridge JA. A novel t(4;22)(q31;q12) produces an EWSR1-SMARCA5 fusion in extraskeletal Ewing sarcoma/ primitive neuroectodermal tumor. Mod Pathol. 2011;24:333-42.
33. Mastrangelo T, Modena P, Tornielli S, Bullrich F, Testi MA, Mezzelani A, Radice P, Azzarelli A, Pilotti S, Croce CM, Pierotti MA, Sozzi G. A novel zinc finger gene is fused to EWS in small round cell tumor. Oncogene. 2000;19:3799-804.
34. Wang L, Bhargava R, Zheng T, Wexler L, Collins MH, Roulston D, Ladanyi M. Undifferentiated small round cell sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3 fusion and of additional cases with the EWS-ETV1 and EWS-FEV fusions. J Mol Diagn. 2007;9:498-509.
35. de Alava E, Lessnick SL,Sorensen PH. Ewing sarcoma. In: Flethcer CM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO classification of tumours of soft tissue and bone. Lyon: International Agency for Research on Cancer (IARC); 2013. p. 305-9.
36. Delattre O, Zucman J, Melot T, Garau XS, Zucker J-M, Lenoir GM, Ambros PF, Sheer D, Turc-Carel C, Triche TJ, Aurias A, Thomas G. The Ewing family of tumors-a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med. 1994;331:294-9.
37. Miettinen M. From morphological to molecular diagnosis of soft tissue tumors. Adv Exp Med Biol. 2006;587:99- 113.
38. Qadir MA, Zhan SH, Kwok B, Bruestle J, Drees B, Popescu OE, Sorensen PH. ChildSeq-RNA: a nextgeneration sequencing-based diagnostic assay to identify known fusion transcripts in childhood sarcomas. J Mol Diagn. 2014;16:361-70.
39. Sweeney RT, Zhang B, Zhu SX, Varma S, Smith KS, Montgomery SB, van de Rijn M, Zehnder J, West RB. Desktop transcriptome sequencing from archival tissue to identify clinically relevant translocations. Am J Surg Pathol. 2013;37:796-803.
40. Turc-Carel C, Aurias A, Mugneret F, Lizard S, Sidaner I, Volk C, Thiery JP, Olschwang S, Philip I, Berger MP, Thierry Philip, Lenoir GM, Mazabraud A. Chromosomes in Ewing's sarcoma. I. An evaluation of 85 cases of remarkable consistency of t(11;22)(q24;q12). Cancer Genet Cytogenet. 1988;32:229-38.
41. Hattinger CM, Rumpler S, Strehl S, Ambros IM, Zoubek A, Potschger U, Gadner H, Ambros PF. Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer. 1999;24:243-54.
42. Armengol G, Tarkkanen M, Virolainen M, Forus A, Valle J, Bohling T, Asko-Seljavaara S, Blomqvist C, Elomaa I, Karaharju E, Kivioja AH, Siimes MA, Tukiainen E, Caballin MR, Myklebost O, Knuutila S. Recurrent gains of 1q, 8 and 12 in the Ewing family of tumours by comparative genomic hybridization. Br J Cancer. 1997;75:1403- 9.
43. Maurici D, Perez-Atayde A, Grier HE, Baldini N, Serra M, Fletcher JA. Frequency and implications of chromosome 8 and 12 gains in Ewing sarcoma. Cancer Genet Cytogenet. 1998;100:106-10.
44. Ozaki T, Paulussen M, Poremba C, Brinkschmidt C, Rerin J, Ahrens S, Hoffmann C, Hillmann A, Wai D, Schaefer KL, Boecker W, Juergens H, Winkelmann W, Dockhorn-Dworniczak B. Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors. Genes Chromosomes Cancer. 2001;32:164-71.
45. Douglass EC, Rowe ST, Valentine M, Parham D, Meyer WH, Thompson EI. A second nonrandom translocation, der(16)t(1;16)(q21;q13), in Ewing sarcoma and peripheral neuroectodermal tumor. Cytogenet Cell Genet. 1990;53:87-90.
46. Hattinger CM, Rumpler S, Ambros IM, Strehl S, Lion T, Zoubek A, Gadner H, Ambros PF. Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors. Genes Chromosomes Cancer. 1996;17:141-50.
47. Mugneret F, Lizard S, Aurias A, Turc-Carel C. Chromosomes in Ewing's sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet. 1988;32:239-45.
48. Stark B, Mor C, Jeison M, Gobuzov R, Cohen IJ, Goshen Y, Stein J, Fisher S, Ash S, Yaniv I, Zaizov R. Additional chromosome 1q aberrations and der(16)t(1;16), correlation to the phenotypic expression and clinical behavior of the Ewing family of tumors. J Neurooncol. 1997;31:3-8.
49. de Alava E, Antonescu CR, Panizo A, Leung D, Meyers PA, Huvos AG, Pardo-Mindan FJ, Healey JH, Ladanyi M. Prognostic impact of p53 status in Ewing sarcoma. Cancer. 2000;89:783-92.
50. Wei G, Antonescu CR, de Alava E, Leung D, Huvos AG, Meyers PA, Healey JH, Ladanyi M. Prognostic impact of INK4A deletion in Ewing sarcoma. Cancer. 2000;89:793-99.
51. Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, Wexler LH, Gorlick R, Meyers P, Ladanyi M. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23:548-58.
52. Lessnick SL, Ladanyi M. Molecular pathogenesis of Ewing sarcoma: new therapeutic and transcriptional targets. Annu Rev Pathol. 2012;7:145-59.
53. Ohno T, Rao VN, Reddy SP. EWS/Fli-1 chimeric protein is a transcriptional activator. Cancer Res. 1993;53:5859- 63.
54. Bailly R-A, Bosselut R, Zucman J, Cornier F, Delattre O, Roussel M, Thomas G, Ghysdael J. DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol. 1994;14:3230-41.
55. Lessnick SL, Braun BS, Denny CT, May WA. Multiple domains mediate transformation by the Ewing's sarcoma EWS/FLI-1 fusion gene. Oncogene. 1995;10:423-31.
56. Ban J, Siligan C, Kreppel M, Aryee D, Kovar H. EWSFLI1 in Ewing's sarcoma: real targets and collateral damage. Adv Exp Med Biol. 2006;587:41-52.
57. Boro A, Pretre K, Rechfeld F, Thalhammer V, Oesch S, Wachtel M, Schafer BW, Niggli FK. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma. Int J Cancer. 2012;131:2153-64.
58. Luo W, Gangwal K, Sankar S, Boucher KM, Thomas D, Lessnick SL. GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance. Oncogene. 2009;28:4126- 32.
59. Grunewald TG, Diebold I, Esposito I, Plehm S, Hauer K, Thiel U, da Silva-Buttkus P, Neff F, Unland R, Muller- Tidow C, Zobywalski C, Lohrig K, Lewandrowski U, Sickmann A, Prazeres da Costa O, Gorlach A, Cossarizza A, Butt E, Richter GH, Burdach S. STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors. Mol Cancer Res. 2012;10:52-65.
60. Hahm KB, Cho K, Lee C, Im YH, Chang J, Choi SG, Sorensen PH, Thiele CJ, Kim SJ. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein [published erratum appears in Nat Genet 1999;23(4):481]. Nat Genet. 1999;23:222-7.
61. Im YH, Kim HT, Lee C, Poulin D, Welford S, Sorensen PH, Denny CT, Kim SJ. EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene. Cancer Res. 2000;60:1536-40.
62. McKinsey EL, Parrish JK, Irwin AE, Niemeyer BF, Kern HB, Birks DK, Jedlicka P. A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs. Oncogene. 2011;30:4910-20.
63. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, Hotfilder M, Lowel D, von Luettichau I, Mossbrugger I, Quintanilla-Martinez L, Kovar H, Staege MS, Muller-Tidow C, Burdach S. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. Proc Natl Acad Sci U S A. 2009;106:5324-9.
64. Bilke S, Schwentner R, Yang F, Kauer M, Jug G, Walker RL, Davis S, Zhu YJ, Pineda M, Meltzer PS, Kovar H. Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer. Genome Res. 2013;23:1797-809.
65. Patel M, Simon JM, Iglesia MD, Wu SB, McFadden AW, Lieb JD, Davis IJ. Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Genome Res. 2012;22:259-70.
66. Owen LA, Kowalewski AA, Lessnick SL. EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing's sarcoma. PLoS One. 2008;3:e1965.
67. Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P, Kovar H. A molecular function map of Ewing's sarcoma. PLoS One. 2009;4:e5415.
68. Stoll G, Surdez D, Tirode F, Laud K, Barillot E, Zinovyev A, Delattre O. Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis. Nucleic Acids Res. 2013;41:8853-71.
69. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-92.
70. Lawlor ER, Thiele CJ. Epigenetic changes in pediatric solid tumors: promising new targets. Clin Cancer Res. 2012;18:2768-79.
71. Laugesen A, Helin K. Chromatin repressive complexes in stem cells, development, and cancer. Cell Stem Cell. 2014;14:735-51.
72. Voss TC, Hager GL. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet. 2014;15:69-81.
73. Riggi N, Suva ML, Suva D, Cironi L, Provero P, Tercier S, Joseph JM, Stehle JC, Baumer K, Kindler V, Stamenkovic I. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. Cancer Res. 2008;68:2176-85.
74. Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9:773-84.
75. Douglas D, Hsu JH, Hung L, Cooper A, Abdueva D, van Doorninck J, Peng G, Shimada H, Triche TJ, Lawlor ER. BMI-1 promotes Ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res. 2008;68:6507- 15.
76. Zwerner JP, Joo J, Warner KL, Christensen L, Hu- Lieskovan S, Triche TJ, May WA. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene. 2008;27:3282-91.
77. Burdach S, Plehm S, Unland R, Dirksen U, Borkhardt A, Staege MS, Muller-Tidow C, Richter GH. Epigenetic maintenance of stemness and malignancy in peripheral neuroectodermal tumors by EZH2. Cell Cycle. 2009;8:1991-6.
78. Zorzi AP, Bernstein M, Samson Y, Wall DA, Desai S, Nicksy D, Wainman N, Eisenhauer E, Baruchel S. A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/ C17 pediatric phase I consortium. Pediatr Blood Cancer. 2013;60:1868-74.
79. Sankar S, Bell R, Stephens B, Zhuo R, Sharma S, Bearss DJ, Lessnick SL. Mechanism and relevance of EWS/FLImediated transcriptional repression in Ewing sarcoma. Oncogene. 2013;32:5089-100.
80. Sankar S, Theisen ER, Bearss J, Mulvihill T, Hoffman LM, Sorna V, Beckerle M, Sharma S, Lessnick SL. Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res. 2014;20:4584-97.
81. Bennani-Baiti IM, Machado I, Llombart-Bosch A, Kovar H. Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol. 2012;43:1300-7.
82. Knoop LL, Baker SJ. EWS/FLI alters 5′-splice site selection. J Biol Chem. 2001;276:22317-22.
83. Knoop LL, Baker SJ. The splicing factor U1C represses EWS/FLI-mediated transactivation. J Biol Chem. 2000;275:24865-71.
84. Paronetto MP, Bernardis I, Volpe E, Bechara E, Sebestyen E, Eyras E, Valcarcel J. Regulation of FAS exon definition and apoptosis by the Ewing sarcoma protein. Cell Rep. 2014;7:1211-26.
85. Paronetto MP, Minana B, Valcarcel J. The Ewing sarcoma protein regulates DNA damage- induced alternative splicing. Mol Cell. 2011;43:353-68.
86. Picarda G, Surget S, Guiho R, Teletchea S, Berreur M, Tirode F, Pellat-Deceunynck C, Heymann D, Trichet V, Redini F. A functional, new short isoform of death receptor 4 in Ewing's sarcoma cell lines may be involved in TRAIL sensitivity/resistance mechanisms. Mol Cancer Res. 2012;10:336-46.
87. Huang G, Zhou Z, Wang H, Kleinerman ES. CAPERalpha alternative splicing regulates the expression of vascular endothelial growth factor(1)(6)(5) in Ewing sarcoma cells. Cancer. 2012;118:2106-16.
88. Iida K, Fukushi J, Matsumoto Y, Oda Y, Takahashi Y, Fujiwara T, Fujiwara-Okada Y, Hatano M, Nabashima A, Kamura S, Iwamoto Y. miR-125b develops chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor. Cancer Cell Int. 2013;13:21.
89. Franzetti GA, Laud-Duval K, Bellanger D, Stern MH, Sastre-Garau X, Delattre O. MiR-30a-5p connects EWSFLI1 and CD99, two major therapeutic targets in Ewing tumor. Oncogene. 2013;32:3915-21.
90. Dylla L, Moore C, Jedlicka P. MicroRNAs in Ewing sarcoma. Front Oncol. 2013;3:65.
91. Dylla L, Jedlicka P. Growth-promoting role of the miR-106a 363 cluster in Ewing sarcoma. PLoS One. 2013;8:e63032.
92. Robin TP, Smith A, McKinsey E, Reaves L, Jedlicka P, Ford HL. EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Mol Cancer Res. 2012;10:1098-108.
93. De Vito C, Riggi N, Suva ML, Janiszewska M, Horlbeck J, Baumer K, Provero P, Stamenkovic I. Let-7a is a direct EWS-FLI-1 target implicated in Ewing's sarcoma development. PLoS One. 2011;6:e23592.
94. Ban J, Jug G, Mestdagh P, Schwentner R, Kauer M, Aryee DN, Schaefer KL, Nakatani F, Scotlandi K, Reiter M, Strunk D, Speleman F, Vandesompele J, Kovar H. Hsamir- 145 is the top EWS-FLI1-repressed microRNA involved in a positive feedback loop in Ewing's sarcoma. Oncogene. 2011;30:2173-80.
95. De Vito C, Riggi N, Cornaz S, Suva ML, Baumer K, Provero P, Stamenkovic I. A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell. 2012;21:807-21.
96. Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Juergens H. Ewing's sarcoma family of tumors: current management. Oncologist. 2006;11:503-19.
97. Ginsberg JP, de Alava E, Ladanyi M, Wexler LH, Kovar H, Paulussen M, Zoubek A, Dockhorn-Dworniczak B, Juergens H, Wunder JS, Andrulis IL, Malik R, Sorensen PH, Womer RB, Barr FG. EWS-FLI1 and EWS-ERG gene fusions are associated with similar clinical phenotypes in Ewing's sarcoma. J Clin Oncol. 1999;17:1809- 14.
98. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275-92.
99. Yu M, Ting DT, Stott SL, Wittner BS, Ozsolak F, Paul S, Ciciliano JC, Smas ME, Winokur D, Gilman AJ, Ulman MJ, Xega K, Contino G, Alagesan B, Brannigan BW, Milos PM, Ryan DP, Sequist LV, Bardeesy N, Ramaswamy S, Toner M, Maheswaran S, Haber DA. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature. 2012;487:510-3.
100. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New Engl J Med. 2012;366:883-92.
101. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012;481:329-34.
102. Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483:589-93.
103. Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, Shefler E, Sivachenko A, Sougnez C, Stewart C, Ally A, Birol I, Chiu R, Corbett RD, Hirst M, Jackman SD, Kamoh B, Khodabakshi AH, Krzywinski M, Lo A, Moore RA, Mungall KL, Qian J, Tam A, Thiessen N, Zhao Y, Cole KA, Diamond M, Diskin SJ, Mosse YP, Wood AC, Ji L, Sposto R, Badgett T, London WB, Moyer Y, Gastier-Foster JM, Smith MA, Guidry Auvil JM, Gerhard DS, Hogarty MD, Jones SJ, Lander ES, Gabriel SB, Getz G, Seeger RC, Khan J, Marra MA, Meyerson M, Maris JM. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279-84.
104. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortes ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Lee RS, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CW, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G. Mutational heterogeneity in cancer and the search for new cancerassociated genes. Nature. 2013;499:214-8.
105. Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, Patidar R, Hurd L, Chen L, Shern JF, Liao H, Wen X, Gerard J, Kim JS, Lopez Guerrero JA, Machado I, Wai DH, Picci P, Triche T, Horvai AE, Miettinen M, Wei JS, Catchpool D, Llombart-Bosch A, Waldman T, Khan J. The genomic landscape of the Ewing sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10:e1004475.
106. Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, Croul S, Bouffet E, Fults DW, Eberhart CG, Garzia L, Van Meter T, Zagzag D, Jabado N, Schwartzentruber J, Majewski J, Scheetz TE, Pfister SM, Korshunov A, Li XN, Scherer SW, Cho YJ, Akagi K, MacDonald TJ, Koster J, McCabe MG, Sarver AL, Collins VP, Weiss WA, Largaespada DA, Collier LS, Taylor MD. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature. 2012;482:529-33.
107. Wiles ET, Bell R, Thomas D, Beckerle M and Lessnick SL. ZEB2 represses the epithelial phenotype, facilitates metastasis in Ewing sarcoma. Genes Cancer. 2013;4:486- 500.
108. Hauer K, Calzada-Wack J, Steiger K, Grunewald TG, Baumhoer D, Plehm S, Buch T, Prazeres da Costa O, Esposito I, Burdach S, Richter GH. DKK2 mediates osteolysis, invasiveness, and metastatic spread in Ewing sarcoma. Cancer Res. 2013;73:967-77.
109. Krook MA, Nicholls LA, Scannell CA, Chugh R, Thomas DG, Lawlor ER. Stress-induced CXCR4 promotes migration and invasion of Ewing sarcoma. Mol Cancer Res. 2014;12:953-64.
110. Bennani-Baiti IM, Cooper A, Lawlor ER, Kauer M, Ban J, Aryee DN, Kovar H. Intercohort gene expression co-analysis reveals chemokine receptors as prognostic indicators in Ewing's sarcoma. Clin Cancer Res. 2010;16:3769-78.
111. Hamdan R, Zhou Z, Kleinerman ES. Blocking SDF- 1alpha/CXCR4 downregulates PDGF-B and inhibits bone marrow-derived pericyte differentiation and tumor vascular expansion in Ewing tumors. Mol Cancer Ther. 2014;13:483-91.
112. Berghuis D, Schilham MW, Santos SJ, Savola S, Knowles HJ, Dirksen U, Schaefer KL, Vakkila J, Hogendoorn PC, Lankester AC. The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease. Clin Sarcoma Res. 2012;2:24.
113. Kang HG, Jenabi JM, Zhang J, Keshelava N, Shimada H, May WA, Ng T, Reynolds CP, Triche TJ,Sorensen PH. Ecadherin cell-cell adhesion in ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. Cancer Res. 2007;67:3094-105.
114. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555-62.
115. Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer Lett. 2008;272:177- 85.
116. Lawlor ER, Scheel C, Irving J, Sorensen PH. Anchorageindependent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors. Oncogene. 2002;21:307-18.
117. Mendoza-Naranjo A, El-Naggar A, Wai DH, Mistry P, Lazic N, Ayala FR, da Cunha IW, Rodriguez-Viciana P, Cheng H, Tavares Guerreiro Fregnani JH, Reynolds P, Arceci RJ, Nicholson A, Triche TJ, Soares FA, Flanagan AM, Wang YZ, Strauss SJ, Sorensen PH. ERBB4 confers metastatic capacity in Ewing sarcoma. EMBO Mol Med. 2013;5:1019-34.
118. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328-37.
119. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54:716-27.
120. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, D'Alessio AC, Young RA, Weinberg RA. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154 61-74.
121. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741-51.
122. Cooper A, van Doorninck J, Ji L, Russell D, Ladanyi M, Shimada H, Krailo M, Womer RB, Hsu JH, Thomas D, Triche TJ, Sposto R, Lawlor ER. Ewing tumors that do not overexpress BMI-1 are a distinct molecular subclass with variant biology: a report from the Children's Oncology Group. Clin Cancer Res. 2011;17:56-66.
123. Lackner MR, Wilson TR, Settleman J. Mechanisms of acquired resistance to targeted cancer therapies. Future Oncol. 2012;8:999-1014.
124. Leuci V, Mesiano G, Gammaitoni L, Aglietta M, Sangiolo D. Genetically redirected T lymphocytes for adoptive immunotherapy of solid tumors. Curr Gene Ther. 2014;14:52-62.
125. Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Chimeric antigen receptor therapy for cancer. Annu Rev Med. 2014;65:333-47.
126. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014;21:231-7.
127. Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, Stearns V, Pardoll DM, Davidson N, Jones PA, Slamon DJ, Baylin SB, Zahnow CA, Ahuja N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5:587-98.
128. Krishnadas DK, Bao L, Bai F, Chencheri SC, Lucas K. Decitabine facilitates immune recognition of sarcoma cells by upregulating CT antigens, MHC molecules, and ICAM-1. Tumour Biol. 2014;35:5753-62.
129. Hong SH, Youbi SE, Hong SP, Kallakury B, Monroe P, Erkizan HV, Barber-Rotenberg JS, Houghton P, Uren A, Toretsky JA. Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing sarcoma. Oncotarget. 2014;5:338-50.
130. Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, Abaan OD, Chou TH, Dakshanamurthy S, Brown ML, Uren A, Toretsky JA. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med. 2009;15:750-6.
131. Alhaddad A, Durieu C, Dantelle G, Le Cam E, Malvy C, Treussart F, Bertrand JR. Influence of the internalization pathway on the efficacy of siRNA delivery by cationic fluorescent nanodiamonds in the Ewing sarcoma cell model. PLoS One. 2012;7:e52207.
132. Takigami I, Ohno T, Kitade Y, Hara A, Nagano A, Kawai G, Saitou M, Matsuhashi A, Yamada K, Shimizu K. Synthetic siRNA targeting the breakpoint of EWS/Fli-1 inhibits growth of Ewing sarcoma xenografts in a mouse model. Int J Cancer. 2011;128:216-26.
133. Sonnemann J, Dreyer L, Hartwig M, Palani CD, Hong le TT, Klier U, Broker B, Volker U, Beck JF. Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells. J Cancer Res Clin Oncol. 2007;133:847-58.
134. Hurtubise A, Bernstein ML, Momparler RL. Preclinical evaluation of the antineoplastic action of 5-aza- 2′-deoxycytidine and different histone deacetylase inhibitors on human Ewing's sarcoma cells. Cancer Cell Int. 2008;8:16.
135. Guan H, Zhou Z, Gallick GE, Jia SF, Morales J, Sood AK, Corey SJ, Kleinerman ES. Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma. Mol Cancer Ther. 2008;7:1807-16.
136. Stebbing J, Paz K, Schwartz GK, Wexler LH, Maki R, Pollock RE, Morris R, Cohen R, Shankar A, Blackman G, Harding V, Vasquez D, Krell J, Ciznadija D, Katz A, Sidransky D. Patient-derived xenografts for individualized care in advanced sarcoma. Cancer. 2014;120:2006- 15.
137. Mendoza A, Hong SH, Osborne T, Khan MA, Campbell K, Briggs J, Eleswarapu A, Buquo L, Ren L, Hewitt SM, Dakir el H, Garfield S, Walker R, Merlino G, Green JE, Hunter KW, Wakefield LM, Khanna C. Modeling metastasis biology and therapy in real time in the mouse lung. J Clin Invest. 2010;120:2979-88.
138. Konantz M, Balci TB, Hartwig UF, Dellaire G, Andre MC, Berman JN, Lengerke C. Zebrafish xenografts as a tool for in vivo studies on human cancer. Ann N Y Acad Sci. 2012;1266:124-37.
139. Daugaard M, Nitsch R, Razaghi B, McDonald L, Jarrar A, Torrino S, Castillo-Lluva S, Rotblat B, Li L, Malliri A, Lemichez E, Mettouchi A, Berman JN, Penninger JM, Sorensen PH. Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes. Nat Commun. 2013;4:2180.
140. Veinotte CJ, Dellaire G, Berman JN. Hooking the big one: the potential of zebrafish xenotransplantation to reform cancer drug screening in the genomic era. Dis Model Mech. 2014;7:745-54.
141. Holzel M, Bovier A, Tuting T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer. 2013;13:365-76.
142. Thibaudeau L, Taubenberger AV, Holzapfel BM, Quent VM, Fuehrmann T, Hesami P, Brown TD, Dalton PD, Power CA, Hollier BG, Hutmacher DW. A tissueengineered humanized xenograft model of human breast cancer metastasis to bone. Dis Model Mech. 2014;7:299- 309.
143. Fong EL, Lamhamedi-Cherradi SE, Burdett E, Ramamoorthy V, Lazar AJ, Kasper FK, Farach-Carson MC, Vishwamitra D, Demicco EG, Menegaz BA, Amin HM, Mikos AG, Ludwig JA. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proc Natl Acad Sci U S A. 2013;110:6500-5.
144. Villasante A, Marturano-Kruik A, Vunjak-Novakovic G. Bioengineered human tumor within a bone niche. Biomaterials. 2014;35:5785-94.
145. Wang CC, Schulz MD. Ewing's sarcoma; a study of fifty cases treated at the Massachusetts General Hospital, 1930-1952 inclusive. N Engl J Med. 1953;248:571-6.
146. Dahlin DC, Coventry MB, Scanlon PW. Ewing's sarcoma. A critical analysis of 165 cases. J Bone Joint Surg Am. 1961;43-A:185-92.
147. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148:349-61.
148. Satelli A, Mitra A, Cutrera JJ, Devarie M, Xia X, Ingram DR, Dibra D, Somaiah N, Torres KE, Ravi V, Ludwig JA, Kleinerman ES, Li S. Universal marker and detection tool for human sarcoma circulating tumor cells. Cancer Res. 2014;74:1645-50.
149. Miller IV, Raposo G, Welsch U, Prazeres da Costa O, Thiel U, Lebar M, Maurer M, Bender HU, von Luettichau I, Richter GH, Burdach S, Grunewald TG. First identification of Ewing's sarcoma-derived extracellular vesicles and exploration of their biological and potential diagnostic implications. Biol Cell. 2013;105:289-303.
150. Yu M, Wan YF, Zou QH. Cell-free circulating mitochondrial DNA in the serum: a potential noninvasive biomarker for Ewing's sarcoma. Arch Med Res. 2012;43:389-94.
151. Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L, Minchella I, Locatelli M, Goldhirsch A, Curigliano G. Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev. 2014;40:648- 55.
152. Khoja L, Lorigan P, Dive C, Keilholz U, Fusi A. Circulating tumor cells as tumor biomarkers in melanoma: detection methods and clinical relevance. Ann Oncol. 2015;26:33-9.