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Understanding the Role of Notch in Osteosarcoma

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Current Advances in Osteosarcoma

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 804))

Abstract

The Notch pathway has been described as an oncogene in osteosarcoma, but the myriad functions of all the members of this complex signaling pathway, both in malignant cells and nonmalignant components of tumors, make it more difficult to define Notch as simply an oncogene or a tumor suppressor. The cell-autonomous behaviors caused by Notch pathway manipulation may vary between cell lines but can include changes in proliferation, migration, invasiveness, oxidative stress resistance, and expression of markers associated with stemness or tumor-initiating cells. Beyond these roles, Notch signaling also plays a vital role in regulating tumor angiogenesis and vasculogenesis, which are vital aspects of osteosarcoma growth and behavior in vivo. Further, osteosarcoma cells themselves express relatively low levels of Notch ligand, making it likely that nonmalignant cells, especially endothelial cells and pericytes, are the major source of Notch activation in osteosarcoma tumors in vivo and in patients. As a result, Notch pathway expression is not expected to be uniform across a tumor but likely to be highest in those areas immediately adjacent to blood vessels. Therapeutic targeting of the Notch pathway is likewise expected to be complicated. Most pharmacologic approaches thus far have focused on inhibition of gamma secretase, a protease of the presenilin complex. This enzyme, however, has numerous other target proteins that would be expected to affect osteosarcoma behavior, including CD44, the WNT/β-catenin pathway, and Her-4. In addition, Notch plays a vital role in tissue and organ homeostasis in numerous systems, and toxicities, especially GI intolerance, have limited the effectiveness of gamma secretase inhibitors. New approaches are in development, and the downstream targets of Notch pathway signaling also may turn out to be good targets for therapy. In summary, a full understanding of the complex functions of Notch in osteosarcoma is only now unfolding, and this deeper knowledge will help position the field to better utilize novel therapies as they are developed.

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References

  1. Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194(3):237–255

    PubMed  CAS  Google Scholar 

  2. Kageyama R, Ohtsuka T (1999) The Notch-Hes pathway in mammalian neural development. Cell Res 9(3):179–188

    PubMed  CAS  Google Scholar 

  3. Hilton M, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg H, Teitelbaum S, Ross F, Kopan R, Long F (2008) Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med 14(3):306–314

    PubMed  CAS  PubMed Central  Google Scholar 

  4. Greenwald I, Kovall R (2013) Notch signaling: genetics and structure. WormBook : the online review of C elegans biology, pp 1–28

    Google Scholar 

  5. Kopan R (2012) Notch signaling. Cold Spring Harb Perspect Biol 4(10):a008904

    Google Scholar 

  6. Pittenger M, Mackay A, Beck S, Jaiswal R, Douglas R, Mosca J, Moorman M, Simonetti D, Craig S, Marshak D (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147

    PubMed  CAS  Google Scholar 

  7. Crigler L, Kazhanie A, Yoon T-J, Zakhari J, Anders J, Taylor B, Virador V (2007) Isolation of a mesenchymal cell population from murine dermis that contains progenitors of multiple cell lineages. FASEB J 21(9):2050–2063

    PubMed  CAS  PubMed Central  Google Scholar 

  8. Tang N, Song W-X, Luo J, Haydon R, He T-C (2008) Osteosarcoma development and stem cell differentiation. Clin Orthopaed Relat Res 466(9):2114–2130

    Google Scholar 

  9. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G (1999) A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Gen Dev 13(8):1025–1036

    CAS  Google Scholar 

  10. Haydon R, Luu H, He T-C (2007) Osteosarcoma and osteoblastic differentiation: a new perspective on oncogenesis. Clin Orthopaed Relat Res 454:237–246

    Google Scholar 

  11. Hong J-H, Hwang E, McManus M, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman B, Sharp P, Hopkins N, Yaffe M (2005) TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309(5737):1074–1078

    PubMed  CAS  Google Scholar 

  12. Lian J, Stein G, Javed A, van Wijnen A, Stein J, Montecino M, Hassan M, Gaur T, Lengner C, Young D (2006) Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endoc Metab Disord 7(1–2):1–16

    CAS  Google Scholar 

  13. Luu H, Song W-X, Luo X, Manning D, Luo J, Deng Z-L, Sharff K, Montag A, Haydon R, He T-C (2007) Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthopaed Res 25(5):665–677

    CAS  Google Scholar 

  14. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng J, Behringer R, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108(1):17–29

    PubMed  CAS  Google Scholar 

  15. Yamaguchi A, Komori T, Suda T (2000) Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endoc Rev 21(4):393–411

    CAS  Google Scholar 

  16. Deng Z-L, Sharff K, Tang N, Song W-X, Luo J, Luo X, Chen J, Bennett E, Reid R, Manning D, Xue A, Montag A, Luu H, Haydon R, He T-C (2008) Regulation of osteogenic differentiation during skeletal development. Front Biosci 13:2001–2021

    PubMed  CAS  Google Scholar 

  17. Olsen B, Reginato A, Wang W (2000) Bone development. Annu Rev Cell Dev Biol 16:191–220

    PubMed  CAS  Google Scholar 

  18. Harada S-i, Rodan G (2003) Control of osteoblast function and regulation of bone mass. Nature 423(6937):349–355

    PubMed  CAS  Google Scholar 

  19. Ralston S, de Crombrugghe B (2006) Genetic regulation of bone mass and susceptibility to osteoporosis. Gen Dev 20(18):2492–2506

    CAS  Google Scholar 

  20. Gazzerro E, Canalis E (2006) Bone morphogenetic proteins and their antagonists. Rev Endoc Metab Disord 7(1–2):51–65

    CAS  Google Scholar 

  21. Krishnan V, Bryant H, Macdougald O (2006) Regulation of bone mass by Wnt signaling. J Clin Investig 116(5):1202–1209

    PubMed  CAS  PubMed Central  Google Scholar 

  22. Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E (2006) Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem 281(10):6203–6210

    PubMed  CAS  Google Scholar 

  23. Banerjee C, McCabe L, Choi J, Hiebert S, Stein J, Stein G, Lian J (1997) Runt homology domain proteins in osteoblast differentiation: AML3/CBFA1 is a major component of a bone-specific complex. J Cell Biochem 66(1):1–8

    PubMed  CAS  Google Scholar 

  24. Ducy P, Zhang R, Geoffroy V, Ridall A, Karsenty G (1997) Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89(5):747–754

    PubMed  CAS  Google Scholar 

  25. Motohiko S, Natsuo Y, Takanobu N, Hirohisa K, Mizuo S, Seiichi H, Yukihiko K, Shintaro N, Takahiro O (1998) Expression of bone matrix proteins mRNA during distraction osteogenesis. J Bone Miner Res 13(8):1221–1231

    Google Scholar 

  26. Xiao Z, Hinson T, Quarles L (1999) Cbfa1 isoform overexpression upregulates osteocalcin gene expression in non-osteoblastic and pre-osteoblastic cells. J Cell Biochem 74(4):596–605

    PubMed  CAS  Google Scholar 

  27. Prince M, Banerjee C, Javed A, Green J, Lian J, Stein G, Bodine P, Komm B (2001) Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts. J Cell Biochem 80(3):424–440

    PubMed  CAS  Google Scholar 

  28. Pregizer S, Barski A, Gersbach C, García A, Frenkel B (2007) Identification of novel Runx2 targets in osteoblasts: cell type-specific BMP-dependent regulation of Tram2. J Cell Biochem 102(6):1458–1471

    PubMed  CAS  Google Scholar 

  29. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson R, Gao Y, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89(5):755–764

    PubMed  CAS  Google Scholar 

  30. Otto F, Thornell A, Crompton T, Denzel A, Gilmour K, Rosewell I, Stamp G, Beddington R, Mundlos S, Olsen B, Selby P, Owen M (1997) Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89(5):765–771

    PubMed  CAS  Google Scholar 

  31. Engin F, Yao Z, Yang T, Zhou G, Bertin T, Jiang M, Chen Y, Wang L, Zheng H, Sutton R, Boyce B, Lee B (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14(3):299–305

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Sciaudone M, Gazzerro E, Priest L, Delany A, Canalis E (2003) Notch 1 impairs osteoblastic cell differentiation. Endocrinology 144(12):5631–5639

    PubMed  CAS  Google Scholar 

  33. Tezuka K-I, Yasuda M, Watanabe N, Morimura N, Kuroda K, Miyatani S, Hozumi N (2002) Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res 17(2):231–239

    PubMed  CAS  Google Scholar 

  34. Zamurovic N, Cappellen D, Rohner D, Susa M (2004) Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem 279(36):37704–37715

    PubMed  CAS  Google Scholar 

  35. Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A (2003) Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 278(34):32227–32235

    PubMed  CAS  Google Scholar 

  36. Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, Takayanagi H (2005) NFAT and Osterix cooperatively regulate bone formation. Nat Med 11(8):880–885

    PubMed  CAS  Google Scholar 

  37. Winslow M, Pan M, Starbuck M, Gallo E, Deng L, Karsenty G, Crabtree G (2006) Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10(6):771–782

    PubMed  CAS  Google Scholar 

  38. Ikeda F, Nishimura R, Matsubara T, Hata K, Reddy S, Yoneda T (2006) Activation of NFAT signal in vivo leads to osteopenia associated with increased osteoclastogenesis and bone-resorbing activity. J Immunol 177(4):2384–2390

    PubMed  CAS  Google Scholar 

  39. Dallas D, Genever P, Patton A, Millichip M, McKie N, Skerry T (1999) Localization of ADAM10 and Notch receptors in bone. Bone 25(1):9–15

    PubMed  CAS  Google Scholar 

  40. Qi H, Rand M, Wu X, Sestan N, Wang W, Rakic P, Xu T, Artavanis-Tsakonas S (1999) Processing of the notch ligand delta by the metalloprotease Kuzbanian. Science 283(5398):91–94

    PubMed  CAS  Google Scholar 

  41. Luo X, Chen J, Song W-X, Tang N, Luo J, Deng Z-L, Sharff K, He G, Bi Y, He B-C, Bennett E, Huang J, Kang Q, Jiang W, Su Y, Zhu G-H, Yin H, He Y, Wang Y, Souris J, Chen L, Zuo G-W, Montag A, Reid R, Haydon R, Luu H, He T-C (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Lab Investig 88(12):1264–1277

    PubMed  CAS  Google Scholar 

  42. Reya T, Morrison S, Clarke M, Weissman I (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    PubMed  CAS  Google Scholar 

  43. Thomas D, Kansara M (2006) Epigenetic modifications in osteogenic differentiation and transformation. Journal of cellular biochemistry 98(4):757–769

    PubMed  CAS  Google Scholar 

  44. Wagner E, He B-C, Chen L, Zuo G-W, Zhang W, Shi Q, Luo Q, Luo X, Liu B, Luo J, Rastegar F, He C, Hu Y, Boody B, Luu H, He T-C, Deng Z-L, Haydon R (2010) Therapeutic Implications of PPARgamma in Human Osteosarcoma. PPAR Res 2010:956427

    PubMed  PubMed Central  Google Scholar 

  45. Thomas D, Johnson S, Sims N, Trivett M, Slavin J, Rubin B, Waring P, McArthur G, Walkley C, Holloway A, Diyagama D, Grim J, Clurman B, Bowtell D, Lee J-S, Gutierrez G, Piscopo D, Carty S, Hinds P (2004) Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. J Cell Biol 167(5):925–934

    PubMed  CAS  PubMed Central  Google Scholar 

  46. Dailey D, Anfinsen K, Pfaff L, Ehrhart E, Charles J, Bønsdorff T, Thamm D, Powers B, Jonasdottir T, Duval D (2013) HES1, a target of Notch signaling, is elevated in canine osteosarcoma, but reduced in the most aggressive tumors. BMC Vet Res 9(1):130

    PubMed  PubMed Central  Google Scholar 

  47. Engin F, Bertin T, Ma O, Jiang MM, Wang L, Sutton RE, Donehower LA, Lee B (2009) Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet 18(8):1464–1470

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Hughes DPM (2009) How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. In: Jaffe N, Bruland OS, Bielack S (eds) Pediatric and adolescent osteosarcoma. Cancer treatment and research, 152nd edn. Springer, New York, NY, pp 479–496

    Google Scholar 

  49. Li Y, Zhang J, Ma D, Zhang L, Si M, Yin H, Li J (2012) Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling. FEBS J 279(12):2247–2259

    PubMed  CAS  Google Scholar 

  50. Mu X, Isaac C, Greco N, Huard J, Weiss K (2013) Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells. Front Oncol 3:143

    PubMed  PubMed Central  Google Scholar 

  51. Tanaka M, Setoguchi T, Hirotsu M, Gao H, Sasaki H, Matsunoshita Y, Komiya S (2009) Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer 100(12):1957–1965

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Zhang P, Yang Y, Nolo R, Zweidler-McKay PA, Hughes DP (2010) Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. Oncogene 29(20):2916–2926. doi:10.1038/onc.2010.62

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Artavanis-Tsakonas S, Rand M, Lake R (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776

    PubMed  CAS  Google Scholar 

  54. Shawber C, Kitajewski J (2004) Notch function in the vasculature: insights from zebrafish, mouse and man. Bioessays 26(3):225–234

    PubMed  CAS  Google Scholar 

  55. Kume T (2009) Novel insights into the differential functions of Notch ligands in vascular formation. J Angiogen Res 1:8

    Google Scholar 

  56. Limbourg F, Takeshita K, Radtke F, Bronson R, Chin M, Liao J (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111(14):1826–1832

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Krebs L, Xue Y, Norton C, Shutter J, Maguire M, Sundberg J, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith G, Stark K, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Gen Dev 14(11):1343–1352

    CAS  Google Scholar 

  58. Swiatek P, Lindsell C, del Amo F, Weinmaster G, Gridley T (1994) Notch1 is essential for postimplantation development in mice. Gen Dev 8(6):707–719

    CAS  Google Scholar 

  59. Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman J, Tsujimoto Y (1999) Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development 126(15):3415–3424

    PubMed  CAS  Google Scholar 

  60. Xue Y, Gao X, Lindsell C, Norton C, Chang B, Hicks C, Gendron-Maguire M, Rand E, Weinmaster G, Gridley T (1999) Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8(5):723–730

    PubMed  CAS  Google Scholar 

  61. Sörensen I, Adams R, Gossler A (2009) DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 113(22):5680–5688

    PubMed  Google Scholar 

  62. HrabÄ de Angelis M, McIntyre 2nd J, Gossler A (1997) Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386(6626):717–721

    Google Scholar 

  63. Gale N, Dominguez M, Noguera I, Pan L, Hughes V, Valenzuela D, Murphy A, Adams N, Lin H, Holash J, Thurston G, Yancopoulos G (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A 101(45):15949–15954

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse DLL4 in artery development. Gen Dev 18(20):2474–2478

    CAS  Google Scholar 

  65. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Gen Dev 18(8):901–911

    CAS  Google Scholar 

  66. Krebs L, Shutter J, Tanigaki K, Honjo T, Stark K, Gridley T (2004) Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Gen Dev 18(20):2469–2473

    CAS  Google Scholar 

  67. Herreman A, Hartmann D, Annaert W, Saftig P, Craessaerts K, Serneels L, Umans L, Schrijvers V, Checler F, Vanderstichele H, Baekelandt V, Dressel R, Cupers P, Huylebroeck D, Zwijsen A, Van Leuven F, De Strooper B (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96(21):11872–11877

    PubMed  CAS  PubMed Central  Google Scholar 

  68. Nakajima M, Yuasa S, Ueno M, Takakura N, Koseki H, Shirasawa T (2003) Abnormal blood vessel development in mice lacking presenilin-1. Mech Dev 120(6):657–667

    PubMed  CAS  Google Scholar 

  69. Uyttendaele H, Ho J, Rossant J, Kitajewski J (2001) Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci U S A 98(10):5643–5648

    PubMed  CAS  PubMed Central  Google Scholar 

  70. Krebs L, Starling C, Chervonsky A, Gridley T (2010) Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 48(3):146–150

    PubMed  CAS  PubMed Central  Google Scholar 

  71. Shawber C, Das I, Francisco E, Kitajewski J (2003) Notch signaling in primary endothelial cells. Ann N Y Acad Sci 995:162–170

    PubMed  CAS  Google Scholar 

  72. Kofler N, Shawber C, Kangsamaksin T, Reed H, Galatioto J, Kitajewski J (2011) Notch signaling in developmental and tumor angiogenesis. Gen Cancer 2(12):1106–1116

    CAS  Google Scholar 

  73. Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2(7):a006502

    PubMed  PubMed Central  Google Scholar 

  74. Ferrara N, Gerber H-P, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    PubMed  CAS  Google Scholar 

  75. Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck T, Pelletier N, Ferrara N (2001) Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem 276(5):3222–3230

    PubMed  CAS  Google Scholar 

  76. Shalaby F, Rossant J, Yamaguchi T, Gertsenstein M, Wu X, Breitman M, Schuh A (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376(6535):62–66

    PubMed  CAS  Google Scholar 

  77. Kappas N, Zeng G, Chappell J, Kearney J, Hazarika S, Kallianos K, Patterson C, Annex B, Bautch V (2008) The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching. J Cell Biol 181(5):847–858

    PubMed  CAS  PubMed Central  Google Scholar 

  78. Shibuya M (2006) Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 39(5):469

    PubMed  CAS  Google Scholar 

  79. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea K, Powell-Braxton L, Hillan K, Moore M (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380(6573):439–442

    PubMed  CAS  Google Scholar 

  80. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380(6573):435–439

    PubMed  CAS  Google Scholar 

  81. Suchting S, Freitas C, le Noble F, Benedito R, Bréant C, Duarte A, Eichmann A (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci U S A 104(9):3225–3230

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Hellström M, Phng L-K, Hofmann J, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson A-K, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe M, Kalén M, Gerhardt H, Betsholtz C (2007) DLL4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445(7129):776–780

    PubMed  Google Scholar 

  83. Lobov I, Renard R, Papadopoulos N, Gale N, Thurston G, Yancopoulos G, Wiegand S (2007) Delta-like ligand 4 (DLL4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A 104(9):3219–3224

    PubMed  CAS  PubMed Central  Google Scholar 

  84. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177

    PubMed  CAS  PubMed Central  Google Scholar 

  85. del Toro R, Prahst C, Mathivet T, Siegfried G, Kaminker J, Larrivee B, Breant C, Duarte A, Takakura N, Fukamizu A, Penninger J, Eichmann A (2010) Identification and functional analysis of endothelial tip cell-enriched genes. Blood 116(19):4025–4033

    PubMed  Google Scholar 

  86. Mats H, Li-Kun P, Holger G (2007) VEGF and notch signaling: the yin and yang of angiogenic sprouting. Cell Adh Migr 1(3):133–136

    Google Scholar 

  87. Benedito R, Hellström M (2013) Notch as a hub for signaling in angiogenesis. Exp Cell Res 319(9):1281–1288

    PubMed  CAS  Google Scholar 

  88. Eilken H, Adams R (2010) Turning on the angiogenic microswitch. Nat Med 16(8):853–854

    PubMed  CAS  Google Scholar 

  89. Harrington L, Sainson R, Williams C, Taylor J, Shi W, Li J-L, Harris A (2008) Regulation of multiple angiogenic pathways by DLL4 and Notch in human umbilical vein endothelial cells. Microvasc Res 75(2):144–154

    PubMed  CAS  Google Scholar 

  90. Eilken H, Adams R (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22(5):617–625

    PubMed  CAS  Google Scholar 

  91. Iruela-Arispe M, Davis G (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16(2):222–231

    PubMed  CAS  Google Scholar 

  92. Dejana E, Tournier-Lasserve E, Weinstein B (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16(2):209–221

    PubMed  CAS  Google Scholar 

  93. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454(7204):656–660

    PubMed  CAS  Google Scholar 

  94. Benedito R, Rocha S, Woeste M, Zamykal M, Radtke F, Casanovas O, Duarte A, Pytowski B, Adams R (2012) Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature 484(7392):110–114

    PubMed  CAS  Google Scholar 

  95. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco C, Murtomäki A, Aranda E, Miura N, Ylä-Herttuala S, Fruttiger M, Mäkinen T, Eichmann A, Pollard J, Gerhardt H, Alitalo K (2011) VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13(10):1202–1213

    PubMed  CAS  PubMed Central  Google Scholar 

  96. Hisaki H, Tsutomu K (2009) Foxc2 transcription factor as a regulator of angiogenesis via induction of integrin β3 expression. Cell Adh Migr 3(1):24–26

    Google Scholar 

  97. Chappell J, Taylor S, Ferrara N, Bautch V (2009) Local guidance of emerging vessel sprouts requires soluble Flt-1. Dev Cell 17(3):377–386

    PubMed  CAS  PubMed Central  Google Scholar 

  98. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams R (2009) The notch ligands DLL4 and Jagged1 have opposing effects on angiogenesis. Cell 137(6):1124–1135

    PubMed  CAS  Google Scholar 

  99. Thomas J-L, Baker K, Han J, Calvo C, Nurmi H, Eichmann A, Alitalo K (2013) Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci 70(10):1779–1792

    PubMed  CAS  PubMed Central  Google Scholar 

  100. Phng L-K, Potente M, Leslie J, Babbage J, Nyqvist D, Lobov I, Ondr J, Rao S, Lang R, Thurston G, Gerhardt H (2009) Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev Cell 16(1):70–82

    PubMed  CAS  Google Scholar 

  101. Sainson R, Aoto J, Nakatsu M, Holderfield M, Conn E, Koller E, Hughes C (2005) Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 19(8):1027–1029

    PubMed  CAS  Google Scholar 

  102. Kageyama R, Masamizu Y, Niwa Y (2007) Oscillator mechanism of Notch pathway in the segmentation clock. Dev Dyn 236(6):1403–1409

    PubMed  CAS  Google Scholar 

  103. Jakobsson L, Franco C, Bentley K, Collins R, Ponsioen B, Aspalter I, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12(10):943–953

    PubMed  CAS  Google Scholar 

  104. Leslie J, Ariza-McNaughton L, Bermange A, McAdow R, Johnson S, Lewis J (2007) Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134(5):839–844

    PubMed  CAS  Google Scholar 

  105. Noguera-Troise I, Daly C, Papadopoulos N, Coetzee S, Boland P, Gale N, Lin H, Yancopoulos G, Thurston G (2006) Blockade of DLL4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444(7122):1032–1037

    PubMed  CAS  Google Scholar 

  106. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang W-C, Chanthery Y, Kowalski J, Watts R, Callahan C, Kasman I, Singh M, Chien M, Tan C, Hongo J-AS, de Sauvage F, Plowman G, Yan M (2006) Inhibition of DLL4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444(7122):1083–1087

    PubMed  CAS  Google Scholar 

  107. Siekmann A, Lawson N (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445(7129):781–784

    PubMed  CAS  Google Scholar 

  108. Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16(2):196–208

    PubMed  CAS  Google Scholar 

  109. Siekmann A, Affolter M, Belting H-G (2013) The tip cell concept 10 years after: new players tune in for a common theme. Exp Cell Res 319(9):1255–1263

    PubMed  CAS  Google Scholar 

  110. Benjamin L, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125(9):1591–1598

    PubMed  CAS  Google Scholar 

  111. Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97(6):512–523

    PubMed  CAS  Google Scholar 

  112. Villa N, Walker L, Lindsell C, Gasson J, Iruela-Arispe M, Weinmaster G (2001) Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108(1–2):161–164

    PubMed  CAS  Google Scholar 

  113. Liu H, Kennard S, Lilly B (2009) NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res 104(4):466–475

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Schadler KL, Zweidler-McKay PA, Guan H, Kleinerman ES (2010) Delta-like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing’s sarcoma. Clin Cancer Res 16(3):848–856

    PubMed  CAS  PubMed Central  Google Scholar 

  115. Stewart KS, Zhou Z, Zweidler-McKay P, Kleinerman ES (2011) Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. Blood 117(2):719–726

    PubMed  CAS  PubMed Central  Google Scholar 

  116. Crowther M, Brown N, Bishop E, Lewis C (2001) Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors. J Leukoc Biol 70(4):478–490

    PubMed  CAS  Google Scholar 

  117. Schmidt T, Carmeliet P (2010) Blood-vessel formation: bridges that guide and unite. Nature 465(7299):697–699

    PubMed  CAS  Google Scholar 

  118. Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S (2006) Potential role of microglia in retinal blood vessel formation. Investig Ophthalmol Vis Sci 47(8):3595–3602

    Google Scholar 

  119. Fantin A, Vieira J, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson S, Ruhrberg C (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840

    PubMed  CAS  PubMed Central  Google Scholar 

  120. Bigas A, Martin D, Milner L (1998) Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines. Mol Cell Biol 18(4):2324–2333

    PubMed  CAS  PubMed Central  Google Scholar 

  121. Monsalve E, Pérez M, Rubio A, Ruiz-Hidalgo M, Baladrón V, García-Ramírez J, Gómez J, Laborda J, Díaz-Guerra M (2006) Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol 176(9):5362–5373

    PubMed  CAS  Google Scholar 

  122. Singh N, Phillips R, Iscove N, Egan S (2000) Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis. Exp Hematol 28(5):527–534

    PubMed  CAS  Google Scholar 

  123. Murakami M, Zheng Y, Hirashima M, Suda T, Morita Y, Ooehara J, Ema H, Fong G-H, Shibuya M (2008) VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler Thromb Vasc Biol 28(4):658–664

    PubMed  CAS  Google Scholar 

  124. Outtz H, Wu J, Wang X, Kitajewski J (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185(7):4363–4373

    PubMed  Google Scholar 

  125. Outtz H, Tattersall I, Kofler N, Steinbach N, Kitajewski J (2011) Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118(12):3436–3439

    PubMed  CAS  PubMed Central  Google Scholar 

  126. Leung D, Cachianes G, Kuang W, Goeddel D, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309

    PubMed  CAS  Google Scholar 

  127. Hu P, Liu W, Wang L, Yang M, Du J (2013) High circulating VEGF level predicts poor overall survival in lung cancer. J Cancer Res Clin Oncol 139(7):1157–1167

    PubMed  CAS  Google Scholar 

  128. Claesson-Welsh L, Welsh M (2013) VEGFA and tumour angiogenesis. J Intern Med 273(2):114–127

    PubMed  CAS  Google Scholar 

  129. Yu X-W, Wu T-Y, Yi X, Ren W-P, Zhou Z-B, Sun Y-Q, Zhang C-Q (2013) Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis. Tumour Biol 35(1):155–160

    PubMed  Google Scholar 

  130. Chen D, Zhang Y-J, K-w Z, Wang W-C (2013) A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma. Tumour Biol 34(3):1895–1899

    PubMed  CAS  Google Scholar 

  131. Lammli J, Fan M, Rosenthal H, Patni M, Rinehart E, Vergara G, Ablah E, Wooley P, Lucas G, Yang S-Y (2012) Expression of vascular endothelial growth factor correlates with the advance of clinical osteosarcoma. Int Orthopaed 36(11):2307–2313

    Google Scholar 

  132. Ranganathan P, Weaver K, Capobianco A (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer 11(5):338–351

    PubMed  CAS  Google Scholar 

  133. Patel N, Li J-L, Generali D, Poulsom R, Cranston D, Harris A (2005) Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65(19):8690–8697

    PubMed  CAS  Google Scholar 

  134. Rehman A, Wang C-Y (2006) Notch signaling in the regulation of tumor angiogenesis. Trend Cell Biol 16(6):293–300

    CAS  Google Scholar 

  135. Dufraine J, Funahashi Y, Kitajewski J (2008) Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27(38):5132–5137

    PubMed  CAS  PubMed Central  Google Scholar 

  136. Chi Sabins N, Taylor J, Fabian K, Appleman L, Maranchie J, Stolz D, Storkus W (2013) DLK1: a novel target for immunotherapeutic remodeling of the tumor blood vasculature. Mol Ther 21(10):1958–1968

    PubMed  CAS  PubMed Central  Google Scholar 

  137. Li J-L, Sainson R, Shi W, Leek R, Harrington L, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner J, Harris A (2007) Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 67(23):11244–11253

    PubMed  CAS  Google Scholar 

  138. Segarra M, Williams C, Sierra MDLL, Bernardo M, McCormick P, Maric D, Regino C, Choyke P, Tosato G (2008) DLL4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth. Blood 112(5):1904–1911

    PubMed  CAS  PubMed Central  Google Scholar 

  139. Trindade A, Kumar S, Scehnet J, Lopes-da-Costa L, Becker J, Jiang W, Liu R, Gill P, Duarte A (2008) Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood 112(5):1720–1729

    PubMed  CAS  PubMed Central  Google Scholar 

  140. Williams C, Li J-L, Murga M, Harris A, Tosato G (2006) Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107(3):931–939

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Zhang J-P, Qin H-Y, Wang L, Liang L, Zhao X-C, Cai W-X, Wei Y-N, Wang C-M, Han H (2011) Overexpression of Notch ligand DLL1 in B16 melanoma cells leads to reduced tumor growth due to attenuated vascularization. Cancer Lett 309(2):220–227

    PubMed  CAS  Google Scholar 

  142. Zhao X-C, Dou G-R, Wang L, Liang L, Tian D-M, Cao X-L, Qin H-Y, Wang C-M, Zhang P, Han H (2013) Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human delta-like 1 targeted to vascular endothelial cells. Neoplasia 15(7):815–825

    PubMed  CAS  PubMed Central  Google Scholar 

  143. Scehnet J, Jiang W, Kumar S, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley E, Duarte A, Gill P (2007) Inhibition of DLL4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109(11):4753–4760

    PubMed  CAS  PubMed Central  Google Scholar 

  144. Yan M, Callahan C, Beyer J, Allamneni K, Zhang G, Ridgway J, Niessen K, Plowman G (2010) Chronic DLL4 blockade induces vascular neoplasms. Nature 463(7282):7

    Google Scholar 

  145. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6, Supplement 16):15–18

    PubMed  CAS  Google Scholar 

  146. Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle L, Reboldi A, Favaro E, Mecarozzi M, Di Mario G, Screpanti I, Ponzoni M, Doglioni C, Amadori A (2009) Cross-talk between tumor and endothelial cells involving the Notch3-DLL4 interaction marks escape from tumor dormancy. Cancer Res 69(4):1314–1323

    PubMed  CAS  Google Scholar 

  147. Indraccolo S, Favaro E, Amadori A (2006) Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis. Cell Cycle 5(16):1751–1755

    PubMed  CAS  Google Scholar 

  148. Almog N, Ma L, Raychowdhury R, Schwager C, Erber R, Short S, Hlatky L, Vajkoczy P, Huber PE, Folkman J, Abdollahi A (2009) Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. Cancer Res 69(3):836–844

    PubMed  CAS  Google Scholar 

  149. Indraccolo S (2013) Insights into the regulation of tumor dormancy by angiogenesis in experimental tumors. Adv Exp Med Biol 734:37–52

    PubMed  Google Scholar 

  150. Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131(5):965–973

    PubMed  CAS  Google Scholar 

  151. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689

    PubMed  CAS  Google Scholar 

  152. Zweidler-McKay P, Pear W (2004) Notch and T cell malignancy. Semin Cancer Biol 14(5):329–340

    PubMed  CAS  Google Scholar 

  153. Hu YY, Zheng MH, Zhang R, Liang YM, Han H (2012) Notch signaling pathway and cancer metastasis. Adv Exp Med Biol 727:186–198

    PubMed  CAS  Google Scholar 

  154. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3(6):565–576

    PubMed  CAS  Google Scholar 

  155. 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 (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435(7044):959–963

    PubMed  Google Scholar 

  156. Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH (2010) Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J Cell Biochem 109(4):726–736

    PubMed  CAS  Google Scholar 

  157. Weng AP, Ferrando AA, Lee W, Morris JPT, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271

    PubMed  CAS  Google Scholar 

  158. Bai F, Tagen M, Colotta C, Miller L, Fouladi M, Stewart CF (2010) Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci 878(25):2348–2352

    PubMed  CAS  PubMed Central  Google Scholar 

  159. Cheng X, O’Neill HC (2009) Oncogenesis and cancer stem cells: current opinions and future directions. J Cell Mol Med 13(11–12):4377–4384

    PubMed  CAS  Google Scholar 

  160. 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 (2011) Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J Clin Oncol 29(26):3529–3534

    PubMed  CAS  PubMed Central  Google Scholar 

  161. Mazumdar J, Dondeti V, Simon MC (2009) Hypoxia-inducible factors in stem cells and cancer. J Cell Mol Med 13(11–12):4319–4328

    PubMed  CAS  PubMed Central  Google Scholar 

  162. Shih Ie M, Wang TL (2007) Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67(5):1879–1882

    PubMed  Google Scholar 

  163. Wang Z, Li Y, Banerjee S, Sarkar FH (2009) Emerging role of Notch in stem cells and cancer. Cancer Lett 279(1):8–12

    PubMed  CAS  PubMed Central  Google Scholar 

  164. Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC, Aster JC, Allman D, Pear WS (2005) Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 106(12):3898–3906

    PubMed  CAS  PubMed Central  Google Scholar 

  165. Kannan S, Sutphin RM, Hall MG, Golfman LS, Fang W, Nolo RM, Akers LJ, Hammitt RA, McMurray JS, Kornblau SM, Melnick AM, Figueroa ME, Zweidler-McKay PA (2013) Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med 210(2):321–337

    PubMed  CAS  PubMed Central  Google Scholar 

  166. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, Millar SE, Pear WS, Parmacek MS (2006) Impaired Notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 66(15):7438–7444

    PubMed  CAS  Google Scholar 

  167. Zage P, Nolo R, Fang W, Stewart J, Garcia-Manero G, Zweidler-McKay P (2012) Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr Blood Cancer 58(5):682–689

    PubMed  PubMed Central  Google Scholar 

  168. Kunnimalaiyaan M, Chen H (2007) Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist 12(5):535–542

    PubMed  CAS  Google Scholar 

  169. Dumont AG, Yang Y, Reynoso D, Katz D, Trent JC, Hughes DP (2012) Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors. Carcinogenesis 33(9):1674–1683

    PubMed  CAS  PubMed Central  Google Scholar 

  170. Hughes DP (2009) How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat Res 152:479–496

    PubMed  Google Scholar 

  171. Capaccione KM, Pine SR (2013) The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis 34(7):1420–1430

    PubMed  CAS  PubMed Central  Google Scholar 

  172. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li Y-M, Eberhart CG (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66(15):7445–7452

    PubMed  CAS  Google Scholar 

  173. Farnie G, Clarke R (2007) Mammary stem cells and breast cancer – role of Notch signalling. Stem Cell Rev 3(2):169–175

    PubMed  CAS  Google Scholar 

  174. Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, Kalemkerian GP, Wicha MS (2013) Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin Cancer Res 19(8):1972–1980

    PubMed  CAS  PubMed Central  Google Scholar 

  175. Korkaya H, Wicha MS (2009) HER-2, Notch, and breast cancer stem cells: targeting an axis of evil. Clin Cancer Res 15(6):1845–1847

    PubMed  CAS  Google Scholar 

  176. Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay JW, Wistuba II, Minna JD (2010) Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res 70(23):9937–9948

    PubMed  CAS  PubMed Central  Google Scholar 

  177. Wang J, Sullenger B, Rich J (2012) Notch signaling in cancer stem cells. Adv Exp Med Biol 727:174–185

    PubMed  CAS  Google Scholar 

  178. Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR, Iwakuma T (2010) CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res 70(11):4602–4612

    PubMed  CAS  PubMed Central  Google Scholar 

  179. Williams S, Maecker H, French D, Liu J, Gregg A, Silverstein L, Cao T, Carano R, Dixit V (2011) USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Cell 146(6):918–930

    PubMed  CAS  Google Scholar 

  180. Wang L, Park P, Lin C (2009) Characterization of stem cell attributes in human osteosarcoma cell lines. Cancer Biol Ther 8(6):543–552

    PubMed  CAS  Google Scholar 

  181. Siclari V, Qin L (2010) Targeting the osteosarcoma cancer stem cell. J Orthop Surg Res 5:78

    PubMed  PubMed Central  Google Scholar 

  182. Gibbs C, Levings P, Ghivizzani S (2011) Evidence for the osteosarcoma stem cell. Curr Orthop Pract 22(4):322–326

    PubMed  PubMed Central  Google Scholar 

  183. Di Fiore R, Fanale D, Drago-Ferrante R, Chiaradonna F, Giuliano M, De Blasio A, Amodeo V, Corsini L, Bazan V, Tesoriere G, Vento R, Russo A (2012) Genetic and molecular characterization of the human osteosarcoma 3AB-OS cancer stem cell line: a possible model for studying osteosarcoma origin and stemness. J Cell Physiol 228(6):1189–1201

    Google Scholar 

  184. Di Fiore R, Santulli A, Ferrante R, Giuliano M, De Blasio A, Messina C, Pirozzi G, Tirino V, Tesoriere G, Vento R (2009) Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment. J Cell Physiol 219(2):301–313

    PubMed  Google Scholar 

  185. Tang Q, Zhao Z, Li J, Liang Y, Yin J, Zou C, Xie X, Zeng Y, Shen J, Kang T, Wang J (2011) Salinomycin inhibits osteosarcoma by targeting its tumor stem cells. Cancer Lett 311(1):113–121

    PubMed  CAS  Google Scholar 

  186. Wilson H, Huelsmeyer M, Chun R, Young K, Friedrichs K, Argyle D (2008) Isolation and characterisation of cancer stem cells from canine osteosarcoma. Vet J 175(1):69–75

    PubMed  CAS  Google Scholar 

  187. Martins-Neves S, Lopes Á, do Carmo A, Paiva A, Simoes P, Abrunhosa A, Gomes C (2012) Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line. BMC Cancer 12:139

    PubMed  CAS  PubMed Central  Google Scholar 

  188. Liu B, Ma W, Jha R, Gurung K (2011) Cancer stem cells in osteosarcoma: recent progress and perspective. Acta Oncol 50(8):1142–1150

    PubMed  CAS  Google Scholar 

  189. Basu-Roy U, Basilico C, Mansukhani A (2012) Perspectives on cancer stem cells in osteosarcoma. Cancer Lett 338(1):158–167

    PubMed  PubMed Central  Google Scholar 

  190. Wang L, Park P, Zhang H, La Marca F, Lin C (2011) Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity. Int J Cancer 128(2):294–303

    PubMed  CAS  Google Scholar 

  191. Wang L, Park P, Zhang H, La Marca F, Claeson A, Valdivia J, Lin C (2011) BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther 11(5):457–463

    PubMed  CAS  PubMed Central  Google Scholar 

  192. Rainusso N, Man T, Lau C, Hicks J, Shen J, Yu A, Wang L, Rosen J (2011) Identification and gene expression profiling of tumor-initiating cells isolated from human osteosarcoma cell lines in an orthotopic mouse model. Cancer Biol Ther 12(4):278–287

    PubMed  CAS  PubMed Central  Google Scholar 

  193. Yang M, Yan M, Zhang R, Li J, Luo Z (2011) Side population cells isolated from human osteosarcoma are enriched with tumor-initiating cells. Cancer Sci 102(10):1774–1781

    PubMed  CAS  Google Scholar 

  194. Huang Y, Dai H, Guo Q (2012) TSSC3 overexpression reduces stemness and induces apoptosis of osteosarcoma tumor-initiating cells. Apoptosis 17(8):749–761

    PubMed  CAS  Google Scholar 

  195. Khanna C, Prehn J, Yeung C, Caylor J, Tsokos M, Helman L (2000) An orthotopic model of murine osteosarcoma with clonally related variants differing in pulmonary metastatic potential. Clin Exp Meta 18(3):261–271

    CAS  Google Scholar 

  196. Khanna C, Khan J, Nguyen P, Prehn J, Caylor J, Yeung C, Trepel J, Meltzer P, Helman L (2001) Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res 61(9):3750–3759

    PubMed  CAS  Google Scholar 

  197. Weiss KR (2010) Inhibition of osteosarcoma metastatic potential with noggin and s-Flt. In: 2010 Meeting of the Musculoskeletal Tumor Society, Philadelphia, PA, 2010

    Google Scholar 

  198. Weiss KR, Cooper GM, Jadlowiec JA, McGough RL 3rd, Huard J (2006) VEGF and BMP expression in mouse osteosarcoma cells. Clin Orthop Relat Res 450:111–117

    PubMed  Google Scholar 

  199. Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, Houvenaeghel G, Extra JM, Bertucci F, Jacquemier J, Xerri L, Dontu G, Stassi G, Xiao Y, Barsky SH, Birnbaum D, Viens P, Wicha MS (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16(1):45–55

    PubMed  CAS  PubMed Central  Google Scholar 

  200. Cheung AM, Wan TS, Leung JC, Chan LY, Huang H, Kwong YL, Liang R, Leung AY (2007) Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 21(7):1423–1430

    PubMed  CAS  Google Scholar 

  201. Cho HJ, Lee TS, Park JB, Park KK, Choe JY, Sin DI, Park YY, Moon YS, Lee KG, Yeo JH, Han SM, Cho YS, Choi MR, Park NG, Lee YS, Chang YC (2007) Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. J Biochem Mol Biol 40(6):1069–1076

    PubMed  CAS  Google Scholar 

  202. Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69(8):3382–3389

    PubMed  CAS  PubMed Central  Google Scholar 

  203. Honoki K, Fujii H, Kubo A, Kido A, Mori T, Tanaka Y, Tsujiuchi T (2010) Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance. Oncol Rep 24(2):501–505

    PubMed  CAS  Google Scholar 

  204. Mu X, Isaac C, Schott T, Huard J, Weiss K (2013) Rapamycin Inhibits ALDH Activity, Resistance to Oxidative Stress, and Metastatic Potential in Murine Osteosarcoma Cells. Sarcoma 2013:11

    Google Scholar 

  205. Hughes DP (2009) Strategies for the targeted delivery of therapeutics for osteosarcoma. Expert Opin Drug Deliv 6(12):1311–1321

    PubMed  CAS  PubMed Central  Google Scholar 

  206. Blake JA, Bult CJ, Eppig JT, Kadin JA, Richardson JE, The Mouse Genome Database Group (2014) The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse. Nucleic Acids Res 42(D1):D810–D817

    Google Scholar 

  207. Jiang R, Lan Y, Chapman HD, Shawber C, Norton CR, Serreze DV, Weinmaster G, Gridley T (1998) Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev 12(7):1046–1057

    Google Scholar 

  208. Sorensen I, Adams RH, Gossler A (2009) DLL1-mediated Notch activation regulates endothelial identity in mouse fetal arteries. Blood 113(22):5680–5688. doi:10.1182/blood-2008-08-174508

  209. Dunwoodie SL, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RS (2002) Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development 129(7):1795–1806

    Google Scholar 

  210. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18(22):2730–2735

    Google Scholar 

  211. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89(4):629–639

    Google Scholar 

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Authors and Affiliations

  1. The Children’s Cancer Hospital at MD Anderson Cancer Center, Houston, TX, USA

    Madonna M. McManus M.S.

  2. The University of Texas Graduate School of Biomedical Sciences at Houston, Unit 853, MOD Lab 1.021d, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Madonna M. McManus M.S.

  3. Department of Orthopedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Kurt R. Weiss M.D.

  4. The Children’s Cancer Hospital, University of Texas at MD Anderson Cancer Center, Houston, TX, USA

    Dennis P. M. Hughes M.D., Ph.D.

Authors
  1. Madonna M. McManus M.S.
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  2. Kurt R. Weiss M.D.
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  3. Dennis P. M. Hughes M.D., Ph.D.
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Correspondence to Dennis P. M. Hughes M.D., Ph.D. .

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Editors and Affiliations

  1. Division of Pediatrics, Department of Cancer Biology, The Mary V. and John A. Reilly Distinguished Chair, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Eugenie S. Kleinerman, M.D.

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McManus, M.M., Weiss, K.R., Hughes, D.P.M. (2014). Understanding the Role of Notch in Osteosarcoma. In: Kleinerman, M.D., E. (eds) Current Advances in Osteosarcoma. Advances in Experimental Medicine and Biology, vol 804. Springer, Cham. https://doi.org/10.1007/978-3-319-04843-7_4

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