Notch Signaling in Pediatric Soft Tissue Sarcoma

  • Cristina Cossetti
  • Alberto Gualtieri
  • Silvia Pomella
  • Elena Carcarino
  • Rossella RotaEmail author


Etiology, biology, response to treatment, and outcome greatly differ between adult and childhood cancers. Soft tissue sarcoma encompasses a heterogeneous group of pediatric sarcomas characterized by a high capacity to invade neighboring tissues. Although in the last years the overall survival in childhood cancers has improved to over 70% for the nonmetastatic forms, subgroups of young patients with metastatic and aggressive disease still show a poor outcome. Moreover, survivors often suffer from long-term morbidity due to the effects of therapy. It is widely accepted that soft tissue sarcomas of childhood develop from mesenchymal progenitor cells affected by chromosomal aberrations and mutations in genetic and epigenetic pathways during development. Therefore, pathways driving tissue differentiation are particularly relevant. Among these, the Notch signaling pathway plays one of the major roles. Notch signaling is evolutionarily conserved among species, working as a cell-to-cell communication system strictly defining cell fate, stem cell renewal, and tissue homeostasis during embryo development and in postnatal life. In the present chapter, we describe recent insights on Notch deregulation in the most prominent pediatric soft tissue sarcomas: rhabdomyosarcomas, Ewing sarcomas, and synovial sarcomas. We also summarize the challenges and opportunities in inhibiting Notch signaling for the treatment of this group of tumors.


Notch signaling Notch receptors Gamma-secretase Soft tissue sarcoma Rhabdomyosarcoma Ewing sarcoma Synovial sarcoma 


DLL1, 3, 4

Delta-like 1, 3, 4


Ewing sarcoma


Genetically engineered mice models


Gamma secretase inhibitors


Mastermind-like 1


Notch extracellular domain


Notch extracellular truncation


Notch intracellular domain


Notch transmembrane domain




Synovial sarcoma



This work was financially supported by the Italian Association for Cancer Research (AIRC IG 15312).

Conflict of Interest/Disclosures

No conflict of interest


  1. 1.
    Visweswaran, M., Pohl, S., Arfuso, F., Newsholme, P., Dilley, R., Pervaiz, S., et al. (2015). Multi-lineage differentiation of mesenchymal stem cells – To Wnt, or not Wnt. The International Journal of Biochemistry & Cell Biology, 68, 139–147.CrossRefGoogle Scholar
  2. 2.
    Happe, C. L., & Engler, A. J. (2016). Mechanical forces reshape differentiation cues that guide cardiomyogenesis. Circulation Research, 118(2), 296–310.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Briscoe, J., & Small, S. (2015). Morphogen rules: Design principles of gradient-mediated embryo patterning. Development, 142(23), 3996–4009.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Luo, S. X., & Huang, E. J. (2015). Dopaminergic neurons and brain reward pathways: From neurogenesis to circuit assembly. The American Journal of Pathology, 186(3), 478–488.PubMedCrossRefGoogle Scholar
  5. 5.
    Li, X. Y., Zhai, W. J., & Teng, C. B. (2015). Notch signaling in pancreatic development. International Journal of Molecular Sciences, 17(1), 48.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Luxan, G., D’Amato, G., MacGrogan, D., & de la Pompa, J. L. (2016). Endocardial Notch signaling in cardiac development and disease. Circulation Research, 118(1), e1–e18.Google Scholar
  7. 7.
    Krantz, I. D., Colliton, R. P., Genin, A., Rand, E. B., Li, L., Piccoli, D. A., et al. (1998). Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. American Journal of Human Genetics, 62(6), 1361–1369.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    McDaniell, R., Warthen, D. M., Sanchez-Lara, P. A., Pai, A., Krantz, I. D., Piccoli, D. A., et al. (2006). NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. American Journal of Human Genetics, 79(1), 169–173.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Federico, A., Bianchi, S., & Dotti, M. T. (2005). The spectrum of mutations for CADASIL diagnosis. Neurological Sciences, 26(2), 117–124.PubMedCrossRefGoogle Scholar
  10. 10.
    Sparrow, D. B., Chapman, G., Wouters, M. A., Whittock, N. V., Ellard, S., Fatkin, D., et al. (2006). Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. American Journal of Human Genetics, 78(1), 28–37.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Lee, S. J., Kim, K. H., Pak, S. C., Kang, Y. N., Yoon, G. S., & Park, K. K. (2015). Notch signaling affects biliary fibrosis via transcriptional regulation of RBP-jkappa in an animal model of chronic liver disease. International Journal of Clinical and Experimental Pathology, 8(10), 12688–12697.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Bansal, R., van Baarlen, J., Storm, G., & Prakash, J. (2015). The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Scientific Reports, 5, 18272.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Vieira, N. M., Elvers, I., Alexander, M. S., Moreira, Y. B., Eran, A., Gomes, J. P., et al. (2015). Jagged 1 rescues the duchenne muscular dystrophy phenotype. Cell, 163(5), 1204–1213.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Lafkas, D., Shelton, A., Chiu, C., de Leon Boenig, G., Chen, Y., Stawicki, S. S., et al. (2015). Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature, 528(7580), 127–131.PubMedGoogle Scholar
  15. 15.
    Hu, B., Wu, Z., Bai, D., Liu, T., Ullenbruch, M. R., & Phan, S. H. (2015). Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. The American Journal of Pathology, 185(11), 3066–3075.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Louvi, A., & Artavanis-Tsakonas, S. (2012). Notch and disease: A growing field. Seminars in Cell & Developmental Biology, 23(4), 473–480.CrossRefGoogle Scholar
  17. 17.
    Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., et al. (1991). TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell, 66(4), 649–661.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Pear, W. S., Aster, J. C., Scott, M. L., Hasserjian, R. P., Soffer, B., Sklar, J., et al. (1996). Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. The Journal of Experimental Medicine, 183(5), 2283–2291.PubMedCrossRefGoogle Scholar
  19. 19.
    Weng, A. P., Ferrando, A. A., Lee, W., JPt, M., Silverman, L. B., Sanchez-Irizarry, C., et al. (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306(5694), 269–271.PubMedCrossRefGoogle Scholar
  20. 20.
    Bovee, J. V., & Hogendoorn, P. C. (2010). Molecular pathology of sarcomas: Concepts and clinical implications. Virchows Archiv, 456(2), 193–199.PubMedCrossRefGoogle Scholar
  21. 21.
    Grunewald, T. G., & Fulda, S. (2016). Editorial: Biology-driven targeted therapy of pediatric soft-tissue and bone tumors: Current opportunities and future challenges. Frontiers in Oncology, 6, 39.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Thacker, M. M. (2013). Malignant soft tissue tumors in children. The Orthopedic Clinics of North America, 44(4), 657–667.PubMedCrossRefGoogle Scholar
  23. 23.
    Walter, D., Satheesha, S., Albrecht, P., Bornhauser, B. C., D’Alessandro, V., Oesch, S. M., et al. (2011). CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres. PLoS One, 6(5), e19506.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    De Vito, C., Riggi, N., Cornaz, S., Suva, M. L., Baumer, K., Provero, P., et al. (2012). A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell, 21(6), 807–821.PubMedCrossRefGoogle Scholar
  25. 25.
    Espinoza, I., & Miele, L. (2013). Notch inhibitors for cancer treatment. Pharmacology & Therapeutics, 139(2), 95–110.CrossRefGoogle Scholar
  26. 26.
    Teodorczyk, M., & Schmidt, M. H. (2015). Notching on cancer’s door: Notch signaling in brain tumors. Frontiers in Oncology, 4, 341.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Dominguez, M. (2014). Oncogenic programmes and Notch activity: An ‘organized crime’? Seminars in Cell & Developmental Biology, 28, 78–85.CrossRefGoogle Scholar
  28. 28.
    Lardelli, M., Williams, R., & Lendahl, U. (1995). Notch-related genes in animal development. The International Journal of Developmental Biology, 39(5), 769–780.PubMedGoogle Scholar
  29. 29.
    Blaumueller, C. M., Qi, H., Zagouras, P., & Artavanis-Tsakonas, S. (1997). Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane. Cell, 90(2), 281–291.PubMedCrossRefGoogle Scholar
  30. 30.
    Hori, K., Sen, A., & Artavanis-Tsakonas, S. (2013). Notch signaling at a glance. Journal of Cell Science, 126(Pt 10), 2135–2140.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Rebay, I., Fleming, R. J., Fehon, R. G., Cherbas, L., Cherbas, P., & Artavanis-Tsakonas, S. (1991). Specific EGF repeats of Notch mediate interactions with Delta and Serrate: Implications for Notch as a multifunctional receptor. Cell, 67(4), 687–699.CrossRefGoogle Scholar
  32. 32.
    del Amo, F. F., Gendron-Maguire, M., Swiatek, P. J., Jenkins, N. A., NG, C., & Gridley, T. (1993). Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics, 15(2), 259–264.PubMedCrossRefGoogle Scholar
  33. 33.
    Weinmaster, G., Roberts, V. J., & Lemke, G. (1992). Notch2: A second mammalian Notch gene. Development, 116(4), 931–941.PubMedGoogle Scholar
  34. 34.
    Lardelli, M., Dahlstrand, J., & Lendahl, U. (1994). The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mechanisms of Development, 46(2), 123–136.PubMedCrossRefGoogle Scholar
  35. 35.
    Uyttendaele, H., Marazzi, G., Wu, G., Yan, Q., Sassoon, D., & Kitajewski, J. (1996). Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development, 122(7), 2251–2259.PubMedGoogle Scholar
  36. 36.
    Aster, J. C., Simms, W. B., Zavala-Ruiz, Z., Patriub, V., North, C. L., & Blacklow, S. C. (1999). The folding and structural integrity of the first LIN-12 module of human Notch1 are calcium-dependent. Biochemistry, 38(15), 4736–4742.PubMedCrossRefGoogle Scholar
  37. 37.
    Gordon, W. R., Vardar-Ulu, D., Histen, G., Sanchez-Irizarry, C., Aster, J. C., & Blacklow, S. C. (2007). Structural basis for autoinhibition of Notch. Nature Structural & Molecular Biology, 14(4), 295–300.CrossRefGoogle Scholar
  38. 38.
    Sanchez-Irizarry, C., Carpenter, A. C., Weng, A. P., Pear, W. S., Aster, J. C., & Blacklow, S. C. (2004). Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Molecular and Cellular Biology, 24(21), 9265–9273.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Tamura, K., Taniguchi, Y., Minoguchi, S., Sakai, T., Tun, T., Furukawa, T., et al. (1995). Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Current Biology, 5(12), 1416–1423.PubMedCrossRefGoogle Scholar
  40. 40.
    Lubman, O. Y., Korolev, S. V., & Kopan, R. (2004). Anchoring notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data. Molecular Cell, 13(5), 619–626.PubMedCrossRefGoogle Scholar
  41. 41.
    Nam, Y., Sliz, P., Song, L., Aster, J. C., & Blacklow, S. C. (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell, 124(5), 973–983.PubMedCrossRefGoogle Scholar
  42. 42.
    Lieber, T., Kidd, S., Alcamo, E., Corbin, V., & Young, M. W. (1993). Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes & Development, 7(10), 1949–1965.CrossRefGoogle Scholar
  43. 43.
    Kurooka, H., Kuroda, K., & Honjo, T. (1998). Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Research, 26(23), 5448–5455.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Rechsteiner, M. (1988). Regulation of enzyme levels by proteolysis: The role of pest regions. Advances in Enzyme Regulation, 27, 135–151.PubMedCrossRefGoogle Scholar
  45. 45.
    Ong, C. T., Cheng, H. T., Chang, L. W., Ohtsuka, T., Kageyama, R., Stormo, G. D., et al. (2006). Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. The Journal of Biological Chemistry, 281(8), 5106–5119.PubMedCrossRefGoogle Scholar
  46. 46.
    Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J. L., & Gossler, A. (1995). Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development, 121(8), 2407–2418.PubMedGoogle Scholar
  47. 47.
    Dunwoodie, S. L., Henrique, D., Harrison, S. M., & Beddington, R. S. (1997). Mouse Dll3: A novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development, 124(16), 3065–3076.PubMedGoogle Scholar
  48. 48.
    Shutter, J. R., Scully, S., Fan, W., Richards, W. G., Kitajewski, J., Deblandre, G. A., et al. (2000). Dll4, a novel Notch ligand expressed in arterial endothelium. Genes & Development, 14(11), 1313–1318.Google Scholar
  49. 49.
    Lindsell, C. E., Shawber, C. J., Boulter, J., & Weinmaster, G. (1995). Jagged: A mammalian ligand that activates Notch1. Cell, 80(6), 909–917.PubMedCrossRefGoogle Scholar
  50. 50.
    Shawber, C., Boulter, J., Lindsell, C. E., & Weinmaster, G. (1996). Jagged2: A serrate-like gene expressed during rat embryogenesis. Developmental Biology, 180(1), 370–376.PubMedCrossRefGoogle Scholar
  51. 51.
    Parks, A. L., Stout, J. R., Shepard, S. B., Klueg, K. M., Dos Santos, A. A., Parody, T. R., et al. (2006). Structure-function analysis of delta trafficking, receptor binding and signaling in Drosophila. Genetics, 174(4), 1947–1961.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Shimizu, K., Chiba, S., Kumano, K., Hosoya, N., Takahashi, T., Kanda, Y., et al. (1999). Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods. The Journal of Biological Chemistry, 274(46), 32961–32969.PubMedCrossRefGoogle Scholar
  53. 53.
    Schmidt, M. H., Bicker, F., Nikolic, I., Meister, J., Babuke, T., Picuric, S., et al. (2009). Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nature Cell Biology, 11(7), 873–880.PubMedCrossRefGoogle Scholar
  54. 54.
    Hu, Q. D., Ang, B. T., Karsak, M., Hu, W. P., Cui, X. Y., Duka, T., et al. (2003). F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell, 115(2), 163–175.PubMedCrossRefGoogle Scholar
  55. 55.
    Ayaz, F., & Osborne, B. A. (2014). Non-canonical notch signaling in cancer and immunity. Frontiers in Oncology, 4, 345.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    D’Souza, B., Meloty-Kapella, L., & Weinmaster, G. (2010). Canonical and non-canonical Notch ligands. Current Topics in Developmental Biology, 92, 73–129.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Guruharsha, K. G., Kankel, M. W., & Artavanis-Tsakonas, S. (2012). The Notch signalling system: Recent insights into the complexity of a conserved pathway. Nature Reviews. Genetics, 13(9), 654–666.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bruckner, K., Perez, L., Clausen, H., & Cohen, S. (2000). Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature, 406(6794), 411–415.PubMedCrossRefGoogle Scholar
  59. 59.
    Moloney, D. J., Panin, V. M., Johnston, S. H., Chen, J., Shao, L., Wilson, R., et al. (2000). Fringe is a glycosyltransferase that modifies Notch. Nature, 406(6794), 369–375.PubMedCrossRefGoogle Scholar
  60. 60.
    Moloney, D. J., Shair, L. H., Lu, F. M., Xia, J., Locke, R., Matta, K. L., et al. (2000). Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules. The Journal of Biological Chemistry, 275(13), 9604–9611.PubMedCrossRefGoogle Scholar
  61. 61.
    Okajima, T., Xu, A., & Irvine, K. D. (2003). Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe. The Journal of Biological Chemistry, 278(43), 42340–42345.PubMedCrossRefGoogle Scholar
  62. 62.
    Panin, V. M., Papayannopoulos, V., Wilson, R., & Irvine, K. D. (1997). Fringe modulates Notch-ligand interactions. Nature, 387(6636), 908–912.PubMedCrossRefGoogle Scholar
  63. 63.
    Cohen, B., Bashirullah, A., Dagnino, L., Campbell, C., Fisher, W. W., Leow, C. C., et al. (1997). Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genetics, 16(3), 283–288.PubMedCrossRefGoogle Scholar
  64. 64.
    Pakkiriswami, S., Couto, A., Nagarajan, U., & Georgiou, M. (2016). Glycosylated Notch and cancer. Frontiers in Oncology, 6, 37.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Xu, K., Usary, J., Kousis, P. C., Prat, A., Wang, D. Y., Adams, J. R., et al. (2012). Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. Cancer Cell, 21(5), 626–641.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Mukherjee, A., Veraksa, A., Bauer, A., Rosse, C., Camonis, J., & Artavanis-Tsakonas, S. (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nature Cell Biology, 7(12), 1191–1201.PubMedCrossRefGoogle Scholar
  67. 67.
    Qiu, L., Joazeiro, C., Fang, N., Wang, H. Y., Elly, C., Altman, Y., et al. (2000). Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. The Journal of Biological Chemistry, 275(46), 35734–35737.PubMedCrossRefGoogle Scholar
  68. 68.
    Sakata, T., Sakaguchi, H., Tsuda, L., Higashitani, A., Aigaki, T., Matsuno, K., et al. (2004). Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Current Biology, 14(24), 2228–2236.PubMedCrossRefGoogle Scholar
  69. 69.
    Jehn, B. M., Dittert, I., Beyer, S., von der Mark, K., & Bielke, W. (2002). c-Cbl binding and ubiquitin-dependent lysosomal degradation of membrane-associated Notch1. The Journal of Biological Chemistry, 277(10), 8033–8040.PubMedCrossRefGoogle Scholar
  70. 70.
    Conner, S. D. (2016). Regulation of Notch signaling through intracellular transport. International Review of Cell and Molecular Biology, 323, 107–127.PubMedCrossRefGoogle Scholar
  71. 71.
    Santolini, E., Puri, C., Salcini, A. E., Gagliani, M. C., Pelicci, P. G., Tacchetti, C., et al. (2000). Numb is an endocytic protein. The Journal of Cell Biology, 151(6), 1345–1352.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    McGill, M. A., & McGlade, C. J. (2003). Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. The Journal of Biological Chemistry, 278(25), 23196–23203.PubMedCrossRefGoogle Scholar
  73. 73.
    Foltz, D. R., Santiago, M. C., Berechid, B. E., & Nye, J. S. (2002). Glycogen synthase kinase-3beta modulates notch signaling and stability. Current Biology, 12(12), 1006–1011.PubMedCrossRefGoogle Scholar
  74. 74.
    Ingles-Esteve, J., Espinosa, L., Milner, L. A., Caelles, C., & Bigas, A. (2001). Phosphorylation of Ser2078 modulates the Notch2 function in 32D cell differentiation. The Journal of Biological Chemistry, 276(48), 44873–44880.PubMedCrossRefGoogle Scholar
  75. 75.
    Fryer, C. J., White, J. B., & Jones, K. A. (2004). Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Molecular Cell, 16(4), 509–520.PubMedCrossRefGoogle Scholar
  76. 76.
    Popko-Scibor, A. E., Lindberg, M. J., Hansson, M. L., Holmlund, T., & Wallberg, A. E. (2011). Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1. Biochemical and Biophysical Research Communications, 416(3–4), 300–306.PubMedCrossRefGoogle Scholar
  77. 77.
    Palermo, R., Checquolo, S., Giovenco, A., Grazioli, P., Kumar, V., Campese, A. F., et al. (2012). Acetylation controls Notch3 stability and function in T-cell leukemia. Oncogene, 31(33), 3807–3817.PubMedCrossRefGoogle Scholar
  78. 78.
    Ishitani, T., Hirao, T., Suzuki, M., Isoda, M., Ishitani, S., Harigaya, K., et al. (2010). Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nature Cell Biology, 12(3), 278–285.PubMedCrossRefGoogle Scholar
  79. 79.
    Rustighi, A., Tiberi, L., Soldano, A., Napoli, M., Nuciforo, P., Rosato, A., et al. (2009). The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology, 11(2), 133–142.PubMedCrossRefGoogle Scholar
  80. 80.
    Rustighi, A., Zannini, A., Tiberi, L., Sommaggio, R., Piazza, S., Sorrentino, G., et al. (2014). Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Molecular Medicine, 6(1), 99–119.PubMedCrossRefGoogle Scholar
  81. 81.
    Baik, S. H., Fane, M., Park, J. H., Cheng, Y. L., Yang-Wei Fann, D., Yun, U. J., et al. (2015). Pin1 promotes neuronal death in stroke by stabilizing Notch intracellular domain. Annals of Neurology, 77(3), 504–516.PubMedCrossRefGoogle Scholar
  82. 82.
    Franciosa, G., Diluvio, G., Del Gaudio, F., Giuli, M. V., Palermo, R., Grazioli, P., et al. (2016). Prolyl-isomerase Pin1 controls Notch3 protein expression and regulates T-ALL progression. Oncogene, 35(36), 4741–4751.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Cho, S., Lu, M., He, X., Ee, P. L., Bhat, U., Schneider, E., et al. (2011). Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 108(51), 20778–20783.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Wang, Z., Li, Y., Ahmad, A., Banerjee, S., Azmi, A. S., Kong, D., et al. (2011). Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. Journal of Cellular Biochemistry, 112(1), 78–88.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Zhao, B., Zou, J., Wang, H., Johannsen, E., Peng, C. W., Quackenbush, J., et al. (2011). Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proceedings of the National Academy of Sciences of the United States of America, 108(36), 14902–14907.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J. R., et al. (2000). A novel proteolytic cleavage involved in Notch signaling: The role of the disintegrin-metalloprotease TACE. Molecular Cell, 5(2), 207–216.PubMedCrossRefGoogle Scholar
  87. 87.
    Musse, A. A., Meloty-Kapella, L., & Weinmaster, G. (2012). Notch ligand endocytosis: Mechanistic basis of signaling activity. Seminars in Cell & Developmental Biology, 23(4), 429–436.CrossRefGoogle Scholar
  88. 88.
    Saxena, M. T., Schroeter, E. H., Mumm, J. S., & Kopan, R. (2001). Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. The Journal of Biological Chemistry, 276(43), 40268–40273.PubMedCrossRefGoogle Scholar
  89. 89.
    Schroeter, E. H., Kisslinger, J. A., & Kopan, R. (1998). Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature, 393(6683), 382–386.PubMedCrossRefGoogle Scholar
  90. 90.
    Chen, F., Hasegawa, H., Schmitt-Ulms, G., Kawarai, T., Bohm, C., Katayama, T., et al. (2006). TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature, 440(7088), 1208–1212.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang, Y. W., Luo, W. J., Wang, H., Lin, P., Vetrivel, K. S., Liao, F., et al. (2005). Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components. The Journal of Biological Chemistry, 280(17), 17020–17026.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Lee, S. F., Shah, S., Yu, C., Wigley, W. C., Li, H., Lim, M., et al. (2004). A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. The Journal of Biological Chemistry, 279(6), 4144–4152.PubMedCrossRefGoogle Scholar
  93. 93.
    Prokop, S., Shirotani, K., Edbauer, D., Haass, C., & Steiner, H. (2004). Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complex. The Journal of Biological Chemistry, 279(22), 23255–23261.PubMedCrossRefGoogle Scholar
  94. 94.
    Fortini, M. E., & Artavanis-Tsakonas, S. (1994). The suppressor of hairless protein participates in notch receptor signaling. Cell, 79(2), 273–282.PubMedCrossRefGoogle Scholar
  95. 95.
    Wu, L., Aster, J. C., Blacklow, S. C., Lake, R., Artavanis-Tsakonas, S., & Griffin, J. D. (2000). MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nature Genetics, 26(4), 484–489.PubMedCrossRefGoogle Scholar
  96. 96.
    Wallberg, A. E., Pedersen, K., Lendahl, U., & Roeder, R. G. (2002). p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Molecular and Cellular Biology, 22(22), 7812–7819.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kurooka, H., & Honjo, T. (2000). Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. The Journal of Biological Chemistry, 275(22), 17211–17220.PubMedCrossRefGoogle Scholar
  98. 98.
    Kitagawa, M. (2016). Notch signalling in the nucleus: Roles of Mastermind-like (MAML) transcriptional coactivators. Journal of Biochemistry, 159(3), 287–294.PubMedGoogle Scholar
  99. 99.
    Wang, Z., Ahmad, A., Li, Y., Azmi, A. S., Miele, L., & Sarkar, F. H. (2011). Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Research, 31(4), 1105–1113.PubMedGoogle Scholar
  100. 100.
    Castel, D., Mourikis, P., Bartels, S. J., Brinkman, A. B., Tajbakhsh, S., & Stunnenberg, H. G. (2013). Dynamic binding of RBPJ is determined by Notch signaling status. Genes & Development, 27(9), 1059–1071.CrossRefGoogle Scholar
  101. 101.
    Choi, J. W., Pampeno, C., Vukmanovic, S., & Meruelo, D. (2002). Characterization of the transcriptional expression of Notch-1 signaling pathway members, Deltex and HES-1, in developing mouse thymocytes. Developmental and Comparative Immunology, 26(6), 575–588.PubMedCrossRefGoogle Scholar
  102. 102.
    Oswald, F., Liptay, S., Adler, G., & Schmid, R. M. (1998). NF-kappaB2 is a putative target gene of activated Notch-1 via RBP-Jkappa. Molecular and Cellular Biology, 18(4), 2077–2088.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Cheng, P., Zlobin, A., Volgina, V., Gottipati, S., Osborne, B., Simel, E. J., et al. (2001). Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells. Journal of Immunology, 167(8), 4458–4467.CrossRefGoogle Scholar
  104. 104.
    Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M., Mammucari, C., Oh, H., et al. (2001). Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. The EMBO Journal, 20(13), 3427–3436.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ronchini, C., & Capobianco, A. J. (2001). Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): Implication for cell cycle disruption in transformation by Notch(ic). Molecular and Cellular Biology, 21(17), 5925–5934.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Weng, A. P., Millholland, J. M., Yashiro-Ohtani, Y., Arcangeli, M. L., Lau, A., Wai, C., et al. (2006). c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes & Development, 20(15), 2096–2109.CrossRefGoogle Scholar
  107. 107.
    Andersen, P., Uosaki, H., Shenje, L. T., & Kwon, C. (2012). Non-canonical Notch signaling: Emerging role and mechanism. Trends in Cell Biology, 22(5), 257–265.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Sanalkumar, R., Dhanesh, S. B., & James, J. (2010). Non-canonical activation of Notch signaling/target genes in vertebrates. Cellular and Molecular Life Sciences, 67(17), 2957–2968.PubMedCrossRefGoogle Scholar
  109. 109.
    de Celis, J. F., & Bray, S. (1997). Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development, 124(17), 3241–3251.PubMedGoogle Scholar
  110. 110.
    Li, Y., & Baker, N. E. (2004). The roles of cis-inactivation by Notch ligands and of neuralized during eye and bristle patterning in Drosophila. BMC Developmental Biology, 4, 5.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Miller, A. C., Lyons, E. L., & Herman, T. G. (2009). cis-Inhibition of Notch by endogenous Delta biases the outcome of lateral inhibition. Current Biology, 19(16), 1378–1383.PubMedCrossRefGoogle Scholar
  112. 112.
    Becam, I., Fiuza, U. M., Arias, A. M., & Milan, M. (2010). A role of receptor Notch in ligand cis-inhibition in Drosophila. Current Biology, 20(6), 554–560.PubMedCrossRefGoogle Scholar
  113. 113.
    Loeb, D. M., Thornton, K., & Shokek, O. (2008). Pediatric soft tissue sarcomas. The Surgical Clinics of North America, 88(3), 615–627. vii.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Tapscott, S. J., Thayer, M. J., & Weintraub, H. (1993). Deficiency in rhabdomyosarcomas of a factor required for MyoD activity and myogenesis. Science, 259(5100), 1450–1453.PubMedCrossRefGoogle Scholar
  115. 115.
    De Giovanni, C., Landuzzi, L., Nicoletti, G., Lollini, P. L., & Nanni, P. (2009). Molecular and cellular biology of rhabdomyosarcoma. Future Oncology, 5(9), 1449–1475.PubMedCrossRefGoogle Scholar
  116. 116.
    Parham, D. M., & Barr, F. G. (2013). Classification of rhabdomyosarcoma and its molecular basis. Advances in Anatomic Pathology, 20(6), 387–397.PubMedCrossRefGoogle Scholar
  117. 117.
    Taulli, R., Bersani, F., Foglizzo, V., Linari, A., Vigna, E., Ladanyi, M., et al. (2009). The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. The Journal of Clinical Investigation, 119(8), 2366–2378.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Ciarapica, R., Carcarino, E., Adesso, L., De Salvo, M., Bracaglia, G., Leoncini, P. P., et al. (2014). Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS. BMC Cancer, 14, 139.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kikuchi, K., Taniguchi, E., Chen, H. I., Svalina, M. N., Abraham, J., Huang, E. T., et al. (2013). Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. Skeletal Muscle, 3(1), 27.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Chen, E. Y., Dobrinski, K. P., Brown, K. H., Clagg, R., Edelman, E., Ignatius, M. S., et al. (2013). Cross-species array comparative genomic hybridization identifies novel oncogenic events in zebrafish and human embryonal rhabdomyosarcoma. PLoS Genetics, 9(8), e1003727.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Hettmer, S., Liu, J., Miller, C. M., Lindsay, M. C., Sparks, C. A., Guertin, D. A., et al. (2011). Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells. Proceedings of the National Academy of Sciences of the United States of America, 108(50), 20002–20007.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Abraham, J., Nunez-Alvarez, Y., Hettmer, S., Carrio, E., Chen, H. I., Nishijo, K., et al. (2014). Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes & Development, 28(14), 1578–1591.CrossRefGoogle Scholar
  123. 123.
    Nitzki, F., Zibat, A., Frommhold, A., Schneider, A., Schulz-Schaeffer, W., Braun, T., et al. (2011). Uncommitted precursor cells might contribute to increased incidence of embryonal rhabdomyosarcoma in heterozygous Patched1-mutant mice. Oncogene, 30(43), 4428–4436.PubMedCrossRefGoogle Scholar
  124. 124.
    Hatley, M. E., Tang, W., Garcia, M. R., Finkelstein, D., Millay, D. P., Liu, N., et al. (2012). A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell, 22(4), 536–546.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Meza, J. L., Anderson, J., Pappo, A. S., Meyer, W. H., & Children’s Oncology G. (2006). Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: The Children’s Oncology Group. Journal of Clinical Oncology, 24(24), 3844–3851.PubMedCrossRefGoogle Scholar
  126. 126.
    Arndt, C. A., Stoner, J. A., Hawkins, D. S., Rodeberg, D. A., Hayes-Jordan, A. A., Paidas, C. N., et al. (2009). Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: Children’s oncology group study D9803. Journal of Clinical Oncology, 27(31), 5182–5188.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Williamson, D., Missiaglia, E., de Reynies, A., Pierron, G., Thuille, B., Palenzuela, G., et al. (2010). Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. Journal of Clinical Oncology, 28(13), 2151–2158.PubMedCrossRefGoogle Scholar
  128. 128.
    Chen, X., Stewart, E., Shelat, A. A., Qu, C., Bahrami, A., Hatley, M., et al. (2013). Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell, 24(6), 710–724.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Shern, J. F., Chen, L., Chmielecki, J., Wei, J. S., Patidar, R., Rosenberg, M., et al. (2014). Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discovery, 4(2), 216–231.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Hahn, H., Wojnowski, L., Zimmer, A. M., Hall, J., Miller, G., & Zimmer, A. (1998). Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nature Medicine, 4(5), 619–622.PubMedCrossRefGoogle Scholar
  131. 131.
    Zibat, A., Missiaglia, E., Rosenberger, A., Pritchard-Jones, K., Shipley, J., Hahn, H., et al. (2010). Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene, 29(48), 6323–6330.PubMedCrossRefGoogle Scholar
  132. 132.
    Nitzki, F., Cuvelier, N., Drager, J., Schneider, A., Braun, T., & Hahn, H. (2016). Hedgehog/Patched-associated rhabdomyosarcoma formation from delta1-expressing mesodermal cells. Oncogene, 35(22), 2923–2931.PubMedCrossRefGoogle Scholar
  133. 133.
    Pressey, J. G., Anderson, J. R., Crossman, D. K., Lynch, J. C., & Barr, F. G. (2011). Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: A report from the Children’s Oncology Group. Pediatric Blood & Cancer, 57(6), 930–938.CrossRefGoogle Scholar
  134. 134.
    Kohsaka, S., Shukla, N., Ameur, N., Ito, T., Ng, C. K., Wang, L., et al. (2014). A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nature Genetics, 46(6), 595–600.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Davicioni, E., Anderson, J. R., Buckley, J. D., Meyer, W. H., & Triche, T. J. (2010). Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: A report from the children’s oncology group. Journal of Clinical Oncology, 28(7), 1240–1246.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Galili, N., Davis, R. J., Fredericks, W. J., Mukhopadhyay, S., Rauscher, F. J., 3rd, Emanuel, B. S., et al. (1993). Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nature Genetics, 5(3), 230–235.PubMedCrossRefGoogle Scholar
  137. 137.
    Davis, R. J., D’Cruz, C. M., Lovell, M. A., Biegel, J. A., & Barr, F. G. (1994). Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Research, 54(11), 2869–2872.PubMedGoogle Scholar
  138. 138.
    Marshall, A. D., Picchione, F., Geltink, R. I., & Grosveld, G. C. (2013). PAX3-FOXO1 induces up-regulation of Noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis. Neoplasia, 15(7), 738–748.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Missiaglia, E., Williamson, D., Chisholm, J., Wirapati, P., Pierron, G., Petel, F., et al. (2012). PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. Journal of Clinical Oncology, 30(14), 1670–1677.PubMedCrossRefGoogle Scholar
  140. 140.
    Mourikis, P., & Tajbakhsh, S. (2014). Distinct contextual roles for Notch signalling in skeletal muscle stem cells. BMC Developmental Biology, 14, 2.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Francis, P., Namlos, H. M., Muller, C., Eden, P., Fernebro, J., Berner, J. M., et al. (2007). Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: Hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics, 8, 73.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Terry, J., Saito, T., Subramanian, S., Ruttan, C., Antonescu, C. R., Goldblum, J. R., et al. (2007). TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. The American Journal of Surgical Pathology, 31(2), 240–246.PubMedCrossRefGoogle Scholar
  143. 143.
    Jagdis, A., Rubin, B. P., Tubbs, R. R., Pacheco, M., & Nielsen, T. O. (2009). Prospective evaluation of TLE1 as a diagnostic immunohistochemical marker in synovial sarcoma. The American Journal of Surgical Pathology, 33(12), 1743–1751.PubMedCrossRefGoogle Scholar
  144. 144.
    Su, L., Sampaio, A. V., Jones, K. B., Pacheco, M., Goytain, A., Lin, S., et al. (2012). Deconstruction of the SS18-SSX fusion oncoprotein complex: Insights into disease etiology and therapeutics. Cancer Cell, 21(3), 333–347.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    May, W. A., Arvand, A., Thompson, A. D., Braun, B. S., Wright, M., & Denny, C. T. (1997). EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. Nature Genetics, 17(4), 495–497.PubMedCrossRefGoogle Scholar
  146. 146.
    Baliko, F., Bright, T., Poon, R., Cohen, B., Egan, S. E., & BA, A. (2007). Inhibition of notch signaling induces neural differentiation in Ewing sarcoma. The American Journal of Pathology, 170(5), 1686–1694.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Ban, J., Bennani-Baiti, I. M., Kauer, M., Schaefer, K. L., Poremba, C., Jug, G., et al. (2008). EWS-FLI1 suppresses NOTCH-activated p53 in Ewing’s sarcoma. Cancer Research, 68(17), 7100–7109.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Bennani-Baiti, I. M., Aryee, D. N., Ban, J., Machado, I., Kauer, M., Muhlbacher, K., et al. (2011). Notch signalling is off and is uncoupled from HES1 expression in Ewing’s sarcoma. The Journal of Pathology, 225(3), 353–363.PubMedCrossRefGoogle Scholar
  149. 149.
    Ban, J., Aryee, D. N., Fourtouna, A., van der Ent, W., Kauer, M., Niedan, S., et al. (2014). Suppression of deacetylase SIRT1 mediates tumor-suppressive NOTCH response and offers a novel treatment option in metastatic Ewing sarcoma. Cancer Research, 74(22), 6578–6588.PubMedCrossRefGoogle Scholar
  150. 150.
    Ventura, S., Aryee, D. N., Felicetti, F., De Feo, A., Mancarella, C., Manara, M. C., et al. (2016). CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-kappaB signaling. Oncogene, 35(30), 3944–3954.PubMedCrossRefGoogle Scholar
  151. 151.
    Sang, L., Coller, H. A., & Roberts, J. M. (2008). Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science, 321(5892), 1095–1100.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Roma, J., Masia, A., Reventos, J., Sanchez de Toledo, J., & Gallego, S. (2011). Notch pathway inhibition significantly reduces rhabdomyosarcoma invasiveness and mobility in vitro. Clinical Cancer Research, 17(3), 505–513.PubMedCrossRefGoogle Scholar
  153. 153.
    Belyea, B. C., Naini, S., Bentley, R. C., & Linardic, C. M. (2011). Inhibition of the Notch-Hey1 axis blocks embryonal rhabdomyosarcoma tumorigenesis. Clinical Cancer Research, 17(23), 7324–7336.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Raimondi, L., Ciarapica, R., De Salvo, M., Verginelli, F., Gueguen, M., Martini, C., et al. (2012). Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21(Cip1) expression and hampers tumour cell growth in vitro and in vivo. Cell Death and Differentiation, 19(5), 871–881.PubMedCrossRefGoogle Scholar
  155. 155.
    Nagao, H., Setoguchi, T., Kitamoto, S., Ishidou, Y., Nagano, S., Yokouchi, M., et al. (2012). RBPJ is a novel target for rhabdomyosarcoma therapy. PLoS One, 7(7), e39268.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    De Salvo, M., Raimondi, L., Vella, S., Adesso, L., Ciarapica, R., Verginelli, F., et al. (2014). Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells. PLoS One, 9(5), e96238.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Diao, Y., Guo, X., Jiang, L., Wang, G., Zhang, C., Wan, J., et al. (2014). miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma. The Journal of Biological Chemistry, 289(1), 529–539.PubMedCrossRefGoogle Scholar
  158. 158.
    Kitagawa, M., Oyama, T., Kawashima, T., Yedvobnick, B., Kumar, A., Matsuno, K., et al. (2001). A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters. Molecular and Cellular Biology, 21(13), 4337–4346.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Hu, Y. Y., Zheng, M. H., Zhang, R., Liang, Y. M., & Han, H. (2012). Notch signaling pathway and cancer metastasis. Advances in Experimental Medicine and Biology, 727, 186–198.PubMedCrossRefGoogle Scholar
  160. 160.
    Liu, Z. H., Dai, X. M., & Du, B. (2015). Hes1: A key role in stemness, metastasis and multidrug resistance. Cancer Biology & Therapy, 16(3), 353–359.CrossRefGoogle Scholar
  161. 161.
    Weidle, U. H., Birzele, F., & Kruger, A. (2015). Molecular targets and pathways involved in liver metastasis of colorectal cancer. Clinical & Experimental Metastasis, 32(6), 623–635.CrossRefGoogle Scholar
  162. 162.
    Masia, A., Almazan-Moga, A., Velasco, P., Reventos, J., Toran, N., Sanchez de Toledo, J., et al. (2012). Notch-mediated induction of N-cadherin and alpha9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells. British Journal of Cancer, 107(8), 1374–1383.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Liu, Z. J., Xiao, M., Balint, K., Smalley, K. S., Brafford, P., Qiu, R., et al. (2006). Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Research, 66(8), 4182–4190.PubMedCrossRefGoogle Scholar
  164. 164.
    Wang, T., Holt, C. M., Xu, C., Ridley, C., POJ, R., Baron, M., et al. (2007). Notch3 activation modulates cell growth behaviour and cross-talk to Wnt/TCF signalling pathway. Cellular Signalling, 19(12), 2458–2467.PubMedCrossRefGoogle Scholar
  165. 165.
    Shukla, N., Ameur, N., Yilmaz, I., Nafa, K., Lau, C. Y., Marchetti, A., et al. (2012). Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clinical Cancer Research, 18(3), 748–757.PubMedCrossRefGoogle Scholar
  166. 166.
    Gustafsson, M. K., Pan, H., Pinney, D. F., Liu, Y., Lewandowski, A., Epstein, D. J., et al. (2002). Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. Genes & Development, 16(1), 114–126.CrossRefGoogle Scholar
  167. 167.
    Straface, G., Aprahamian, T., Flex, A., Gaetani, E., Biscetti, F., Smith, R. C., et al. (2009). Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration. Journal of Cellular and Molecular Medicine, 13(8B), 2424–2435.PubMedCrossRefGoogle Scholar
  168. 168.
    Koleva, M., Kappler, R., Vogler, M., Herwig, A., Fulda, S., & Hahn, H. (2005). Pleiotropic effects of sonic hedgehog on muscle satellite cells. Cellular and Molecular Life Sciences, 62(16), 1863–1870.PubMedCrossRefGoogle Scholar
  169. 169.
    Bren-Mattison, Y., & Olwin, B. B. (2002). Sonic hedgehog inhibits the terminal differentiation of limb myoblasts committed to the slow muscle lineage. Developmental Biology, 242(2), 130–148.PubMedCrossRefGoogle Scholar
  170. 170.
    Hahn, H., Nitzki, F., Schorban, T., Hemmerlein, B., Threadgill, D., & Rosemann, M. (2004). Genetic mapping of a Ptch1-associated rhabdomyosarcoma susceptibility locus on mouse chromosome 2. Genomics, 84(5), 853–858.PubMedCrossRefGoogle Scholar
  171. 171.
    Calzada-Wack, J., Schnitzbauer, U., Walch, A., Wurster, K. H., Kappler, R., Nathrath, M., et al. (2002). Analysis of the PTCH coding region in human rhabdomyosarcoma. Human Mutation, 20(3), 233–234.PubMedCrossRefGoogle Scholar
  172. 172.
    Bridge, J. A., Liu, J., Weibolt, V., Baker, K. S., Perry, D., Kruger, R., et al. (2000). Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: An intergroup rhabdomyosarcoma study. Genes, Chromosomes & Cancer, 27(4), 337–344.CrossRefGoogle Scholar
  173. 173.
    Tostar, U., Malm, C. J., Meis-Kindblom, J. M., Kindblom, L. G., Toftgard, R., & Unden, A. B. (2006). Deregulation of the hedgehog signalling pathway: A possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. The Journal of Pathology, 208(1), 17–25.PubMedCrossRefGoogle Scholar
  174. 174.
    Rubin, B. P., Nishijo, K., Chen, H. I., Yi, X., Schuetze, D. P., Pal, R., et al. (2011). Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell, 19(2), 177–191.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Ingram, W. J., McCue, K. I., Tran, T. H., Hallahan, A. R., & Wainwright, B. J. (2008). Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene, 27(10), 1489–1500.PubMedCrossRefGoogle Scholar
  176. 176.
    Esiashvili, N., Goodman, M., & Marcus, R. B., Jr. (2008). Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. Journal of Pediatric Hematology/Oncology, 30(6), 425–430.PubMedCrossRefGoogle Scholar
  177. 177.
    van den Berg, H., Dirksen, U., Ranft, A., & Jurgens, H. (2008). Ewing tumors in infants. Pediatric Blood & Cancer, 50(4), 761–764.CrossRefGoogle Scholar
  178. 178.
    Grier, H. E., Krailo, M. D., Tarbell, N. J., Link, M. P., Fryer, C. J., Pritchard, D. J., et al. (2003). Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. The New England Journal of Medicine, 348(8), 694–701.PubMedCrossRefGoogle Scholar
  179. 179.
    Womer, R. B., West, D. C., Krailo, M. D., Dickman, P. S., Pawel, B. R., Grier, H. E., et al. (2012). Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children’s Oncology Group. Journal of Clinical Oncology, 30(33), 4148–4154.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Gaspar, N., Hawkins, D. S., Dirksen, U., Lewis, I. J., Ferrari, S., Le Deley, M. C., et al. (2015). Ewing sarcoma: Current management and future approaches through collaboration. Journal of Clinical Oncology, 33(27), 3036–3046.PubMedCrossRefGoogle Scholar
  181. 181.
    Roberts, P., Burchill, S. A., Brownhill, S., Cullinane, C. J., Johnston, C., Griffiths, M. J., et al. (2008). Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing’s sarcoma family of tumors: A study by the United Kingdom Cancer Cytogenetics and the Children’s Cancer and Leukaemia Group. Genes, Chromosomes & Cancer, 47(3), 207–220.CrossRefGoogle Scholar
  182. 182.
    Postel-Vinay, S., Veron, A. S., Tirode, F., Pierron, G., Reynaud, S., Kovar, H., et al. (2012). Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nature Genetics, 44(3), 323–327.PubMedCrossRefGoogle Scholar
  183. 183.
    Tuna, M., Ju, Z., CI, A., & Mills, G. B. (2012). Soft tissue sarcoma subtypes exhibit distinct patterns of acquired uniparental disomy. BMC Medical Genomics, 5, 60.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Delattre, O., Zucman, J., Plougastel, B., Desmaze, C., Melot, T., Peter, M., et al. (1992). Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature, 359(6391), 162–165.PubMedCrossRefGoogle Scholar
  185. 185.
    May, W. A., Gishizky, M. L., Lessnick, S. L., Lunsford, L. B., Lewis, B. C., Delattre, O., et al. (1993). Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. Proceedings of the National Academy of Sciences of the United States of America, 90(12), 5752–5756.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Lawlor, E. R., & Sorensen, P. H. (2015). Twenty years on: What do we really know about Ewing sarcoma and what is the path forward? Critical Reviews in Oncogenesis, 20(3–4), 155–171.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    van Doorninck, J. A., Ji, L., Schaub, B., Shimada, H., Wing, M. R., Krailo, M. D., et al. (2010). Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: A report from the Children’s Oncology Group. Journal of Clinical Oncology, 28(12), 1989–1994.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Le Deley, M. C., Delattre, O., Schaefer, K. L., Burchill, S. A., Koehler, G., Hogendoorn, P. C., et al. (2010). Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: Prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. Journal of Clinical Oncology, 28(12), 1982–1988.PubMedCrossRefGoogle Scholar
  189. 189.
    Riggi, N., Cironi, L., Provero, P., Suva, M. L., Kaloulis, K., Garcia-Echeverria, C., et al. (2005). Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Research, 65(24), 11459–11468.PubMedCrossRefGoogle Scholar
  190. 190.
    Riggi, N., Suva, M. L., & Stamenkovic, I. (2009). Ewing’s sarcoma origin: From duel to duality. Expert Review of Anticancer Therapy, 9(8), 1025–1030.PubMedCrossRefGoogle Scholar
  191. 191.
    Riggi, N., Suva, M. L., De Vito, C., Provero, P., Stehle, J. C., Baumer, K., et al. (2010). EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes & Development, 24(9), 916–932.CrossRefGoogle Scholar
  192. 192.
    von Levetzow, C., Jiang, X., Gwye, Y., von Levetzow, G., Hung, L., Cooper, A., et al. (2011). Modeling initiation of Ewing sarcoma in human neural crest cells. PLoS One, 6(4), e19305.CrossRefGoogle Scholar
  193. 193.
    May, W. A., Lessnick, S. L., Braun, B. S., Klemsz, M., Lewis, B. C., Lunsford, L. B., et al. (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. Molecular and Cellular Biology, 13(12), 7393–7398.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Bilke, S., Schwentner, R., Yang, F., Kauer, M., Jug, G., Walker, R. L., et al. (2013). Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer. Genome Research, 23(11), 1797–1809.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Patel, M., Simon, J. M., Iglesia, M. D., Wu, S. B., McFadden, A. W., Lieb, J. D., et al. (2012). Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription. Genome Research, 22(2), 259–270.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Owen, L. A., Kowalewski, A. A., & Lessnick, S. L. (2008). EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma. PLoS One, 3(4), e1965.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Stoll, G., Surdez, D., Tirode, F., Laud, K., Barillot, E., Zinovyev, A., et al. (2013). Systems biology of Ewing sarcoma: A network model of EWS-FLI1 effect on proliferation and apoptosis. Nucleic Acids Research, 41(19), 8853–8871.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Zwerner, J. P., Guimbellot, J., & May, W. A. (2003). EWS/FLI function varies in different cellular backgrounds. Experimental Cell Research, 290(2), 414–419.PubMedCrossRefGoogle Scholar
  199. 199.
    Smith, R., Owen, L. A., Trem, D. J., Wong, J. S., Whangbo, J. S., Golub, T. R., et al. (2006). Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell, 9(5), 405–416.PubMedCrossRefGoogle Scholar
  200. 200.
    Bennani-Baiti, I. M., Machado, I., Llombart-Bosch, A., & Kovar, H. (2012). Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. Human Pathology, 43(8), 1300–1307.PubMedCrossRefGoogle Scholar
  201. 201.
    Mulligan, P., Yang, F., Di Stefano, L., Ji, J. Y., Ouyang, J., Nishikawa, J. L., et al. (2011). A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Molecular Cell, 42(5), 689–699.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Wang, J., Scully, K., Zhu, X., Cai, L., Zhang, J., Prefontaine, G. G., et al. (2007). Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature, 446(7138), 882–887.PubMedCrossRefGoogle Scholar
  203. 203.
    Di Stefano, L., Walker, J. A., Burgio, G., Corona, D. F., Mulligan, P., Naar, A. M., et al. (2011). Functional antagonism between histone H3K4 demethylases in vivo. Genes & Development, 25(1), 17–28.CrossRefGoogle Scholar
  204. 204.
    Rocchi, A., Manara, M. C., Sciandra, M., Zambelli, D., Nardi, F., Nicoletti, G., et al. (2010). CD99 inhibits neural differentiation of human Ewing sarcoma cells and thereby contributes to oncogenesis. The Journal of Clinical Investigation, 120(3), 668–680.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Schenkel, A. R., Mamdouh, Z., Chen, X., Liebman, R. M., & Muller, W. A. (2002). CD99 plays a major role in the migration of monocytes through endothelial junctions. Nature Immunology, 3(2), 143–150.PubMedCrossRefGoogle Scholar
  206. 206.
    Alberti, I., Bernard, G., Rouquette-Jazdanian, A. K., Pelassy, C., Pourtein, M., Aussel, C., et al. (2002). CD99 isoforms expression dictates T cell functional outcomes. The FASEB Journal, 16(14), 1946–1948.PubMedCrossRefGoogle Scholar
  207. 207.
    Miyagawa, Y., Okita, H., Nakaijima, H., Horiuchi, Y., Sato, B., Taguchi, T., et al. (2008). Inducible expression of chimeric EWS/ETS proteins confers Ewing’s family tumor-like phenotypes to human mesenchymal progenitor cells. Molecular and Cellular Biology, 28(7), 2125–2137.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Hu-Lieskovan, S., Zhang, J., Wu, L., Shimada, H., Schofield, D. E., & Triche, T. J. (2005). EWS-FLI1 fusion protein up-regulates critical genes in neural crest development and is responsible for the observed phenotype of Ewing’s family of tumors. Cancer Research, 65(11), 4633–4644.PubMedCrossRefGoogle Scholar
  209. 209.
    Nakatani, F., Ferracin, M., Manara, M. C., Ventura, S., Del Monaco, V., Ferrari, S., et al. (2012). miR-34a predicts survival of Ewing’s sarcoma patients and directly influences cell chemo-sensitivity and malignancy. The Journal of Pathology, 226(5), 796–805.PubMedCrossRefGoogle Scholar
  210. 210.
    Marino, M. T., Grilli, A., Baricordi, C., Manara, M. C., Ventura, S., Pinca, R. S., et al. (2014). Prognostic significance of miR-34a in Ewing sarcoma is associated with cyclin D1 and ki-67 expression. Annals of Oncology, 25(10), 2080–2086.PubMedCrossRefGoogle Scholar
  211. 211.
    Li, Y., Guessous, F., Zhang, Y., Dipierro, C., Kefas, B., Johnson, E., et al. (2009). MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Research, 69(19), 7569–7576.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Bu, P., Chen, K. Y., Chen, J. H., Wang, L., Walters, J., Shin, Y. J., et al. (2013). A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell, 12(5), 602–615.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Osipo, C., Golde, T. E., Osborne, B. A., & Miele, L. A. (2008). Off the beaten pathway: The complex cross talk between Notch and NF-kappaB. Laboratory Investigation, 88(1), 11–17.CrossRefGoogle Scholar
  214. 214.
    Ducimetiere, F., Lurkin, A., Ranchere-Vince, D., Decouvelaere, A. V., Péoc'h, M., Istier, L., et al. (2011). Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. PLoS One, 6(8), e20294.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Palmerini, E., Paioli, A., & Ferrari, S. (2014). Emerging therapeutic targets for synovial sarcoma. Expert Review of Anticancer Therapy, 14(7), 791–806.PubMedCrossRefGoogle Scholar
  216. 216.
    Nielsen, T. O., Poulin, N. M., & Ladanyi, M. (2015). Synovial sarcoma: Recent discoveries as a roadmap to new avenues for therapy. Cancer Discovery, 5(2), 124–134.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Herzog, C. E. (2005). Overview of sarcomas in the adolescent and young adult population. Journal of Pediatric Hematology/Oncology, 27(4), 215–218.PubMedCrossRefGoogle Scholar
  218. 218.
    Sultan, I., Rodriguez-Galindo, C., Saab, R., Yasir, S., Casanova, M., & Ferrari, A. (2009). Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: An analysis of 1268 patients. Cancer, 115(15), 3537–3547.PubMedCrossRefGoogle Scholar
  219. 219.
    Nagai, M., Tanaka, S., Tsuda, M., Endo, S., Kato, H., Sonobe, H., et al. (2001). Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha. Proceedings of the National Academy of Sciences of the United States of America, 98(7), 3843–3848.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Carmody Soni, E. E., Schlottman, S., Erkizan, H. V., Uren, A., & Toretsky, J. A. (2014). Loss of SS18-SSX1 inhibits viability and induces apoptosis in synovial sarcoma. Clinical Orthopaedics and Related Research, 472(3), 874–882.PubMedCrossRefGoogle Scholar
  221. 221.
    Naka, N., Takenaka, S., Araki, N., Miwa, T., Hashimoto, N., Yoshioka, K., et al. (2010). Synovial sarcoma is a stem cell malignancy. Stem Cells, 28(7), 1119–1131.PubMedGoogle Scholar
  222. 222.
    Cironi, L., Provero, P., Riggi, N., Janiszewska, M., Suva, D., Suva, M. L., et al. (2009). Epigenetic features of human mesenchymal stem cells determine their permissiveness for induction of relevant transcriptional changes by SYT-SSX1. PLoS One, 4(11), e7904.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Haldar, M., Randall, R. L., & Capecchi, M. R. (2008). Synovial sarcoma: From genetics to genetic-based animal modeling. Clinical Orthopaedics and Related Research, 466(9), 2156–2167.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Panagopoulos, I., Mertens, F., Isaksson, M., Limon, J., Gustafson, P., Skytting, B., et al. (2001). Clinical impact of molecular and cytogenetic findings in synovial sarcoma. Genes, Chromosomes & Cancer, 31(4), 362–372.CrossRefGoogle Scholar
  225. 225.
    Zollner, S. K., Rossig, C., & Toretsky, J. A. (2015). Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer. Cancer Metastasis Reviews, 34(3), 417–428.PubMedCrossRefGoogle Scholar
  226. 226.
    Thaete, C., Brett, D., Monaghan, P., Whitehouse, S., Rennie, G., Rayner, E., et al. (1999). Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus. Human Molecular Genetics, 8(4), 585–591.PubMedCrossRefGoogle Scholar
  227. 227.
    Kato, H., Tjernberg, A., Zhang, W., Krutchinsky, A. N., An, W., Takeuchi, T., et al. (2002). SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones. The Journal of Biological Chemistry, 277(7), 5498–5505.PubMedCrossRefGoogle Scholar
  228. 228.
    Middeljans, E., Wan, X., Jansen, P. W., Sharma, V., Stunnenberg, H. G., & Logie, C. (2012). SS18 together with animal-specific factors defines human BAF-type SWI/SNF complexes. PLoS One, 7(3), e33834.PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Kadoch, C., & Crabtree, G. R. (2013). Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell, 153(1), 71–85.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Soulez, M., Saurin, A. J., Freemont, P. S., & Knight, J. C. (1999). SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex. Oncogene, 18(17), 2739–2746.PubMedCrossRefGoogle Scholar
  231. 231.
    Grbavec, D., & Stifani, S. (1996). Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochemical and Biophysical Research Communications, 223(3), 701–705.PubMedCrossRefGoogle Scholar
  232. 232.
    Su, L., Cheng, H., Sampaio, A. V., Nielsen, T. O., & Underhill, T. M. (2010). EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. Oncogene, 29(30), 4352–4361.PubMedCrossRefGoogle Scholar
  233. 233.
    Valente, A. L., Tull, J., & Zhang, S. (2013). Specificity of TLE1 expression in unclassified high-grade sarcomas for the diagnosis of synovial sarcoma. Applied Immunohistochemistry & Molecular Morphology, 21(5), 408–413.CrossRefGoogle Scholar
  234. 234.
    Macy, M. E., Sawczyn, K. K., Garrington, T. P., Graham, D. K., & Gore, L. (2008). Pediatric developmental therapies: Interesting new drugs now in early-stage clinical trials. Current Oncology Reports, 10(6), 477–490.PubMedPubMedCentralCrossRefGoogle Scholar
  235. 235.
    Zweidler-McKay, P. A. (2008). Notch signaling in pediatric malignancies. Current Oncology Reports, 10(6), 459–468.PubMedCrossRefGoogle Scholar
  236. 236.
    Fouladi, M., Stewart, C. F., Olson, J., Wagner, L. M., Onar-Thomas, A., Kocak, M., et al. (2011). Phase I trial of MK-0752 in children with refractory CNS malignancies: A pediatric brain tumor consortium study. Journal of Clinical Oncology, 29(26), 3529–3534.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Luistro, L., He, W., Smith, M., Packman, K., Vilenchik, M., Carvajal, D., et al. (2009). Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Research, 69(19), 7672–7680.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Messersmith, W. A., Shapiro, G. I., Cleary, J. M., Jimeno, A., Dasari, A., Huang, B., et al. (2015). A Phase I, dose-finding study in patients with advanced solid malignancies of the oral gamma-secretase inhibitor PF-03084014. Clinical Cancer Research, 21(1), 60–67.PubMedCrossRefGoogle Scholar
  239. 239.
    De Strooper, B., Iwatsubo, T., & Wolfe, M. S. (2012). Presenilins and gamma-secretase: Structure, function, and role in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 2(1), a006304.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Bigas, A., Martin, D. I., & Milner, L. A. (1998). Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Molecular and Cellular Biology, 18(4), 2324–2333.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Fan, X., Mikolaenko, I., Elhassan, I., Ni, X., Wang, Y., Ball, D., et al. (2004). Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Research, 64(21), 7787–7793.PubMedCrossRefGoogle Scholar
  242. 242.
    Shimizu, K., Chiba, S., Saito, T., Kumano, K., Hamada, Y., & Hirai, H. (2002). Functional diversity among Notch1, Notch2, and Notch3 receptors. Biochemical and Biophysical Research Communications, 291(4), 775–779.PubMedCrossRefGoogle Scholar
  243. 243.
    Nefedova, Y., Cheng, P., Alsina, M., Dalton, W. S., & Gabrilovich, D. I. (2004). Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood, 103(9), 3503–3510.PubMedCrossRefGoogle Scholar
  244. 244.
    Graziani, I., Eliasz, S., De Marco, M. A., Chen, Y., Pass, H. I., De May, R. M., et al. (2008). Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Research, 68(23), 9678–9685.PubMedCrossRefGoogle Scholar
  245. 245.
    Sun, Y., Lowther, W., Kato, K., Bianco, C., Kenney, N., Strizzi, L., et al. (2005). Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling. Oncogene, 24(34), 5365–5374.PubMedCrossRefGoogle Scholar
  246. 246.
    Verginelli, F., Adesso, L., Limon, I., Alisi, A., Gueguen, M., Panera, N., et al. (2015). Activation of an endothelial Notch1-Jagged1 circuit induces VCAM1 expression, an effect amplified by interleukin-1beta. Oncotarget, 6(41), 43216–43229.PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Chiorean, E. G., LoRusso, P., Strother, R. M., Diamond, J. R., Younger, A., Messersmith, W. A., et al. (2015). A phase I first-in-human study of enoticumab (REGN421), a fully human Delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clinical Cancer Research, 21(12), 2695–2703.PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    Weng, A. P., Nam, Y., Wolfe, M. S., Pear, W. S., Griffin, J. D., Blacklow, S. C., et al. (2003). Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Molecular and Cellular Biology, 23(2), 655–664.PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Moellering, R. E., Cornejo, M., Davis, T. N., Del Bianco, C., Aster, J. C., Blacklow, S. C., et al. (2009). Direct inhibition of the NOTCH transcription factor complex. Nature, 462(7270), 182–188.PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    Funahashi, Y., Hernandez, S. L., Das, I., Ahn, A., Huang, J., Vorontchikhina, M., et al. (2008). A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Research, 68(12), 4727–4735.PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Varnum-Finney, B., Wu, L., Yu, M., Brashem-Stein, C., Staats, S., Flowers, D., et al. (2000). Immobilization of Notch ligand, Delta-1, is required for induction of notch signaling. Journal of Cell Science, 113(Pt 23), 4313–4318.PubMedGoogle Scholar
  252. 252.
    Small, D., Kovalenko, D., Kacer, D., Liaw, L., Landriscina, M., Di Serio, C., et al. (2001). Soluble Jagged 1 represses the function of its transmembrane form to induce the formation of the Src-dependent chord-like phenotype. The Journal of Biological Chemistry, 276(34), 32022–32030.PubMedCrossRefGoogle Scholar
  253. 253.
    Six, E., Ndiaye, D., Laabi, Y., Brou, C., Gupta-Rossi, N., Israel, A., et al. (2003). The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proceedings of the National Academy of Sciences of the United States of America, 100(13), 7638–7643.PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    LaVoie, M. J., Fraering, P. C., Ostaszewski, B. L., Ye, W., Kimberly, W. T., Wolfe, M. S., et al. (2003). Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. The Journal of Biological Chemistry, 278(39), 37213–37222.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Cristina Cossetti
    • 1
  • Alberto Gualtieri
    • 1
  • Silvia Pomella
    • 1
  • Elena Carcarino
    • 1
  • Rossella Rota
    • 1
    Email author
  1. 1.Laboratory of Angiogenesis, Department of OncohematologyOspedale Pediatrico Bambino GesùRomeItaly

Personalised recommendations