Notch Signaling Pathway and Cancer Metastasis

  • Yi-Yang Hu
  • Min-hua Zheng
  • Rui Zhang
  • Ying-Min Liang
  • Hua HanEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 727)


Cancer metastasis is the leading cause of cancer-related deaths all over the world at present. Accumulated researches have demonstrated that cancer metastasis is composed of a series of successive incidents, mainly including epithelial-mesenchymal transition (EMT), malignant cell migration, resistance to anoikis, and angiogenesis and lymphangiogenesis processes. However, the complicated cellular and molecular mechanisms underlying and modulating these processes have not been well elucidated. Thus, studies on cancer metastasis mechanism may propose possibilities to therapeutically interfere with signaling pathways required for each step of cancer metastasis, therefore inhibiting the outgrowth of distant metastasis of tumors. Recent insights have linked the Notch signaling pathway, a critical pathways governing embryonic development and maintaining tumor stemness, to cancer metastasis. This chapter highlights the current evidence for aberration of the Notch signaling in metastasis of tumors such as osteosarcoma, breast cancer, prostate cancer, and melanoma. In these studies, Notch activity seems to participate in cancer metastasis by modulating the EMT, tumor angiogenesis processes, and the anoikis-resistance of tumor cells. Therefore, manipulating Notch signaling may represent a promising alternative/ complement therapeutic strategy targeting cancer metastasis besides cancer stemness.


Prostate Cancer Pancreatic Cancer Cancer Metastasis Metastatic Prostate Cancer Notch Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet 2007; 369:1742–1757.PubMedCrossRefGoogle Scholar
  2. 2.
    Geiger TR, Peeper DS. Metastasis mechanisms. Biochim Biophys Acta 2009; 1796:293–308.PubMedGoogle Scholar
  3. 3.
    Kaplan RN, Riba RD, Zacharoulis S et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the premetastatic niche. Nature 2005; 438:820–827.PubMedCrossRefGoogle Scholar
  4. 4.
    Greenburg G, Hay ED. Cytoskeleton and thyroglobulin expression change during transformation of thyroid epithelium to mesenchyme-like cells. Development 1988; 102:605–622.PubMedGoogle Scholar
  5. 5.
    Jechlinger M, Grunert S, Tamir IH et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003; 22:7155–7169.PubMedCrossRefGoogle Scholar
  6. 6.
    Christofori G, Semb H. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999; 24:73–76.PubMedCrossRefGoogle Scholar
  7. 7.
    Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 2003;3:362–374.PubMedCrossRefGoogle Scholar
  8. 8.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442–454.PubMedCrossRefGoogle Scholar
  9. 9.
    Bell CD, Waizbard E. Variability of cell size in primary and metastatic human breast carcinoma. Invasion Metastasis 1986; 6:11–20.PubMedGoogle Scholar
  10. 10.
    Nabeshima K, Inoue T, Shimao Y et al. Cohort migration of carcinoma cells: differentiated colorectal carcinoma cells move as coherent cell clusters or sheets. Histol Histopathol 1999; 14:1183–1197.PubMedGoogle Scholar
  11. 11.
    Günthert U, Hofmann M, Rudy W et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991; 65:13–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Padua D, Zhang XH, Wang Q et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133:66–77.PubMedCrossRefGoogle Scholar
  13. 13.
    Felding-Habermann B, O’Toole TE, Smith JW et al. Integrin activation controls metastasis in human breast cancer. Proc Natl Acad Sci USA 2001; 98:1853–1858.PubMedCrossRefGoogle Scholar
  14. 14.
    Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124:619–626.PubMedCrossRefGoogle Scholar
  15. 15.
    Geiger TR, Peeper DS. The neurotrophic receptor TrkB in anoikis resistance and metastasis: a perspective. Cancer Res 2005; 65:7033–7036.PubMedCrossRefGoogle Scholar
  16. 16.
    Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol 1997; 9:701–706.PubMedCrossRefGoogle Scholar
  17. 17.
    Avizienyte E, Wyke AW, Jones RJ et al. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol 2002; 4:632–638.PubMedGoogle Scholar
  18. 18.
    Douma S, Van Laar T, Zevenhoven J et al. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004; 430:1034–1039.PubMedCrossRefGoogle Scholar
  19. 19.
    Gimbrone MA Jr, Leapman SB, Cotran RS et al. Tumor dormancy in vivo by prevention of neovascularization. J Exp Med 1972; 136:261–276.PubMedCrossRefGoogle Scholar
  20. 20.
    Hashizume H, Baluk P, Morikawa et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 2000; 156:1363–1380.PubMedCrossRefGoogle Scholar
  21. 21.
    Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 2007; 26:319–331.PubMedCrossRefGoogle Scholar
  22. 22.
    Cao Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer 2005; 5:735–743.PubMedCrossRefGoogle Scholar
  23. 23.
    Stacker SA, Achen MG, Jussila L et al. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2002; 2:573–583.PubMedCrossRefGoogle Scholar
  24. 24.
    Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989; 8:98–101.PubMedGoogle Scholar
  25. 25.
    Fidler IJ. The pathogenesis of cancer metastasis: the seed and soil’ hypothesis revisited. Nat Rev Cancer 2003; 3:453–458.PubMedCrossRefGoogle Scholar
  26. 26.
    Lapidot T, Sirard C, Vormoor J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367:645–648.PubMedCrossRefGoogle Scholar
  27. 27.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730–737.PubMedCrossRefGoogle Scholar
  28. 28.
    Al-Hajj M, Wicha MS, Benito-Hernandez A et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100:3983–3988.PubMedCrossRefGoogle Scholar
  29. 29.
    Singh SK, Clarke ID, Terasaki M et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63:5821–5828.PubMedGoogle Scholar
  30. 30.
    Ho MM, Ng AV, Lam S et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 2007; 67:4827–4833.PubMedCrossRefGoogle Scholar
  31. 31.
    Mani SA, Guo W, Liao MJ et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133:704–715.PubMedCrossRefGoogle Scholar
  32. 32.
    Hermann PC, Huber SL, Herrler T et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1:313–323.PubMedCrossRefGoogle Scholar
  33. 33.
    Berezovska OP, Glinskii AB, Yang Z et al. Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle 2006; 5:1886–1901.PubMedCrossRefGoogle Scholar
  34. 34.
    Wharton KA, Johansen KM, Xu T et al. Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985; 43:567–581.PubMedCrossRefGoogle Scholar
  35. 35.
    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006; 7:678–689.PubMedCrossRefGoogle Scholar
  36. 36.
    Martinez Arias A, Zecchini V, Brennan K et al. CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr Opin Genet Dev 2002; 12:524–533.CrossRefGoogle Scholar
  37. 37.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009; 137:216–233.PubMedCrossRefGoogle Scholar
  38. 38.
    Koch U, Radtke F. Notch and cancer: a double-edged sword. Cell Mol Life Sci 2007; 64:2746–2762.PubMedCrossRefGoogle Scholar
  39. 39.
    Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 2003; 4:786–797.PubMedGoogle Scholar
  40. 40.
    Ilagan MX, Kopan R. SnapShot: notch signaling pathway. Cell 2007; 128:1246.PubMedCrossRefGoogle Scholar
  41. 41.
    Longhi A, Errani C, De Paolis M et al. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev 2006; 32:423–436.PubMedCrossRefGoogle Scholar
  42. 42.
    Bulman MP, Kusumi K, Frayling TM et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet 2000; 24:438–441.PubMedCrossRefGoogle Scholar
  43. 43.
    Sciaudone M, Gazzerro E, Priest L et al. Notch 1 impairs osteoblastic cell differentiation. Endocrinology 2003; 144:5631–5639.PubMedCrossRefGoogle Scholar
  44. 44.
    Schnabel M, Fichtel I, Gotzen L et al. Differential expression of Notch genes in human osteoblastic cells. Int J Mol Med 2002; 9:229–232.PubMedGoogle Scholar
  45. 45.
    Zhang P, Yang Y, Zweidler-McKay PA et al. Critical role of notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res 2008; 14:2962–2969.PubMedCrossRefGoogle Scholar
  46. 46.
    Callahan R, Egan SE. Notch signaling in mammary development and oncogenesis. J Mammary Gland Biol Neoplasia 2004; 9:145–163.PubMedCrossRefGoogle Scholar
  47. 47.
    Leong KG, Niessen K, Kulic I et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 2007; 204:2935–2948.PubMedCrossRefGoogle Scholar
  48. 48.
    Chen J, Imanaka N, Chen J et al. Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer 2010; 102:351–360.PubMedCrossRefGoogle Scholar
  49. 49.
    Martin TA, Goyal A, Watkins G et al. Expression of the transcription factors snail, slug and twist and their clinical significance in human breast cancer. Ann Surg Oncol 2005; 12:488–496.PubMedCrossRefGoogle Scholar
  50. 50.
    Martin DB, Gifford DR, Wright ME et al. Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004; 64:347–355.PubMedCrossRefGoogle Scholar
  51. 51.
    Shou J, Ross S, Koeppen H et al. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res 2001; 61:7291–7297.PubMedGoogle Scholar
  52. 52.
    Santagata S, Demichelis F, Riva A et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res 2004; 64:6854–6857.PubMedCrossRefGoogle Scholar
  53. 53.
    Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer 2003;3:559–570.PubMedCrossRefGoogle Scholar
  54. 54.
    Hendrix MJ, Seftor EA, Seftor RE et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 2007; 7:246–255.PubMedCrossRefGoogle Scholar
  55. 55.
    Hoek K, Rimm DL, Williams KR et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res 2004; 64:5270–5282.PubMedCrossRefGoogle Scholar
  56. 56.
    Balint K, Xiao M, Pinnix CC et al. Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. J Clin Invest 2005; 115:3166–3176.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu ZJ, Xiao M, Balint K et al. Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res 2006; 66:4183–4190.Google Scholar
  58. 58.
    Wang Z, Banerjee S, Li Y et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 2006; 66:2778–2784.PubMedCrossRefGoogle Scholar
  59. 59.
    Yeh TS, Wu CW, Hsu KW et al. The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2. Cancer Res 2009; 69:5039–5048.PubMedCrossRefGoogle Scholar
  60. 60.
    Veenendaal LM, Kranenburg O, Smakman N et al. Differential Notch and TGFbeta signaling in primary colorectal tumors and their corresponding metastases. Cell Oncol 2008; 30:1–11.PubMedGoogle Scholar
  61. 61.
    Wang YC, Hu XB, He F et al. Lipopolysaccharide-induced maturation of bone marrow-derived dendritic cells is regulated by notch signaling through the up-regulation of CXCR4. J Biol Chem 2009; 284:15993–6003.PubMedCrossRefGoogle Scholar
  62. 62.
    Sahlgren C, Gustafsson MV, Jin S et al. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 2008; 105:6392–6397.PubMedCrossRefGoogle Scholar
  63. 63.
    Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14:818–829.PubMedCrossRefGoogle Scholar
  64. 64.
    Blokzijl A, Dahlqvist C, Reissmann E et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol 2003; 163:723–728.PubMedCrossRefGoogle Scholar
  65. 65.
    Zavadil J, Cermak L, Soto-Nieves N et al. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004; 23:1155–1165.PubMedCrossRefGoogle Scholar
  66. 66.
    Zheng MH, Shi M, Pei Z et al. The transcription factor RBP-J is essential for retinal cell differentiation and lamination. Mol Brain 2009; 2:38.PubMedCrossRefGoogle Scholar
  67. 67.
    Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell 2009;16:196–208.PubMedCrossRefGoogle Scholar
  68. 68.
    Duarte A, Hirashima M, Benedito R et al. Dosage-sentitive requirement for mouse Dll4 in artery development. Genes Dev 2004; 18:2474–2478.PubMedCrossRefGoogle Scholar
  69. 69.
    Suchting S, Freitas C, le Noble F et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 2007; 104:3225–3230.PubMedCrossRefGoogle Scholar
  70. 70.
    Patel NS, Li JL, Generali D et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 2005; 65:8690–8697.PubMedCrossRefGoogle Scholar
  71. 71.
    Williams CK, Segarra M, Sierra de L et al. Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res 2008; 68:1889–1895.PubMedCrossRefGoogle Scholar
  72. 72.
    Dou GR, Wang YC, Hu XB et al. RBP-J, the transcription factor downstream of Notch receptors, is essential for the maintenance of vascular homeostasis in adult mice. FASEB J 2008; 22:1606–1617.PubMedCrossRefGoogle Scholar
  73. 73.
    Scehnet JS, Jiang W, Kumar SR et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 2007; 109:4753–4760.PubMedCrossRefGoogle Scholar
  74. 74.
    Ridgway J, Zhang G, Wu Y et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006; 444:1083–1087.PubMedCrossRefGoogle Scholar
  75. 75.
    Noguera-Troise I, Daly C, Papadopoulos NJ et al. Blockade of Dll4 inhibits tumour growth by promoting nonproductive angiogenesis. Nature 2006; 444:1032–1037.PubMedCrossRefGoogle Scholar
  76. 76.
    Thurston G, Noguera-Troise I, Yancopoulos GD et al. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 2007; 7:327–331.PubMedCrossRefGoogle Scholar
  77. 77.
    Sainson RC, Harris AL. Anti-Dll4 therapy: can we block tumour growth by increasing angiogenesis? Trends Mol Med 2007; 13:389–395.PubMedCrossRefGoogle Scholar
  78. 78.
    Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12:895–904.PubMedCrossRefGoogle Scholar
  79. 79.
    Gupta GP, Nguyen DX, Chiang AC et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 2007; 446:765–770.PubMedCrossRefGoogle Scholar
  80. 80.
    Hu XB, Feng F, Wang YC et al. Blockade of Notch signaling in tumor-bearing mice may lead to tumor regression, progression, or metastasis, depending on tumor cell types. Neoplasia 2009; 11:32–38.PubMedGoogle Scholar
  81. 81.
    Rangarajan A, Syal R, Selvarajah S et al. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/ Akt. Virology 2001;286:23–30.PubMedCrossRefGoogle Scholar
  82. 82.
    Harrison H, Farnie G, Howell SJ et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010; 70:709–718.PubMedCrossRefGoogle Scholar
  83. 83.
    Fan X, Khaki L, Zhu TS et al. Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 2009; 28:5–16.Google Scholar
  84. 84.
    Wang YC, He F, Feng F et al. Notch signaling determines the M1 versus M2 polarization of macrophages in anti-tumor immune responses. Cancer Res 2010;70(12):4840–4849.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Yi-Yang Hu
    • 1
  • Min-hua Zheng
    • 1
  • Rui Zhang
    • 2
  • Ying-Min Liang
    • 1
  • Hua Han
    • 1
    Email author
  1. 1.Department of Medical Genetics and Developmental Biology, State Key Laboratory of Cancer BiologyFourth Military Medical UniversityXi’anChina
  2. 2.Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer BiologyFourth Military Medical UniversityXi’anChina

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