Abstract
Ewing’s Sarcoma Family of Tumors (ESFT) are highly malignant tumors of bone and soft tissue that occur in children, adolescents, and young adults (Arndt and Crist 1999; Toretsky 2003). Currently, the standard therapy for ESFT patients is a five-drug regimen that consists of alternating cycles of doxorubicin/vincristine/cyclophosphamide and etoposide/ifosfamide over the course of approximately 9 months. Side effects include nausea, vomiting, and severe hematologic cytopenias, and patients often develop life-threatening infections while receiving chemotherapy. Patients who present with localized ESFT have approximately 70% disease-free survival. Patients who present with metastatic ESFT have a poor prognosis, reporting only 20% disease-free survival despite receiving intensive therapy (Grier et al. 2003). These clinical response rates have persisted for the past decade, even after patients received dose-intensifying chemotherapy and bone-marrow transplantation. Current treatment-related morbidity includes cardiac, musculoskeletal, and second malignancies (Fuchs et al. 2003). We need to discover novel therapeutic approaches to reduce treatment-related morbidity as well as improve overall survival. Novel therapies should exploit tumor vulnerability based on ESFT ontogeny, oncogenesis, and tumor-maintenance pathways.
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References
Abaan, O. D., Levenson, A., Khan, O., Furth, P. A., Uren, A. and Toretsky, J. A., 2005. PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing’s sarcoma tumorigenesis. Oncogene 24:2715–2722.
Abadie, A., Besancon, F. and Wietzerbin, J., 2004. Type I interferon and TNFalpha cooperate with type II interferon for TRAIL induction and triggering of apoptosis in SK-N-MC EWING tumor cells. Oncogene 23:4911–4920.
Abadie, A. and Wietzerbin, J., 2003. Involvement of TNF-related apoptosis-inducing ligand (TRAIL) induction in interferon gamma-mediated apoptosis in Ewing tumor cells. Ann N Y Acad Sci 1010:117–120.
Ambros, I. M., Ambros, P. F., Strehl, S., Kovar, H., Gadner, H. and Salzer-Kuntschik, M., 1991. MIC2 is a specific marker for Ewing’s sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing’s sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 67:1886–1893.
Anderson, S. F., Schlegel, B. P., Nakajima, T., Wolpin, E. S. and Parvin, J. D., 1998. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet 19:254–256.
Aratani, S., Fujii, R., Oishi, T., Fujita, H., Amano, T., Ohshima, T., Hagiwara, M., Fukamizu, A. and Nakajima, T., 2001. Dual roles of RNA helicase A in CREB-dependent transcription. Mol Cell Biol 21:4460–4469.
Arndt, C. A. and Crist, W. M., 1999. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 341:342–352.
Aryee, D. N., Kreppel, M., Bachmaier, R., Uren, A., Muehlbacher, K., Wagner, S., Breiteneder, H., Ban, J., Toretsky, J. A. and Kovar, H., 2006. Single-chain antibodies to the EWS NH2 terminus structurally discriminate between intact and chimeric EWS in Ewing’s sarcoma and interfere with the transcriptional activity of EWS in vivo. Cancer Res 66:9862–9869.
Ashkenazi, A., 2002. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2:420–430.
Baer, C., Nees, M., Breit, S., Selle, B., Kulozik, A. E., Schaefer, K. L., Braun, Y., Wai, D. and Poremba, C., 2004. Profiling and functional annotation of mRNA gene expression in pediatric rhabdomyosarcoma and Ewing’s sarcoma. Int J Cancer 110:687–694.
Baliko, F., Bright, T., Poon, R., Cohen, B., Egan, S. E. and Alman, B. A., 2007. Inhibition of notch signaling induces neural differentiation in Ewing sarcoma. Am J Pathol 170:1686–1694.
Baserga, R., 1995. The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 55:249–252.
Beauchamp, E., Bulut, G., Abaan, O., Chen, K., Merchant, A., Matsui, W., Endo, Y., Rubin, J. S., Toretsky, J. and Uren, A., 2009. GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein. J Biol Chem 284:9074–9082.
Begent, R. H., Verhaar, M. J., Chester, K. A., Casey, J. L., Green, A. J., Napier, M. P., Hope-Stone, L. D., Cushen, N., Keep, P. A., Johnson, C. J., Hawkins, R. E., Hilson, A. J. and Robson, L., 1996. Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library. Nat Med 2:979–984.
Benini, S., Manara, M. C., Baldini, N., Cerisano, V., Massimo, S., Mercuri, M., Lollini, P. L., Nanni, P., Picci, P. and Scotlandi, K., 2001. Inhibition of insulin-like growth factor I receptor increases the antitumor activity of doxorubicin and vincristine against Ewing’s sarcoma cells. Clin Cancer Res 7:1790–1797.
Bertolotti, A., Melot, T., Acker, J., Vigneron, M., Delattre, O. and Tora, L., 1998. EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes. Mol Cell Biol 18:1489–1497.
Bond, M., Bernstein, M. L., Pappo, A., Schultz, K. R., Krailo, M., Blaney, S. M. and Adamson, P. C., 2007. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a children’s oncology group study. Pediatr Blood Cancer 50(2):254–258
Bozzi, F., Tamborini, E., Negri, T., Pastore, E., Ferrari, A., Luksch, R., Casanova, M., Pierotti, M. A., Bellani, F. F. and Pilotti, S., 2007. Evidence for activation of KIT, PDGFRalpha, and PDGFRbeta receptors in the Ewing sarcoma family of tumors. Cancer 109:1638–1645.
Braun, B. S., Frieden, R., Lessnick, S. L., May, W. A. and Denny, C. T., 1995. Identification of target genes for the Ewing’s sarcoma EWS/FLI fusion protein by representational difference analysis. Mol Cell Biol 15:4623–4630.
Braunreiter, C. L., Hancock, J. D., Coffin, C. M., Boucher, K. M. and Lessnick, S. L., 2006. Expression of EWS-ETS fusions in NIH3T3 cells reveals significant differences to Ewing’s sarcoma. Cell Cycle 5:2753–2759.
Butler, A. A., Yakar, S., Gewolb, I. H., Karas, M., Okubo, Y. and LeRoith, D., 1998. Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp Biochem Physiol B Biochem Mol Biol 121:19–26.
Castillero-Trejo, Y., Eliazer, S., Xiang, L., Richardson, J. A. and Ilaria, R. L., Jr., 2005. 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 65:8698–8705.
Cavazzana, A., 1994. [The recent progress of biology in pediatric oncology (editorial)]. Pediatr Med Chir 16:197–199.
Chan, D., Wilson, T. J., Xu, D., Cowdery, H. E., Sanij, E., Hertzog, P. J. and Kola, I., 2003. Transformation induced by Ewing’s sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1. Br J Cancer 88:137–145.
Chansky, H. A., Barahmand-Pour, F., Mei, Q., Kahn-Farooqi, W., Zielinska-Kwiatkowska, A., Blackburn, M., Chansky, K., Conrad, E. U., III, Bruckner, J. D., Greenlee, T. K. and Yang, L., 2004. Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing’s sarcoma cells in vitro. J Orthop Res 22:910–917.
Chansky, H. A., Hu, M., Hickstein, D. D. and Yang, L., 2001. Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein. Cancer Res 61:3586–3590.
Codrington, R., Pannell, R., Forster, A., Drynan, L. F., Daser, A., Lobato, N., Metzler, M. and Rabbitts, T. H., 2005. The Ews-ERG fusion protein can initiate neoplasia from lineage-committed haematopoietic cells. PLoS Biol 3:e242.
Collini, P., Sampietro, G., Bertulli, R., Casali, P. G., Luksch, R., Mezzelani, A., Sozzi, G. and Pilotti, S., 2001. Cytokeratin immunoreactivity in 41 cases of ES/PNET confirmed by molecular diagnostic studies. Am J Surg Pathol 25:273–274.
de Alava, E., Kawai, A., Healey, J. H., Fligman, I., Meyers, P. A., Huvos, A. G., Gerald, W. L., Jhanwar, S. C., Argani, P., Antonescu, C. R., Pardo-Mindan, F. J., Ginsberg, J., Womer, R., Lawlor, E. R., Wunder, J., Andrulis, I., Sorensen, P. H., Barr, F. G. and Ladanyi, M., 1998. EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 16:1248–1255.
Deneen, B. and Denny, C. T., 2001. Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation. Oncogene 20:6731–6741.
Deneen, B., Hamidi, H. and Denny, C. T., 2003. Functional analysis of the EWS/ETS target gene uridine phosphorylase. Cancer Res 63:4268–4274.
Denzin, L. K., Whitlow, M. and Voss, E. W., Jr., 1991. Single-chain site-specific mutations of fluorescein-amino acid contact residues in high affinity monoclonal antibody 4-4-20. J Biol Chem 266:14095–14103.
Dobson, C. L., Warren, A. J., Pannell, R., Forster, A., Lavenir, I., Corral, J., Smith, A. J. and Rabbitts, T. H., 1999. The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. EMBO J 18:3564–3574.
Dohjima, T., Lee, N. S., Li, H., Ohno, T. and Rossi, J. J., 2003. Small interfering RNAs expressed from a Pol III promoter suppress the EWS/Fli-1 transcript in an Ewing sarcoma cell line. Mol Ther 7:811–816.
Doolittle, R. F., Hunkapiller, M. W., Hood, L. E., Devare, S. G., Robbins, K. C., Aaronson, S. A. and Antoniades, H. N., 1983. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221(4607):275–277.
DuBois, S. G., Krailo, M. D., Lessnick, S. L., Smith, R., Chen, Z., Marina, N., Grier, H. E. and Stegmaier, K., 2009. Phase II study of intermediate-dose cytarabine in patients with relapsed or refractory Ewing sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 52:324–327.
Duiker, E. W., Mom, C. H., de Jong, S., Willemse, P. H., Gietema, J. A., van der Zee, A. G. and de Vries, E. G., 2006. The clinical trail of TRAIL. Eur J Cancer 42:2233–2240.
Dworzak, M. N., Fritsch, G., Buchinger, P., Fleischer, C., Printz, D., Zellner, A., Schollhammer, A., Steiner, G., Ambros, P. F. and Gadner, H., 1994. Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood. Blood 83:415–425.
Eliazer, S., Spencer, J., Ye, D., Olson, E. and Ilaria, R. L., Jr., 2003. Alteration of mesodermal cell differentiation by EWS/FLI-1, the oncogene implicated in Ewing’s sarcoma. Mol Cell Biol 23:482–492.
Erkizan, V., Kong, Y., Merchant, M. S., Schlottman, S., Barber, J., Abaan, O. D., Chou, T., Dakshanamurthy, S., Brown, M. L., Uren, A. and Toretsky, J., 2009. Small molecule selected to disrupt mutant transcription factor EWS-FLI1 interaction with RNA Helicase A inhibits Ewing’s Sarcoma. Nature Medicine 15(7):750–756.
Ewing, J., 1921. Diffuse endothelioma of bone. Proc N Y Pathol Soc 21:17.
Fantl, W. J., Johnson, D. E. and Williams, L. T., 1993. Signalling by receptor tyrosine kinases. Annu Rev Biochem 62:453–481.
Fellinger, E. J., Garin-Chesa, P., Triche, T. J., Huvos, A. G. and Rettig, W. J., 1991. Immunohistochemical analysis of Ewing’s sarcoma cell surface antigen p30/32MIC2. Am J Pathol 139:317–325.
Fesik, S. W., 2005. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885.
Forster, A., Pannell, R., Drynan, L. F., Codrington, R., Daser, A., Metzler, M., Lobato, M. N. and Rabbitts, T. H., 2005. The invertor knock-in conditional chromosomal translocation mimic. Nat Methods 2:27–30.
Fuchs, B., Inwards, C. Y. and Janknecht, R., 2004. Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing’s sarcoma. Clin Cancer Res 10:1344–1353.
Fuchs, B., Valenzuela, R. G., Inwards, C., Sim, F. H. and Rock, M. G., 2003. Complications in long-term survivors of Ewing sarcoma. Cancer 98:2687–2692.
Fukuma, M., Okita, H., Hata, J. and Umezawa, A., 2003. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene 22:1–9.
Gill, Z. P., Perks, C. M., Newcomb, P. V. and Holly, J. M., 1997. Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. J Biol Chem 272:25602–25607.
Girnita, L., Girnita, A., Wang, M., Meis-Kindblom, J. M., Kindblom, L. G. and Larsson, O., 2000. A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing’s sarcoma cells. Oncogene 19:4298–4301.
Grier, H. E., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., Gebhardt, M. C., Dickman, P. S., Perlman, E. J., Meyers, P. A., Donaldson, S. S., Moore, S., Rausen, A. R., Vietti, T. J. and Miser, J. S., 2003. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348:694–701.
Gu, M., Antonescu, C. R., Guiter, G., Huvos, A. G., Ladanyi, M. and Zakowski, M. F., 2000. Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol 24:410–416.
Guan, H., Zhou, Z., Wang, H., Jia, S. F., Liu, W. and Kleinerman, E. S., 2005. A small interfering RNA targeting vascular endothelial growth factor inhibits Ewing’s sarcoma growth in a xenograft mouse model. Clin Cancer Res 11:2662–2669.
Hahm, K. B., Cho, K., Lee, C., Im, Y. H., Chang, J., Choi, S. G., Sorensen, P. H., Thiele, C. J. and Kim, S. J., 1999. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet 23:222–227.
Haldar, M., Hancock, J. D., Coffin, C. M., Lessnick, S. L. and Capecchi, M. R., 2007. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell 11:375–388.
Hamilton, G., Havel, M. and Mallinger, R., 1989. Expression of a new human THY-1 related antigen in Ewing’s sarcoma and peripheral neuroectodermal tumors. Immunol Lett 22:205–209.
Hamilton, G., Mallinger, R. and Havel, M., 1989. Ewing’s-sarcoma-associated HBA-71 tumor antigen represents a new differentiation marker of human thymocytes. J Cancer Res Clin Oncol 115:592–596.
Hamilton, G., Mallinger, R., Hofbauer, S. and Havel, M., 1991. The monoclonal HBA-71 antibody modulates proliferation of thymocytes and Ewing’s sarcoma cells by interfering with the action of insulin-like growth factor I. Thymus 18:33–41.
Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J. and Yonezawa, K., 2002. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189.
Hara, K., Yonezawa, K., Weng, Q. P., Kozlowski, M. T., Belham, C. and Avruch, J., 1998. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273:14484–14494.
Heinrich, M. C., Blanke, C. D., Druker, B. J. and Corless, C. L., 2002. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703.
Heldin, C. H., Johnsson, A., Wennergren, S., Wernstedt, C., Betsholtz, C. and Westermark, B., 1986. A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. Nature 319:511–514.
Helman, L. J. and Meltzer, P., 2003. Mechanisms of sarcoma development. Nat Rev Cancer 3:685–694.
Hofbauer, S., Hamilton, G., Theyer, G., Wollmann, K. and Gabor, F., 1993. Insulin-like growth factor-I-dependent growth and in vitro chemosensitivity of Ewing’s sarcoma and peripheral primitive neuroectodermal tumour cell lines. Eur J Cancer 29A:241–245.
Hu-Lieskovan, S., Heidel, J. D., Bartlett, D. W., Davis, M. E. and Triche, T. J., 2005. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res 65:8984–8992.
Huang, H. Y., Illei, P. B., Zhao, Z., Mazumdar, M., Huvos, A. G., Healey, J. H., Wexler, L. H., Gorlick, R., Meyers, P. and Ladanyi, M., 2005. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol 23:548–558.
Jaboin, J., Wild, J., Hamidi, H., Khanna, C., Kim, C. J., Robey, R., Bates, S. E. and Thiele, C. J., 2002. MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res 62:6108–6115.
Jia, S. F., Zhou, R. R. and Kleinerman, E. S., 2003. Nude mouse lung metastases models of osteosarcoma and Ewing’s sarcoma for evaluating new therapeutic strategies. Methods Mol Med 74:495–505.
Kang, H. G., Jenabi, J. M., Zhang, J., Keshelava, N., Shimada, H., May, W. A., Ng, T., Reynolds, C. P., Triche, T. J. and Sorensen, P. H., 2007. E-cadherin cell-cell adhesion in Ewing tumor cells mediates suppression of anoikis through activation of the ErbB4 tyrosine kinase. Cancer Res 67:3094–3105.
Karnieli, E., Werner, H., Rauscher, F. J., III, Benjamin, L. E. and LeRoith, D., 1996. The IGF-I receptor gene promoter is a molecular target for the Ewing’s sarcoma-Wilms’ tumor 1 fusion protein. J Biol Chem 271:19304–19309
Keller, C., Arenkiel, B. R., Coffin, C. M., El-Bardeesy, N., DePinho, R. A. and Capecchi, M. R., 2004. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev 18:2614–2626.
Khan, J., Wei, J. S., Ringner, M., Saal, L. H., Ladanyi, M., Westermann, F., Berthold, F., Schwab, M., Antonescu, C. R., Peterson, C. and Meltzer, P. S., 2001. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7:673–679.
Kikuchi, R., Murakami, M., Sobue, S., Iwasaki, T., Hagiwara, K., Takagi, A., Kojima, T., Asano, H., Suzuki, M., Banno, Y., Nozawa, Y. and Murate, T., 2007. Ewing’s sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter. Oncogene 26:1802–1810.
Kim, S., Denny, C. T. and Wisdom, R., 2006. Cooperative DNA binding with AP-1 proteins is required for transformation by EWS-Ets fusion proteins. Mol Cell Biol 26:2467–2478.
Kinsey, M., Smith, R. and Lessnick, S. L., 2006. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing’s sarcoma. Mol Cancer Res 4:851–859.
Knoop, L. L. and Baker, S. J., 2000. The splicing factor U1C represses EWS/FLI-mediated transactivation. J Biol Chem 275:24865–24871.
Knoop, L. L. and Baker, S. J., 2001. EWS/FLI alters 5′-splice site selection. J Biol Chem 276:22317–22322.
Kontny, H. U., Hammerle, K., Klein, R., Shayan, P., Mackall, C. L. and Niemeyer, C. M., 2001. Sensitivity of Ewing’s sarcoma to TRAIL-induced apoptosis. Cell Death Differ 8:506–514.
Kontny, H. U., Lehrnbecher, T. M., Chanock, S. J. and Mackall, C. L., 1998. Simultaneous expression of Fas and nonfunctional Fas ligand in Ewing’s sarcoma. Cancer Res 58:5842–5849.
Kovar, H., Aryee, D. N., Jug, G., Henockl, C., Schemper, M., Delattre, O., Thomas, G. and Gadner, H., 1996. EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. Cell Growth Differ 7:429–437.
Kovar, H., Ban, J. and Pospisilova, S., 2003. Potentials for RNAi in sarcoma research and therapy: Ewing’s sarcoma as a model. Semin Cancer Biol 13:275–281.
Kreppel, M., Aryee, D. N., Schaefer, K. L., Amann, G., Kofler, R., Poremba, C. and Kovar, H., 2006. Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing’s sarcoma cells. Oncogene 25:2795–2800.
Lambert, G., Bertrand, J. R., Fattal, E., Subra, F., Pinto-Alphandary, H., Malvy, C., Auclair, C. and Couvreur, P., 2000. EWS fli-1 antisense nanocapsules inhibits Ewing sarcoma-related tumor in mice. Biochem Biophys Res Commun 279:401–406.
LaRochelle, W. J., Jensen, R. A., Heidaran, M. A., May-Siroff, M., Wang, L. M., Aaronson, S. A. and Pierce, J. H., 1993. Inhibition of platelet-derived growth factor autocrine growth stimulation by a monoclonal antibody to the human alpha platelet-derived growth factor receptor. Cell Growth Differ 4:547–553.
Lawlor, E. R., Scheel, C., Irving, J. and Sorensen, P. H., 2002. Anchorage-independent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors. Oncogene 21:307–318.
Lee, T. H., Bolontrade, M. F., Worth, L. L., Guan, H., Ellis, L. M. and Kleinerman, E. S., 2006. Production of VEGF165 by Ewing’s sarcoma cells induces vasculogenesis and the incorporation of CD34+ stem cells into the expanding tumor vasculature. Int J Cancer 119:839–846.
Lessnick, S. L., Dacwag, C. S. and Golub, T. R., 2002. The Ewing’s sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts. Cancer Cell 1:393–401.
Li, R., Pei, H. and Watson, D. K., 2000. Regulation of Ets function by protein–protein interactions. Oncogene 19:6514–6523.
Li, X., Ponten, A., Aase, K., Karlsson, L., Abramsson, A., Uutela, M., Backstrom, G., Hellstrom, M., Bostrom, H., Li, H., Soriano, P., Betsholtz, C., Heldin, C. H., Alitalo, K., Ostman, A. and Eriksson, U., 2000. PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol 2:302–309.
Lin, P. P., Pandey, M. K., Jin, F., Xiong, S., Deavers, M., Parant, J. M. and Lozano, G., 2008. EWS-FLI1 induces developmental abnormalities and accelerates sarcoma formation in a transgenic mouse model. Cancer Res 68:8968–8975.
Lipinski, M., Braham, K., Philip, I., Wiels, J., Philip, T., Goridis, C., Lenoir, G. M. and Tursz, T., 1987. Neuroectoderm-associated antigens on Ewing’s sarcoma cell lines. Cancer Res 47:183–187.
Lissat, A., Vraetz, T., Tsokos, M., Klein, R., Braun, M., Koutelia, N., Fisch, P., Romero, M. E., Long, L., Noellke, P., Mackall, C. L., Niemeyer, C. M. and Kontny, U., 2007. Interferon-gamma sensitizes resistant Ewing’s sarcoma cells to tumor necrosis factor apoptosis-inducing ligand-induced apoptosis by up-regulation of caspase-8 without altering chemosensitivity. Am J Pathol 170:1917–1930.
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J. and Haber, D. A., 2004. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139.
Maksimenko, A., Lambert, G., Bertrand, J. R., Fattal, E., Couvreur, P. and Malvy, C., 2003. Therapeutic potentialities of EWS-Fli-1 mRNA-targeted vectorized antisense oligonucleotides. Ann N Y Acad Sci 1002:72–77.
Maksimenko, A., Malvy, C., Lambert, G., Bertrand, J. R., Fattal, E., Maccario, J. and Couvreur, P., 2003. Oligonucleotides targeted against a junction oncogene are made efficient by nanotechnologies. Pharm Res 20:1565–1567.
Mateo-Lozano, S., Gokhale, P. C., Soldatenkov, V. A., Dritschilo, A., Tirado, O. M. and Notario, V., 2006. Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing’s sarcoma. Clin Cancer Res 12:6781–6790.
Matsunobu, T., Tanaka, K., Matsumoto, Y., Nakatani, F., Sakimura, R., Hanada, M., Li, X., Oda, Y., Naruse, I., Hoshino, H., Tsuneyoshi, M., Miura, H. and Iwamoto, Y., 2004. The prognostic and therapeutic relevance of p27kip1 in Ewing’s family tumors. Clin Cancer Res 10:1003–1012.
May, W. A., Lessnick, S. L., Braun, B. S., Klemsz, M., Lewis, B. C., Lunsford, L. B., Hromas, R. and Denny, C. T., 1993. The Ewing’s sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol Cell Biol 13:7393–7398.
McKeon, C., Thiele, C. J., Ross, R. A., Kwan, M., Triche, T. J., Miser, J. S. and Israel, M. A., 1988. Indistinguishable patterns of protooncogene expression in two distinct but closely related tumors: Ewing’s sarcoma and neuroepithelioma. Cancer Res 48:4307–4311.
Mendiola, M., Carrillo, J., Garcia, E., Lalli, E., Hernandez, T., de Alava, E., Tirode, F., Delattre, O., Garcia-Miguel, P., Lopez-Barea, F., Pestana, A. and Alonso, J., 2006. The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer 118:1381–1389.
Merchant, M. S., Woo, C. W., Mackall, C. L. and Thiele, C. J., 2002. Potential use of imatinib in Ewing’s sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst 94:1673–1679.
Merchant, M. S., Yang, X., Melchionda, F., Romero, M., Klein, R., Thiele, C. J., Tsokos, M., Kontny, H. U. and Mackall, C. L., 2004. Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing’s sarcoma. Cancer Res 64:8349–8356.
Nakajima, T., Uchida, C., Anderson, S. F., Lee, C. G., Hurwitz, J., Parvin, J. D. and Montminy, M., 1997. RNA helicase A mediates association of CBP with RNA polymerase II. Cell 90:1107–1112.
Nakatani, F., Tanaka, K., Sakimura, R., Matsumoto, Y., Matsunobu, T., Li, X., Hanada, M., Okada, T. and Iwamoto, Y., 2003. Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein. J Biol Chem 278:15105–15115.
Ng, K. P., Potikyan, G., Savene, R. O., Denny, C. T., Uversky, V. N. and Lee, K. A., 2007. Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins. Proc Natl Acad Sci U S A 104:479–484.
Nishimori, H., Sasaki, Y., Yoshida, K., Irifune, H., Zembutsu, H., Tanaka, T., Aoyama, T., Hosaka, T., Kawaguchi, S., Wada, T., Hata, J., Toguchida, J., Nakamura, Y. and Tokino, T., 2002. The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors. Oncogene 21:8302–8309.
Noguera, R., Triche, T. J., Navarro, S., Tsokos, M. and Llombart, B. A., 1992. Dynamic model of differentiation in Ewing’s sarcoma cells. Comparative analysis of morphologic, immunocytochemical, and oncogene expression parameters [see comments]. Lab Invest 66:143–151.
Ostman, A. and Heldin, C. H., 2001. Involvement of platelet-derived growth factor in disease: development of specific antagonists. Adv Cancer Res 80:1–38.
Ouchida, M., Ohno, T., Fujimura, Y., Rao, V. N. and Reddy, E. S., 1995. Loss of tumorigenicity of Ewing’s sarcoma cells expressing antisense RNA to EWS-fusion transcripts. Oncogene 11:1049–1054.
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., Mardis, E., Kupfer, D., Wilson, R., Kris, M. and Varmus, H., 2004. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–13311.
Petermann, R., Mossier, B. M., Aryee, D. N., Khazak, V., Golemis, E. A. and Kovar, H., 1998. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Oncogene 17:603–610.
Potikyan, G., Savene, R. O., Gaulden, J. M., France, K. A., Zhou, Z., Kleinerman, E. S., Lessnick, S. L. and Denny, C. T., 2007. EWS/FLI1 regulates tumor angiogenesis in Ewing’s sarcoma via suppression of thrombospondins. Cancer Res 67:6675–6684.
Prieur, A., Tirode, F., Cohen, P. and Delattre, O., 2004. 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 24:7275–7283.
Rajah, R., Valentinis, B. and Cohen, P., 1997. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. J Biol Chem 272:12181–12188.
Reya, T., Morrison, S. J., Clarke, M. F. and Weissman, I. L., 2001. Stem cells, cancer, and cancer stem cells. Nature 414:105–111.
Riggi, N., Cironi, L., Provero, P., Suva, M. L., Kaloulis, K., Garcia-Echeverria, C., Hoffmann, F., Trumpp, A. and Stamenkovic, I., 2005. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res 65:11459–11468.
Ronnstrand, L., 2004. Signal transduction via the stem cell factor receptor/c-Kit. Cell Mol Life Sci 61:2535–2548.
Rorie, C. J., Thomas, V. D., Chen, P., Pierce, H. H., O’Bryan, J. P. and Weissman, B. E., 2004. The Ews/Fli-1 fusion gene switches the differentiation program of neuroblastomas to Ewing sarcoma/peripheral primitive neuroectodermal tumors. Cancer Res 64:1266–1277.
Sakimura, R., Tanaka, K., Nakatani, F., Matsunobu, T., Li, X., Hanada, M., Okada, T., Nakamura, T., Matsumoto, Y. and Iwamoto, Y., 2005. Antitumor effects of histone deacetylase inhibitor on Ewing’s family tumors. Int J Cancer 116:784–792.
Saylors, R. L., III, Stine, K. C., Sullivan, J., Kepner, J. L., Wall, D. A., Bernstein, M. L., Harris, M. B., Hayashi, R. and Vietti, T. J., 2001. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19:3463–3469.
Schuetz, A. N., Rubin, B. P., Goldblum, J. R., Shehata, B., Weiss, S. W., Liu, W., Wick, M. R. and Folpe, A. L., 2005. Intercellular junctions in Ewing sarcoma/primitive neuroectodermal tumor: additional evidence of epithelial differentiation. Mod Pathol 18:1403–1410.
Schweigerer, L., Neufeld, G. and Gospodarowicz, D., 1987. Basic fibroblast growth factor as a growth inhibitor for cultured human tumor cells. J Clin Invest 80:1516–1520.
Scotlandi, K., Benini, S., Nanni, P., Lollini, P. L., Nicoletti, G., Landuzzi, L., Serra, M., Manara, M. C., Picci, P. and Baldini, N., 1998. Blockage of insulin-like growth factor-I receptor inhibits the growth of Ewing’s sarcoma in athymic mice. Cancer Res 58:4127–4131.
Scotlandi, K., Manara, M. C., Nicoletti, G., Lollini, P. L., Lukas, S., Benini, S., Croci, S., Perdichizzi, S., Zambelli, D., Serra, M., Garcia-Echeverria, C., Hofmann, F. and Picci, P., 2005. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res 65:3868–3876.
Scotlandi, K., Perdichizzi, S., Bernard, G., Nicoletti, G., Nanni, P., Lollini, P. L., Curti, A., Manara, M. C., Benini, S., Bernard, A. and Picci, P., 2006. Targeting CD99 in association with doxorubicin: an effective combined treatment for Ewing’s sarcoma. Eur J Cancer 42:91–96.
Scotlandi, K., Perdichizzi, S., Manara, M. C., Serra, M., Benini, S., Cerisano, V., Strammiello, R., Mercuri, M., Reverter-Branchat, G., Faircloth, G., D’Incalci, M. and Picci, P., 2002. Effectiveness of Ecteinascidin-743 against drug-sensitive and -resistant bone tumor cells. Clin Cancer Res 8:3893–3903.
Siligan, C., Ban, J., Bachmaier, R., Spahn, L., Kreppel, M., Schaefer, K. L., Poremba, C., Aryee, D. N. and Kovar, H., 2005. EWS-FLI1 target genes recovered from Ewing’s sarcoma chromatin. Oncogene 24:2512–2524.
Singleton, J. R., Dixit, V. M. and Feldman, E. L., 1996. Type I insulin-like growth factor receptor activation regulates apoptotic proteins. J Biol Chem 271:31791–31794.
Smith, R., Owen, L. A., Trem, D. J., Wong, J. S., Whangbo, J. S., Golub, T. R. and Lessnick, S. L., 2006. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell 9:405–416.
Spahn, L., Siligan, C., Bachmaier, R., Schmid, J. A., Aryee, D. N. and Kovar, H., 2003. Homotypic and heterotypic interactions of EWS, FLI1 and their oncogenic fusion protein. Oncogene 22:6819–6829.
Staege, M. S., Hutter, C., Neumann, I., Foja, S., Hattenhorst, U. E., Hansen, G., Afar, D. and Burdach, S. E., 2004. DNA microarrays reveal relationship of Ewing family tumors to both endothelial and fetal neural crest-derived cells and define novel targets. Cancer Res 64:8213–8221.
Stegmaier, K., Wong, J. S., Ross, K. N., Chow, K. T., Peck, D., Wright, R. D., Lessnick, S. L., Kung, A. L. and Golub, T. R., 2007. Signature-based small molecule screening identifies cytosine arabinoside as an EWS/FLI modulator in Ewing sarcoma. PLoS Med 4:e122.
Takeda, K., Stagg, J., Yagita, H., Okumura, K. and Smyth, M. J., 2007. Targeting death-inducing receptors in cancer therapy. Oncogene 26:3745–3757.
Tamborini, E., Bonadiman, L., Albertini, V., Pierotti, M. A. and Pilotti, S., 2003. Re: Potential use of imatinib in Ewing’s sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst 95:1087–1088; author reply 1088–1089
Tanaka, K., Iwakuma, T., Harimaya, K., Sato, H. and Iwamoto, Y., 1997. EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing’s sarcoma and primitive neuroectodermal tumor cells. J Clin Invest 99:239–247.
Tanaka, S., Ito, T. and Wands, J. R., 1996. Neoplastic transformation induced by insulin receptor substrate-1 overexpression requires an interaction with both Grb2 and Syp signaling molecules. J Biol Chem 271:14610–14616.
Tang, H. and Wong-Staal, F., 2000. Specific interaction between RNA helicase A and Tap, two cellular proteins that bind to the constitutive transport element of type D retrovirus. J Biol Chem 275:32694–32700.
Tirado, O. M., Mateo-Lozano, S., Villar, J., Dettin, L. E., Llort, A., Gallego, S., Ban, J., Kovar, H. and Notario, V., 2006. Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing’s sarcoma cells. Cancer Res 66:9937–9947.
Tirode, F., Laud-Duval, K., Prieur, A., Delorme, B., Charbord, P. and Delattre, O., 2007. Mesenchymal stem cell features of Ewing tumors. Cancer Cell 11:421–429.
Torchia, E. C., Boyd, K., Rehg, J. E., Qu, C. and Baker, S. J., 2007. EWS/FLI-1 induces rapid onset of myeloid/erythroid leukemia in mice. Mol Cell Biol 27:7918–7934.
Torchia, E. C., Jaishankar, S. and Baker, S. J., 2003. Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res 63:3464–3468.
Toretsky, J. A., 2003. Ewing sarcoma and primitive neuroectodermal tumors. January 17, 2003. http://www.emedicine.com/ped/topic2589.htm
Toretsky, J. A., Connell, Y., Neckers, L. and Bhat, N. K., 1997. Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides. J Neurooncol 31:9–16.
Toretsky, J. A., Erkizan, V., Levenson, A., Abaan, O. D., Parvin, J. D., Cripe, T. P., Rice, A. M., Lee, S. B. and Uren, A., 2006. Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase A. Cancer Res 66:5574–5581.
Toretsky, J. A., Kalebic, T., Blakesley, V., LeRoith, D. and Helman, L. J., 1997. The insulin-like growth factor-I receptor is required for EWS/FLI-1 transformation of fibroblasts. J Biol Chem 272:30822–30827.
Toretsky, J. A., Steinberg, S. M., Thakar, M., Counts, D., Pironis, B., Parente, C., Eskenazi, A., Helman, L. and Wexler, L. H., 2001. Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors. Cancer 92:2941–2947.
Toretsky, J. A., Thakar, M., Eskenazi, A. E. and Frantz, C. N., 1999. Phosphoinositide 3-hydroxide kinase blockade enhances apoptosis in the Ewing’s sarcoma family of tumors. Cancer Res 59:5745–5750.
Turc-Carel, C., Philip, I., Berger, M.-P., Philip, T. and Lenoir, G. M., 1984. Chromosome study of Ewing’s sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12). Cancer Genet Cytogenet 12:1–19.
Uren, A., Merchant, M. S., Sun, C. J., Vitolo, M. I., Sun, Y., Tsokos, M., Illei, P. B., Ladanyi, M., Passaniti, A., Mackall, C. and Toretsky, J. A., 2003. Beta-platelet-derived growth factor receptor mediates motility and growth of Ewing’s sarcoma cells. Oncogene 22:2334–2342.
Uren, A., Tcherkasskaya, O. and Toretsky, J. A., 2004. Recombinant EWS-FLI1 oncoprotein activates transcription. Biochemistry 43:13579–13589.
Uren, A., Wolf, V., Sun, Y. F., Azari, A., Rubin, J. S. and Toretsky, J. A., 2004. Wnt/Frizzled signaling in Ewing sarcoma. Pediatr Blood Cancer 43:243–249.
Valentinis, B. and Baserga, R., 1996. The IGF-I receptor protects tumor cells from apoptosis induced by high concentrations of serum. Biochem Biophys Res Commun 224:362–368.
van Valen, F., Winkelmann, W. and Jurgens, H., 1992. Type I and type II insulin-like growth factor receptors and their function in human Ewing’s sarcoma cells. J Cancer Res Clin Oncol 118:269–275.
Vormoor, J., Baersch, G., Decker, S., Hotfilder, M., Schafer, K. L., Pelken, L., Rube, C., van Valen, F., Jurgens, H. and Dockhorn-Dworniczak, B., 2001. Establishment of an in vivo model for pediatric Ewing tumors by transplantation into NOD/scid mice. Pediatr Res 49:332–341.
Wagner, L. M., McAllister, N., Goldsby, R. E., Rausen, A. R., McNall-Knapp, R. Y., McCarville, M. B. and Albritton, K., 2007. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer 48:132–139.
Waterfield, M. D., Scrace, G. T., Whittle, N., Stroobant, P., Johnsson, A., Wasteson, A., Westemark, B., Heldin, C.-H., Huang, J. S. and Deuel, T. F., 1983. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 304:35–39.
Watson, D. K., Robinson, L., Hodge, D. R., Kola, I., Papas, T. S. and Seth, A., 1997. FLI1 and EWS-FLI1 function as ternary complex factors and ELK1 and SAP1a function as ternary and quaternary complex factors on the Egr1 promoter serum response elements. Oncogene 14:213–221.
Weidner, N. and Tjoe, J., 1994. Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing’s sarcoma and peripheral neuroepithelioma. Am J Surg Pathol 18:486–494.
Welford, S. M., Hebert, S. P., Deneen, B., Arvand, A. and Denny, C. T., 2001. DNA binding domain-independent pathways are involved in EWS/FLI1-mediated oncogenesis. J Biol Chem 276:41977–41984.
Westwood, G., Dibling, B. C., Cuthbert-Heavens, D. and Burchill, S. A., 2002. Basic fibroblast growth factor (bFGF)-induced cell death is mediated through a caspase-dependent and p53-independent cell death receptor pathway. Oncogene 21:809–824.
Whang-Peng, J., Triche, T. J., Knutsen, T., Miser, J., Douglass, E. C. and Israel, M. A., 1984. Chromosome translocation in peripheral neuroepithelioma. N Engl J Med 311:584–585.
Whitesell, L., Shifrin, S. D., Schwab, G. and Neckers, L. M., 1992. Benzoquinonoid ansamycins possess selective tumoricidal activity unrelated to src kinase inhibition. Cancer Res 52:1721–1728.
Williams, L. T., 1989. Signal transduction by the platelet-derived growth factor receptor. Science 243:1564–1570.
Williamson, A. J., Dibling, B. C., Boyne, J. R., Selby, P. and Burchill, S. A., 2004. Basic fibroblast growth factor (bFGF)-induced cell death is effected through sustained activation of p38MAPK and up-regulation of the death receptor p75NTR. J Biol Chem 279(46):47912–47928
Yang, L., Chansky, H. A. and Hickstein, D. D., 2000. EWS/Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J Biol Chem 275:37612–37618.
Yee, D., Favoni, R. E., Lebovic, G. S., Lombana, F., Powell, D. R., Reynolds, C. P. and Rosen, N., 1990. Insulin-like growth factor I expression by tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. A potential autocrine growth factor. J Clin Invest 86:1806–1814.
Yin, X., Giap, C., Lazo, J. S. and Prochownik, E. V., 2003. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 22:6151–6159.
Zoubek, A., Dockhorn-Dworniczak, B., Delattre, O., Christiansen, H., Niggli, F., Gatterer-Menz, I., Smith, T. L., Jurgens, H., Gadner, H. and Kovar, H., 1996. Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? J Clin Oncol 14:1245–1251.
Zwerner, J. P., Guimbellot, J. and May, W. A., 2003. EWS/FLI function varies in different cellular backgrounds. Exp Cell Res 290:414–419.
Zwerner, J. P., Joo, J., Warner, K. L., Christensen, L., Hu-Lieskovan, S., Triche, T. J. and May, W. A., 2008. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene 27:3282–3291.
Zwerner, J. P. and May, W. A., 2001. PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors. Oncogene 20:626–633.
Zwerner, J. P. and May, W. A., 2002. Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines. Oncogene 21:3847–3854.
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Toretsky, J.A., Üren, A. (2010). Ewing’s Sarcoma Family of Tumors: Molecular Targets Need Arrows. In: Houghton, P., Arceci, R. (eds) Molecularly Targeted Therapy for Childhood Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69062-9_18
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