Clinical and Translational Oncology

, Volume 11, Issue 1, pp 11–19

Notch signalling in cancer stem cells

  • Victoria Bolós
  • Moisés Blanco
  • Vanessa Medina
  • Guadalupe Aparicio
  • Silvia Díaz-Prado
  • Enrique Grande
Educational Series Molecular Targets in Oncology

Abstract

A new theory about the development of solid tumours is emerging from the idea that solid tumours, like normal adult tissues, contain stem cells (called cancer stem cells) and arise from them. Genetic mutations encoding for proteins involved in critical signalling pathways for stem cells such as BMP, Notch, Hedgehog and Wnt would allow stem cells to undergo uncontrolled proliferation and form tumours. Taking into account that cancer stem cells (CSCs) would represent the real driving force behind tumour growth and that they may be drug resistant, new agents that target the above signalling pathways could be more effective than current anti-solid tumour therapies. In the present paper we will review the molecular basis of the Notch signalling pathway. Additionally, we will pay attention to their role in adult stem cell self-renewal, and cell fate specification and differentiation, and we will also review evidence that supports their implication in cancer.

Keywords

Notch pathway Cancer stem cells 

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References

  1. 1.
    Fiúza UM, Arias AM (2007) Cell and molecular biology of Notch. J Endocrinol 194:459–474PubMedCrossRefGoogle Scholar
  2. 2.
    Ailles LE, Weissman IL (2007) Cancer stem cells in solid tumors. Curr Opin Biotechnol 18:460–466PubMedCrossRefGoogle Scholar
  3. 3.
    Bolós V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363PubMedCrossRefGoogle Scholar
  4. 4.
    Schweisguth F (2004) Regulation of notch signaling activity. Curr Biol 14:R129–138PubMedGoogle Scholar
  5. 5.
    Ehebauer M, Hayward P, Martinez-Arias (2006) Notch signaling pathway. Sci STKE 364:cm7Google Scholar
  6. 6.
    Katoh M, Katoh M (2007) Notch signaling in gastrointestinal tract. Int J Oncol 30:247–251PubMedGoogle Scholar
  7. 7.
    Katsube K, Sakamoto K (2005) Notch in vertebrates — molecular aspects of the signal. Int J Dev Biol 49:369–374PubMedCrossRefGoogle Scholar
  8. 8.
    Le Borgne R, Bardin A, Schweisguth F (2005) The roles of receptor and ligand endocytosis in regulating Notch signaling. Development 132: 1751–1762PubMedCrossRefGoogle Scholar
  9. 9.
    Vodovar N, Schweisguth F (2008) Functions of O-fucosyltransferase in Notch trafficking and signaling: towards the end of a controversy? J Biol 7:7PubMedCrossRefGoogle Scholar
  10. 10.
    Fischer A, Gessler M (2007) Delta-Notch — and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35:4583–4596PubMedCrossRefGoogle Scholar
  11. 11.
    Kageyama R, Masamizu Y, Niwa Y (2007) Oscillator mechanism of Notch pathway in the segmentation clock. Dev Dyn 236:1403–1409PubMedCrossRefGoogle Scholar
  12. 12.
    Schouwey K, Beermann F (2008) The Notch pathway: hair graying and pigment cell homeostasis. Histol Histopathol 23:609–619PubMedGoogle Scholar
  13. 13.
    Watt FM, Estrach S, Ambler CA (2008) Epidermal Notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol 20:171–179PubMedCrossRefGoogle Scholar
  14. 14.
    Niessen K, Karsan A (2007) Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol 293:C1–11PubMedCrossRefGoogle Scholar
  15. 15.
    Siekmann AF, Covassin L, Lawson ND (2008) Modulation of VEGF signalling output by the Notch pathway. Bioessays 30:303–313PubMedCrossRefGoogle Scholar
  16. 16.
    Gridley T (2007) Notch signaling in vascular development and physiology. Development 134: 2709–2718PubMedCrossRefGoogle Scholar
  17. 17.
    Chiba S (2006) Notch signaling in stem cell systems. Stem Cells 24:2437–2447PubMedCrossRefGoogle Scholar
  18. 18.
    Leong KG, Gao WQ (2008) The Notch pathway in prostate development and cancer. Differentiation 76: 699–716PubMedCrossRefGoogle Scholar
  19. 19.
    Koch U, Radtke F (2007) Notch and cancer: a double-edged sword. Cell Mol Life Sci 64:2746–2762PubMedCrossRefGoogle Scholar
  20. 20.
    Lai EC (2004) Notch signaling: control of cell communication and cell fate. Development 131:965–973PubMedCrossRefGoogle Scholar
  21. 21.
    Lewis J (1998) Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 9:583–589PubMedCrossRefGoogle Scholar
  22. 22.
    de Celis JF, Bray S (1997) Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124:3241–3251PubMedGoogle Scholar
  23. 23.
    Huppert SS, Jacobsen TL, Muskavitch MA (1997) Feedback regulation is central to Delta-Notch signalling required for Drosophila wing vein morphogenesis. Development 124:3283–3291PubMedGoogle Scholar
  24. 24.
    Eddison M, Le Roux I, Lewis J (2000) Notch signaling in the development of the inner ear: lessons from Drosophila. Proc Natl Acad Sci U S A 97: 11692–11699PubMedCrossRefGoogle Scholar
  25. 25.
    Savill NJ, Sherratt JA (2003) Control of epidermal stem cell clusters by Notch-mediated lateral induction. Dev Biol 258:141–153PubMedCrossRefGoogle Scholar
  26. 26.
    Nickoloff BJ, Osborne BA, Miele L (2003) Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene 22: 6598–6608PubMedCrossRefGoogle Scholar
  27. 27.
    Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767PubMedCrossRefGoogle Scholar
  28. 28.
    Aster JC (2005) Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int J Hematol 82:295–230PubMedCrossRefGoogle Scholar
  29. 29.
    Charafe-Jauffret E, Monville F, Ginestier C et al (2008) Cancer stem cells in breast: current opinion and future challenges. Pathobiology 75:75–84PubMedCrossRefGoogle Scholar
  30. 30.
    Dontu G, Al-Hajj M, Abdallah WM et al (2003) Stem cells in normal breast development and breast cancer. Cell Prolif 36[Suppl 1]:59–72CrossRefGoogle Scholar
  31. 31.
    Dontu G, Jackson KW, McNicholas E et al (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6:R605–R615PubMedCrossRefGoogle Scholar
  32. 32.
    Chang JC, Li X, Wong H et al (2007) Therapeutic resistance and tumor-initiation: Molecular pathways involved in breast cancer stem cell self-renewal. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) 25[Suppl 18]:528Google Scholar
  33. 33.
    Stylianou S, Clarke RB, Brennan K (2006) Aberrant activation of notch signaling in human breast cancer. Cancer Res 66:1517–1525PubMedCrossRefGoogle Scholar
  34. 34.
    Parr C, Watkins G, Jiang WG (2004) The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 14: 779–786PubMedGoogle Scholar
  35. 35.
    Reedijk M, Odorcic S, Chang L et al (2005) High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65:8530–8537PubMedCrossRefGoogle Scholar
  36. 36.
    Pece S, Serresi M, Santolini E et al (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167:215–221PubMedCrossRefGoogle Scholar
  37. 37.
    Colaluca IN, Tosoni D, Nuciforo P et al (2008) NUMB controls p53 tumour suppressor activity. Nature 451:76–80PubMedCrossRefGoogle Scholar
  38. 38.
    Weijzen S, Rizzo P, Braid M et al (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8:979–986PubMedCrossRefGoogle Scholar
  39. 39.
    Rizzo P, Miao H, D’souza G et al (2008) Crosstalk between notch and the estrogen receptor in breast cancer suggests novel therapeutic approaches. Cancer Res 68:5226–5235PubMedCrossRefGoogle Scholar
  40. 40.
    Osipo C, Patel P, Rizzo P et al (2008) ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 27:5019–5032PubMedCrossRefGoogle Scholar
  41. 41.
    Lee CW, Raskett CM, Prudovsky I, Altieri DC (2008) Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res 68:5273–5281PubMedCrossRefGoogle Scholar
  42. 42.
    Krop IE, Kosh M, Fearen I et al (2006) Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors. ASCO Annual Meeting. Abstract No: 10574Google Scholar
  43. 43.
  44. 44.
    van Es JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502PubMedCrossRefGoogle Scholar
  45. 45.
    Sancho E, Batlle E, Clevers H (2004) Signaling pathways in intestinal development and cancer. Annu Rev Cell Dev Biol 20:695–723PubMedCrossRefGoogle Scholar
  46. 46.
    van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedCrossRefGoogle Scholar
  47. 47.
    Meng RD, Qin L, Shelton CC et al (2008) Use of the Notch signaling pathway to predict disease progression and distant recurrence-free survival in early stage colon cancer. ASCO Annual Meeting. Abstract No: 14500Google Scholar
  48. 48.
    Akiyoshi T, Nakamura M, Yanai K et al (2008) Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology 134: 131–144PubMedCrossRefGoogle Scholar
  49. 49.
    Lim SJ, Fan F, Dallas NA et al (2008) Resistance to oxaliplatin in human intestinal-type gastric cancer cells demonstrates increased migration, invasion and expression of angiogenic factors. ASCO Gastrointestinal Cancer Symposium. Abstract No: 91Google Scholar
  50. 50.
    Duncan AW, Rattis FM, DiMascio LN et al (2005) Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol 6:314–322PubMedCrossRefGoogle Scholar
  51. 51.
    Weng AP, Ferrando AA, Lee W et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306:269–271PubMedCrossRefGoogle Scholar
  52. 52.
    Aster JC (2005) Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int J Hematol 82:295–301PubMedCrossRefGoogle Scholar
  53. 53.
    Deangelo DJ, Stone RM, Silverman LB et al (2006) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. ASCO Annual Meeting. Abstract No: 6585Google Scholar
  54. 54.
    Lowell S, Jones P, Le Roux I et al (2000) Stimulation of human epidermal differentiation by deltanotch signalling at the boundaries of stem-cell clusters. Curr Biol 10:491–500PubMedCrossRefGoogle Scholar
  55. 55.
    Rangarajan A, Talora C, Okuyama R et al (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436PubMedCrossRefGoogle Scholar
  56. 56.
    Nicolas M, Wolfer A, Raj K et al (2003) Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33:416–421PubMedCrossRefGoogle Scholar
  57. 57.
    Thelu J, Rossio P, Favier B (2002) Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol 2:7PubMedCrossRefGoogle Scholar
  58. 58.
    Devgan V, Mammucari C, Millar SE et al (2005) p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev 19:1485–1495PubMedCrossRefGoogle Scholar
  59. 59.
    Kolev V, Mandinova A, Guinea-Viniegra J et al (2008) EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer. Nat Cell Biol 10:902–911PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2009

Authors and Affiliations

  • Victoria Bolós
    • 1
  • Moisés Blanco
    • 2
  • Vanessa Medina
    • 2
    • 3
  • Guadalupe Aparicio
    • 3
  • Silvia Díaz-Prado
    • 2
    • 4
  • Enrique Grande
    • 1
  1. 1.Medical Oncology DepartmentPfizer SpainAlcobendas, MadridSpain
  2. 2.Institute for Biomedical Research (INIBIC)A Coruña University HospitalA CoruñaSpain
  3. 3.Oncology Research UnitA Coruña University HospitalA CoruñaSpain
  4. 4.Medicine DepartmentUniversity of A CoruñaA CoruñaSpain

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