Notch signaling in pediatric soft tissue sarcomas

BMC Medicine

Franco Locatelli¹  Lucio Miele³  Roberta Ciarapica²  Rossella Rota² 

[1]Dipartimento di Scienze Pediatriche, Policlinico San Matteo, IRCCS, Università di Pavia, Viale Camillo Golgi 19, Pavia, 27100, Italy

[2]Department of Oncohematology, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza Sant'Onofrio 4, Roma, 00165, Italy

[3]Cancer Institute, University of Mississippi Medical Center, 2500 N. State Street, Guyton 2 Building, Suite G751-05, Jackson, Mississippi, 39216, USA

关键词: Rhabdomyosarcoma;    Ewing sarcoma;    Synovial sarcoma;    γ-secretase;    mesenchymal cells;    Notch;    soft tissue sarcoma;   

Others  :  857293
DOI  :  10.1186/1741-7015-10-141

 received in 2012-08-01, accepted in 2012-11-16,  发布年份 2012

【 摘 要 】

Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed chromosomal aberrations with de-regulation of the main pathways governing tissue morphogenesis. The Notch signaling pathway is one of the most important molecular networks involved in differentiation processes. Emerging evidence highlights the role of Notch signaling de-regulation in the biology of these pediatric sarcomas. In this review, we present an outline of recently gathered evidence on the role of Notch signaling in soft tissue sarcomas, highlighting its importance in tumor cell biology. The potential challenges and opportunities of targeting Notch signaling in the treatment of pediatric soft tissue sarcomas are also discussed.

【 授权许可】

   
2012 Rota et al; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, Driancourt C, Beau I, Hadchouel M, Meunier-Rotival M: Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: inhibitory effect on Notch signaling. Hum Mol Genet 2007, 16:2683-2692.
• [2]Federico A, Bianchi S, Dotti MT: The spectrum of mutations for CADASIL diagnosis. Neurol Sci 2005, 26:117-124.
• [3]Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL: Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am J Hum Genet 2006, 78:28-37.
• [4]Koch U, Radtke F: Notch in T-ALL: new players in a complex disease. Trends Immunol 2011, 32:434-442.
• [5]Grill J, Bergthold G, Ferreira C: Pediatric ependymomas: will molecular biology change patient management? Curr Opin Oncol 2011, 23(6):638-642.
• [6]Lobry C, Oh P, Aifantis I: Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think. J Exp Med 2011, 208:1931-1935.
• [7]Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, Miele L: Targeting Notch to target cancer stem cells. Clin Cancer Res 2010, 16:3141-3152.
• [8]Wang Z, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH: Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Res 2011, 31:1105-1113.
• [9]Sethi N, Kang Y: Notch signalling in cancer progression and bone metastasis. Br J Cancer 2011, 105:1805-1810.
• [10]Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J: TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991, 66:649-661.
• [11]Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004, 306:269-271.
• [12]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60:277-300.
• [13]Ciarapica R, Miele L, Giordano A, Locatelli F, Rota R: Enhancer of zeste homolog 2 (EZH2) in pediatric soft tissue sarcomas: first implications. BMC Med 2011, 9:63. BioMed Central Full Text
• [14]Taylor BS, Barretina J, Maki RG, Antonescu CR, Singer S, Ladanyi M: Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer 2011, 11:541-557.
• [15]Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O: Mesenchymal stem cell features of Ewing tumors. Cancer Cell 2007, 11:421-429.
• [16]Torchia EC, Jaishankar S, Baker SJ: Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res 2003, 63:3464-3468.
• [17]Walter D, Satheesha S, Albrecht P, Bornhauser BC, D'Alessandro V, Oesch SM, Rehrauer H, Leuschner I, Koscielniak E, Gengler C, Moch H, Bernasconi M, Niggli FK, Schafer BW: CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres. PLoS One 2011, 6:e19506.
• [18]De Vito C, Riggi N, Cornaz S, Suva ML, Baumer K, Provero P, Stamenkovic I: A TARBP2-dependent miRNA expression profile underlies cancer stem cell properties and provides candidate therapeutic reagents in Ewing sarcoma. Cancer Cell 2012, 21:807-821.
• [19]Andersson ER, Sandberg R, Lendahl U: Notch signaling: simplicity in design, versatility in function. Development 2011, 138:3593-3612.
• [20]Kopan R, Ilagan MX: The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009, 137:216-233.
• [21]Iso T, Kedes L, Hamamori Y: HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003, 194:237-255.
• [22]Rustighi A, Tiberi L, Soldano A, Napoli M, Nuciforo P, Rosato A, Kaplan F, Capobianco A, Pece S, Di Fiore PP, Del Sal G: The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol 2009, 11:133-142.
• [23]Ishitani T, Hirao T, Suzuki M, Isoda M, Ishitani S, Harigaya K, Kitagawa M, Matsumoto K, Itoh M: Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex. Nat Cell Biol 2010, 12:278-285.
• [24]Sanalkumar R, Dhanesh SB, James J: Non-canonical activation of Notch signaling/target genes in vertebrates. Cell Mol Life Sci 2010, 67:2957-2968.
• [25]Perumalsamy LR, Marcel N, Kulkarni S, Radtke F, Sarin A: Distinct spatial and molecular features of notch pathway assembly in regulatory T cells. Sci Signal 2012, 5:ra53.
• [26]Gu JW, Rizzo P, Pannuti A, Golde T, Osborne B, Miele L: Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy. Vasc Cell 2012, 4:7. BioMed Central Full Text
• [27]Dotto GP: Notch tumor suppressor function. Oncogene 2008, 27:5115-5123.
• [28]Dumortier A, Durham AD, Di Piazza M, Vauclair S, Koch U, Ferrand G, Ferrero I, Demehri S, Song LL, Farr AG, Leonard WJ, Kopan R, Miele L, Hohl D, Finke D, Radtke F: Atopic dermatitis-like disease and associated lethal myeloproliferative disorder arise from loss of Notch signaling in the murine skin. PLoS One 2010, 5:e9258.
• [29]Haldar M, Randall RL, Capecchi MR: Synovial sarcoma: from genetics to genetic-based animal modeling. Clin Orthop Relat Res 2008, 466:2156-2167.
• [30]Naka N, Takenaka S, Araki N, Miwa T, Hashimoto N, Yoshioka K, Joyama S, Hamada K, Tsukamoto Y, Tomita Y, Ueda T, Yoshikawa H, Itoh K: Synovial sarcoma is a stem cell malignancy. Stem Cells 2010, 28(7):1119-1131.
• [31]Cironi L, Provero P, Riggi N, Janiszewska M, Suva D, Suva ML, Kindler V, Stamenkovic I: Epigenetic features of human mesenchymal stem cells determine their permissiveness for induction of relevant transcriptional changes by SYT-SSX1. PLoS One 2009, 4:e7904.
• [32]Nagai M, Tanaka S, Tsuda M, Endo S, Kato H, Sonobe H, Minami A, Hiraga H, Nishihara H, Sawa H, Nagashima K: Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha. Proc Natl Acad Sci USA 2001, 98:3843-3848.
• [33]Francis P, Namlos HM, Muller C, Eden P, Fernebro J, Berner JM, Bjerkehagen B, Akerman M, Bendahl PO, Isinger A, Rydholm A, Myklebost O, Nilbert M: Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics 2007, 8:73. BioMed Central Full Text
• [34]Baird K, Davis S, Antonescu CR, Harper UL, Walker RL, Chen Y, Glatfelter AA, Duray PH, Meltzer PS: Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res 2005, 65:9226-9235.
• [35]Pretto D, Barco R, Rivera J, Neel N, Gustavson MD, Eid JE: The synovial sarcoma translocation protein SYT-SSX2 recruits beta-catenin to the nucleus and associates with it in an active complex. Oncogene 2006, 25:3661-3669.
• [36]Segal NH, Pavlidis P, Antonescu CR, Maki RG, Noble WS, DeSantis D, Woodruff JM, Lewis JJ, Brennan MF, Houghton AN, Cordon-Cardo C: Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol 2003, 163:691-700.
• [37]Terry J, Saito T, Subramanian S, Ruttan C, Antonescu CR, Goldblum JR, Downs-Kelly E, Corless CL, Rubin BP, van de Rijn M, Ladanyi M, Nielsen TO: TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. Am J Surg Pathol 2007, 31:240-246.
• [38]Jagdis A, Rubin BP, Tubbs RR, Pacheco M, Nielsen TO: Prospective evaluation of TLE1 as a diagnostic immunohistochemical marker in synovial sarcoma. Am J Surg Pathol 2009, 33:1743-1751.
• [39]Kosemehmetoglu K, Vrana JA, Folpe AL: TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms. Mod Pathol 2009, 22:872-878.
• [40]Grbavec D, Stifani S: Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif. Biochem Biophys Res Commun 1996, 223:701-705.
• [41]Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, Poulin N, Yi L, Rossi FM, Kast J, Capecchi MR, Underhill TM, Nielsen TO: Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell 2012, 21:333-347.
• [42]Su L, Cheng H, Sampaio AV, Nielsen TO, Underhill TM: EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. Oncogene 2010, 29:4352-4361.
• [43]Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, Shah K, Socci ND, Weir BA, Ho A, Chiang DY, Reva B, Mermel CH, Getz G, Antipin Y, Beroukhim R, Major JE, Hatton C, Nicoletti R, Hanna M, Sharpe T, Fennell TJ, Cibulskis K, Onofrio RC, Saito T, Shukla N, Lau C, Nelander S, Silver SJ, Sougnez C, et al.: Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 2010, 42:715-721.
• [44]Graziani I, Eliasz S, De Marco MA, Chen Y, Pass HI, De May RM, Strack PR, Miele L, Bocchetta M: Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res 2008, 68:9678-9685.
• [45]Vo K, Amarasinghe B, Washington K, Gonzalez A, Berlin J, Dang TP: Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation. Mol Cancer 2011, 10:138.
• [46]Wong GW, Knowles GC, Mak TW, Ferrando AA, Zuniga-Pflucker JC: HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRbeta-selected mouse thymocytes. Blood 2012, 120:1439-1448.
• [47]Bailis W, Pear WS: Notch and PI3K: how is the road traveled? Blood 2012, 120:1349-1350.
• [48]Staege MS, Hutter C, Neumann I, Foja S, Hattenhorst UE, Hansen G, Afar D, Burdach SE: DNA microarrays reveal relationship of Ewing family tumors to both endothelial and fetal neural crest-derived cells and define novel targets. Cancer Res 2004, 64:8213-8221.
• [49]May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC, Delattre O, Zucman J, Thomas G, Denny CT: Ewing sarcoma 11;22 translocation produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation. Proc Natl Acad Sci USA 1993, 90:5752-5756.
• [50]Smith R, Owen LA, Trem DJ, Wong JS, Whangbo JS, Golub TR, Lessnick SL: Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma. Cancer Cell 2006, 9:405-416.
• [51]Baliko F, Bright T, Poon R, Cohen B, Egan SE, Alman BA: Inhibition of notch signaling induces neural differentiation in Ewing sarcoma. Am J Pathol 2007, 170:1686-1694.
• [52]Ban J, Bennani-Baiti IM, Kauer M, Schaefer KL, Poremba C, Jug G, Schwentner R, Smrzka O, Muehlbacher K, Aryee DN, Kovar H: EWS-FLI1 suppresses NOTCH-activated p53 in Ewing's sarcoma. Cancer Res 2008, 68:7100-7109.
• [53]Beres BJ, George R, Lougher EJ, Barton M, Verrelli BC, McGlade CJ, Rawls JA, Wilson-Rawls J: Numb regulates Notch1, but not Notch3, during myogenesis. Mech Dev 2011, 128:247-257.
• [54]Bennani-Baiti IM, Aryee DN, Ban J, Machado I, Kauer M, Muhlbacher K, Amann G, Llombart-Bosch A, Kovar H: Notch signalling is off and is uncoupled from HES1 expression in Ewing's sarcoma. J Pathol 2011, 225:353-363.
• [55]Bennani-Baiti IM, Machado I, Llombart-Bosch A, Kovar H: Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum Pathol 2012, 43:1300-1307.
• [56]Schildhaus HU, Riegel R, Hartmann W, Steiner S, Wardelmann E, Merkelbach-Bruse S, Tanaka S, Sonobe H, Schule R, Buettner R, Kirfel J: Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. Hum Pathol 2011, 42:1667-1675.
• [57]Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Toiber D, Kulkarni M, Wang Q, Najafi-Shoushtari SH, Mostoslavsky R, Gygi SP, Gill G, Dyson NJ, Naar AM: A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol Cell 2011, 42:689-699.
• [58]Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, Krones A, Ohgi KA, Zhu P, Garcia-Bassets I, Liu F, Taylor H, Lozach J, Jayes FL, Korach KS, Glass CK, Fu XD, Rosenfeld MG: Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007, 446:882-887.
• [59]Di Stefano L, Walker JA, Burgio G, Corona DF, Mulligan P, Naar AM, Dyson NJ: Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev 2011, 25:17-28.
• [60]Loeb DM, Thornton K, Shokek O: Pediatric soft tissue sarcomas. Surg Clin North Am 2008, 88:615-627, vii.
• [61]Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 2002, 20:2672-2679.
• [62]Davicioni E, Anderson JR, Buckley JD, Meyer WH, Triche TJ: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 2010, 28:1240-1246.
• [63]Williamson D, Missiaglia E, de Reynies A, Pierron G, Thuille B, Palenzuela G, Thway K, Orbach D, Lae M, Freneaux P, Pritchard-Jones K, Oberlin O, Shipley J, Delattre O: Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010, 28:2151-2158.
• [64]Missiaglia E, Williamson D, Chisholm J, Wirapati P, Pierron G, Petel F, Concordet JP, Thway K, Oberlin O, Pritchard-Jones K, Delattre O, Delorenzi M, Shipley J: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 2012, 30:1670-1677.
• [65]Conboy IM, Rando TA: The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev Cell 2002, 3:397-409.
• [66]Conboy IM, Conboy MJ, Smythe GM, Rando TA: Notch-mediated restoration of regenerative potential to aged muscle. Science 2003, 302:1575-1577.
• [67]Buas MF, Kadesch T: Regulation of skeletal myogenesis by Notch. Exp Cell Res 2010, 316:3028-3033.
• [68]Sang L, Coller HA, Roberts JM: Control of the reversibility of cellular quiescence by the transcriptional repressor HES1. Science 2008, 321:1095-1100.
• [69]Roma J, Masia A, Reventos J, Sanchez de Toledo J, Gallego S: Notch pathway inhibition significantly reduces rhabdomyosarcoma invasiveness and mobility in vitro. Clin Cancer Res 2011, 17:505-513.
• [70]Belyea BC, Naini S, Bentley RC, Linardic CM: Inhibition of the Notch-Hey1 axis blocks embryonal rhabdomyosarcoma tumorigenesis. Clin Cancer Res 2011, 17:7324-7336.
• [71]Raimondi L, Ciarapica R, De Salvo M, Verginelli F, Gueguen M, Martini C, De Sio L, Cortese G, Locatelli M, Dang TP, Carlesso N, Miele L, Stifani S, Limon I, Locatelli F, Rota R: 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 Differ 2012, 19:871-881.
• [72]Buas MF, Kabak S, Kadesch T: The Notch effector Hey1 associates with myogenic target genes to repress myogenesis. J Biol Chem 2010, 285:1249-1258.
• [73]Buas MF, Kabak S, Kadesch T: Inhibition of myogenesis by Notch: evidence for multiple pathways. J Cell Physiol 2009, 218:84-93.
• [74]Ono Y, Sensui H, Okutsu S, Nagatomi R: Notch2 negatively regulates myofibroblastic differentiation of myoblasts. J Cell Physiol 2007, 210:358-369.
• [75]Shukla N, Ameur N, Yilmaz I, Nafa K, Lau CY, Marchetti A, Borsu L, Barr FG, Ladanyi M: Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin Cancer Res 2012, 18:748-757.
• [76]Nagao H, Setoguchi T, Kitamoto S, Ishidou Y, Nagano S, Yokouchi M, Abematsu M, Kawabata N, Maeda S, Yonezawa S, Komiya S: RBPJ Is a Novel Target for Rhabdomyosarcoma Therapy. PLoS One 2012, 7:e39268.
• [77]Groth C, Fortini ME: Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Semin Cell Dev Biol 2012, 23:465-472.
• [78]Li K, Li Y, Wu W, Gordon WR, Chang DW, Lu M, Scoggin S, Fu T, Vien L, Histen G, Zheng J, Martin-Hollister R, Duensing T, Singh S, Blacklow SC, Yao Z, Aster JC, Zhou BB: Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem 2008, 283:8046-8054.
• [79]Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW: Therapeutic antibody targeting of individual Notch receptors. Nature 2010, 464:1052-1057.
• [80]Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, Singh M, Chien M, Tan C, Hongo JA, de Sauvage F, Plowman G, Yan M: Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006, 444:1083-1087.
• [81]Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE: Direct inhibition of the NOTCH transcription factor complex. Nature 2009, 462:182-188.
• [82]Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H: Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 2003, 22:1511-1516.
• [83]van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H: Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 2005, 435:959-963.
• [84]Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U, Strobl LJ, Honjo T, Clevers H, Radtke F: Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 2008, 9:377-383.
• [85]Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, Bundred NJ, Clarke RB: Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010, 70:709-718.
• [86]Extance A: Alzheimer's failure raises questions about disease-modifying strategies. Nat Rev Drug Discov 2010, 9:749-751.
• [87]Fouladi M, Stewart CF, Olson J, Wagner LM, Onar-Thomas A, Kocak M, Packer RJ, Goldman S, Gururangan S, Gajjar A, Demuth T, Kun LE, Boyett JM, Gilbertson RJ: Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Clin Oncol 2011, 29:3529-3534.
• [88]Krop I, Demuth T, Guthrie T, Wen PY, Mason WP, Chinnaiyan P, Butowski N, Groves MD, Kesari S, Freedman SJ, Blackman S, Watters J, Loboda A, Podtelezhnikov A, Lunceford J, Chen C, Giannotti M, Hing J, Beckman R, Lorusso P: Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 2012, 30:2307-2313.
• [89]Albain KS, Czerlanis C, Zlobin A, Covington KR, Rajan P, Godellas C, Bova D, Lo SS, Robinson P, Sarker S, Gaynor ER, Cooper R, Aranha G, Czaplicki K, Busby B, Rizzo P, Demuth T, Stiff P, Fuqua SAW, Miele L: Modulation of Cancer and Stem Cell Biomarkers by the Notch Inhibitor MK-0752 Added to Endocrine Therapy for Early Stage ER+ Breast Cancer. Cancer Res 2012, 71:S1-5. 24_MeetingAbstracts
• [90]Rizzo P, Miao H, D'Souza G, Osipo C, Song LL, Yun J, Zhao H, Mascarenhas J, Wyatt D, Antico G, Hao L, Yao K, Rajan P, Hicks C, Siziopikou K, Selvaggi S, Bashir A, Bhandari D, Marchese A, Lendahl U, Qin JZ, Tonetti DA, Albain K, Nickoloff BJ, Miele L: Cross-talk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 2008, 68:5226-5235.
• [91]Hao L, Rizzo P, Osipo C, Pannuti A, Wyatt D, Cheung LW, Sonenshein G, Osborne BA, Miele L: Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 2010, 29:201-213.
• [92]Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H, Linn M, Flohr A, Jakob-Rotne R, Jacobsen H, Glenn K, Heimbrook D, Boylan JF: Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009, 69:7672-7680.
• [93]Tolcher AW, Messersmith WA, Mikulski SM, Papadopoulos KP, Kwak EL, Gibbon DG, Patnaik A, Falchook GS, Dasari A, Shapiro GI, Boylan JF, Xu ZX, Wang K, Koehler A, Song J, Middleton SA, Deutsch J, Demario M, Kurzrock R, Wheler JJ: Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 2012, 30:2348-2353.
• [94]Strosberg JR, Yeatman T, Weber J, Coppola D, Schell MJ, Han G, Almhanna K, Kim R, Valone T, Jump H, Sullivan D: A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer 2012, 48:997-1003.
• [95]Pandya K, Meeke K, Clementz AG, Rogowski A, Roberts J, Miele L, Albain KS, Osipo C: Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer 2011, 105:796-806.
• [96]Aster JC, Blacklow SC: Targeting the notch pathway: twists and turns on the road to rational therapeutics. J Clin Oncol 2012, 30:2418-2420.