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Notch Signaling in the Normal Intestine and Intestinal Cancer

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Targeting Notch in Cancer

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Abstract

The intestinal epithelium is a highly proliferative tissue whose integrity depends on the function of intestinal stem cells residing at the bottom of the crypts. The Notch pathway is essential for ISC maintenance and normal tissue differentiation, and it is activated by Delta-like ligands present in the Paneth cells. In intestinal cancer Notch activity is also essential, with Notch signal inhibition leading to a reduction on tumor growth and/or tumor formation associated with enforced differentiation toward the postmitotic secretory lineage. However, general Notch inhibitors are highly toxic, which precludes using them for anticancer therapy. Several strategies are now being tested to reduce Notch inhibitor toxicity such as glucocorticoid co-treatment or intermittent dosing. The use of blocking antibodies against particular ligands or receptors that specifically function in CRC, or in particular CRC subtypes, would represent a novel low-toxicity therapeutic strategy for anticancer treatment. This possibility requires a better understanding of the mechanisms regulating Notch/Notch ligand selectivity in CRC. All these issues are analyzed and discussed in the current chapter.

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References

  1. Paulus, U., et al. (1993). The differentiation and lineage development of goblet cells in the murine small intestinal crypt: Experimental and modelling studies. Journal of Cell Science, 106(Pt 2), 473–483.

    PubMed  Google Scholar 

  2. Pelaseyed, T., et al. (2014). The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological Reviews, 260(1), 8–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shan, M., et al. (2013). Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science, 342(6157), 447–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Engelstoft, M. S., et al. (2013). Enteroendocrine cell types revisited. Current Opinion in Pharmacology, 13(6), 912–921.

    Article  CAS  PubMed  Google Scholar 

  5. Jarvi, O., & Keyrilainen, O. (1956). On the cellular structures of the epithelial invasions in the glandular stomach of mice caused by intramural application of 20-methylcholantren. Acta Pathologica et Microbiologica Scandinavica. Supplement, 39(Suppl 111), 72–73.

    Article  CAS  PubMed  Google Scholar 

  6. Gerbe, F., Legraverend, C., & Jay, P. (2012). The intestinal epithelium tuft cells: Specification and function. Cellular and Molecular Life Sciences, 69(17), 2907–2917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deckx, R. J., Vantrappen, G. R., & Parein, M. M. (1967). Localization of lysozyme activity in a Paneth cell granule fraction. Biochimica et Biophysica Acta, 139(1), 204–207.

    Article  CAS  PubMed  Google Scholar 

  8. Ouellette, A. J., et al. (1992). Purification and primary structure of murine cryptdin-1, a Paneth cell defensin. FEBS Letters, 304(2–3), 146–148.

    Article  CAS  PubMed  Google Scholar 

  9. Bevins, C. L. (2004). The Paneth cell and the innate immune response. Current Opinion in Gastroenterology, 20(6), 572–580.

    Article  PubMed  Google Scholar 

  10. Clevers, H. C., & Bevins, C. L. (2013). Paneth cells: Maestros of the small intestinal crypts. Annual Review of Physiology, 75, 289–311.

    Article  CAS  PubMed  Google Scholar 

  11. Cunliffe, R. N., et al. (2001). Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut, 48(2), 176–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shen, B., et al. (2005). Human defensin 5 expression in intestinal metaplasia of the upper gastrointestinal tract. Journal of Clinical Pathology, 58(7), 687–694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Potten, C. S., & Loeffler, M. (1987). A comprehensive model of the crypts of the small intestine of the mouse provides insight into the mechanisms of cell migration and the proliferation hierarchy. Journal of Theoretical Biology, 127(4), 381–391.

    Article  CAS  PubMed  Google Scholar 

  14. Cheng, H., & Leblond, C. P. (1974). Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. The American Journal of Anatomy, 141(4), 537–561.

    Article  CAS  PubMed  Google Scholar 

  15. Barker, N., et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature, 449(7165), 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  16. Sato, T., et al. (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459(7244), 262–265.

    Article  CAS  PubMed  Google Scholar 

  17. Sato, T., et al. (2011). Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature, 469(7330), 415–418.

    Article  CAS  PubMed  Google Scholar 

  18. Rothenberg, M. E., et al. (2012). Identification of a cKit(+) colonic crypt base secretory cell that supports Lgr5(+) stem cells in mice. Gastroenterology, 142(5), 1195–1205 e6.

    Article  CAS  PubMed  Google Scholar 

  19. Bjerknes, M., & Cheng, H. (1981). The stem-cell zone of the small intestinal epithelium. III. Evidence from columnar, enteroendocrine, and mucous cells in the adult mouse. The American Journal of Anatomy, 160(1), 77–91.

    Article  CAS  PubMed  Google Scholar 

  20. Sangiorgi, E., & Capecchi, M. R. (2008). Bmi1 is expressed in vivo in intestinal stem cells. Nature Genetics, 40(7), 915–920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tian, H., et al. (2011). A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature, 478(7368), 255–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, L., & Clevers, H. (2010). Coexistence of quiescent and active adult stem cells in mammals. Science, 327(5965), 542–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Munoz, J., et al. (2012). The Lgr5 intestinal stem cell signature: Robust expression of proposed quiescent ‘+4’ cell markers. The EMBO Journal, 31(14), 3079–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lopez-Arribillaga, E., et al. (2015). Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development, 142(1), 41–50.

    Article  CAS  PubMed  Google Scholar 

  25. Montgomery, R. K., et al. (2011). Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proceedings of the National Academy of Sciences of the United States of America, 108(1), 179–184.

    Article  CAS  PubMed  Google Scholar 

  26. Powell, A. E., et al. (2012). The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell, 149(1), 146–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takeda, N., et al. (2011). Interconversion between intestinal stem cell populations in distinct niches. Science, 334(6061), 1420–1424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. van der Flier, L. G., et al. (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology, 137(1), 15–17.

    Article  PubMed  Google Scholar 

  29. van der Flier, L. G., et al. (2009). Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell, 136(5), 903–912.

    Article  PubMed  CAS  Google Scholar 

  30. Itzkovitz, S., et al. (2012). Single-molecule transcript counting of stem-cell markers in the mouse intestine. Nature Cell Biology, 14(1), 106–114.

    Article  CAS  Google Scholar 

  31. Hsu, S. Y., Liang, S. G., & Hsueh, A. J. (1998). Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Molecular Endocrinology, 12(12), 1830–1845.

    Article  CAS  PubMed  Google Scholar 

  32. de Lau, W. B., Snel, B., & Clevers, H. C. (2012). The R-spondin protein family. Genome Biology, 13(3), 242.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Glinka, A., et al. (2011). LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Reports, 12(10), 1055–1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Carmon, K. S., et al. (2011). R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America, 108(28), 11452–11457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Walker, F., et al. (2011). LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One, 6(7), e22733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hao, H. X., et al. (2012). ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature, 485(7397), 195–200.

    Article  CAS  PubMed  Google Scholar 

  37. Koo, B. K., et al. (2012). Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature, 488(7413), 665–669.

    Article  CAS  PubMed  Google Scholar 

  38. Schuijers, J., et al. (2015). Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts. Cell Stem Cell, 16(2), 158–170.

    Article  CAS  PubMed  Google Scholar 

  39. Wong, V. W., et al. (2012). Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling. Nature Cell Biology, 14(4), 401–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, H., et al. (2004). Role of histone H2A ubiquitination in Polycomb silencing. Nature, 431(7010), 873–878.

    Article  CAS  PubMed  Google Scholar 

  41. de Napoles, M., et al. (2004). Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Developmental Cell, 7(5), 663–676.

    Article  PubMed  Google Scholar 

  42. Cao, R., Tsukada, Y., & Zhang, Y. (2005). Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Molecular Cell, 20(6), 845–854.

    Article  CAS  PubMed  Google Scholar 

  43. Buchwald, G., et al. (2006). Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. The EMBO Journal, 25(11), 2465–2474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. van der Lugt, N. M., et al. (1994). Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes & Development, 8(7), 757–769.

    Article  Google Scholar 

  45. Jung, P., et al. (2011). Isolation and in vitro expansion of human colonic stem cells. Nature Medicine, 17(10), 1225–1227.

    Article  CAS  PubMed  Google Scholar 

  46. Ootani, A., et al. (2009). Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nature Medicine, 15(6), 701–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sato, T., et al. (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 141(5), 1762–1772.

    Article  CAS  PubMed  Google Scholar 

  48. Dekkers, J. F., et al. (2013). A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nature Medicine, 19(7), 939–945.

    Article  CAS  PubMed  Google Scholar 

  49. Lindemans, C. A., et al. (2015). Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature, 528(7583), 560–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schwank, G., et al. (2013). Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell, 13(6), 653–658.

    Article  CAS  PubMed  Google Scholar 

  51. VanDussen, K. L., et al. (2015). Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut, 64(6), 911–920.

    Article  CAS  PubMed  Google Scholar 

  52. Stanley, P. (2007). Regulation of Notch signaling by glycosylation. Current Opinion in Structural Biology, 17(5), 530–535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stanley, P., & Okajima, T. (2010). Roles of glycosylation in Notch signaling. Current Topics in Developmental Biology, 92, 131–164.

    Article  CAS  PubMed  Google Scholar 

  54. Guiu, J., et al. (2013). Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling. The Journal of Experimental Medicine, 210(1), 71–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pellegrinet, L., et al. (2011). Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology, 140(4), 1230–1240.e1–7.

    Article  CAS  PubMed  Google Scholar 

  56. Riccio, O., et al. (2008). 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 Reports, 9(4), 377–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. VanDussen, K. L., et al. (2012). Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells. Development, 139(3), 488–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fre, S., et al. (2011). Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One, 6(10), e25785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rodilla, V., et al. (2009). Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 106(15), 6315–6320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schroder, N., & Gossler, A. (2002). Expression of Notch pathway components in fetal and adult mouse small intestine. Gene Expression Patterns, 2(3–4), 247–250.

    Article  CAS  PubMed  Google Scholar 

  61. Jensen, J., et al. (2000). Control of endodermal endocrine development by Hes-1. Nature Genetics, 24(1), 36–44.

    Article  CAS  PubMed  Google Scholar 

  62. van Es, J. H., et al. (2005). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature, 435(7044), 959–963.

    Article  PubMed  CAS  Google Scholar 

  63. Fre, S., et al. (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature, 435(7044), 964–968.

    Article  CAS  PubMed  Google Scholar 

  64. Guilmeau, S., et al. (2008). Intestinal deletion of Pofut1 in the mouse inactivates notch signaling and causes enterocolitis. Gastroenterology, 135(3), 849–860.e1–6.

    Article  CAS  PubMed  Google Scholar 

  65. Jarriault, S., et al. (1995). Signalling downstream of activated mammalian notch. Nature, 377(6547), 355–358.

    Article  CAS  PubMed  Google Scholar 

  66. Yang, Q., et al. (2001). Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science, 294(5549), 2155–2158.

    Article  CAS  PubMed  Google Scholar 

  67. van Es, J. H., et al. (2010). Intestinal stem cells lacking the Math1 tumour suppressor are refractory to Notch inhibitors. Nature Communications, 1, 18.

    PubMed  Google Scholar 

  68. Ferlay, J., et al. (2013). Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. European Journal of Cancer, 49(6), 1374–1403.

    Article  CAS  PubMed  Google Scholar 

  69. Fodde, R., & Smits, R. (2001). Disease model: Familial adenomatous polyposis. Trends in Molecular Medicine, 7(8), 369–373.

    Article  CAS  PubMed  Google Scholar 

  70. Fearon, E. R., & Vogelstein, B. (1990). A genetic model for colorectal tumorigenesis. Cell, 61(5), 759–767.

    Article  CAS  PubMed  Google Scholar 

  71. Levy, D. B., et al. (1994). Inactivation of both APC alleles in human and mouse tumors. Cancer Research, 54(22), 5953–5958.

    CAS  PubMed  Google Scholar 

  72. Gregorieff, A., & Clevers, H. (2005). Wnt signaling in the intestinal epithelium: From endoderm to cancer. Genes & Development, 19(8), 877–890.

    Article  CAS  Google Scholar 

  73. Albuquerque, C., et al. (2002). The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Human Molecular Genetics, 11(13), 1549–1560.

    Article  CAS  PubMed  Google Scholar 

  74. Crabtree, M., et al. (2003). Refining the relation between ‘first hits’ and ‘second hits’ at the APC locus: The ‘loose fit’ model and evidence for differences in somatic mutation spectra among patients. Oncogene, 22(27), 4257–4265.

    Article  CAS  PubMed  Google Scholar 

  75. Ichii, S., et al. (1993). Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). Oncogene, 8(9), 2399–2405.

    CAS  PubMed  Google Scholar 

  76. Su, L. K., et al. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science, 256(5057), 668–670.

    Article  CAS  PubMed  Google Scholar 

  77. Stamos, J. L., & Weis, W. I. (2013). The beta-catenin destruction complex. Cold Spring Harbor Perspectives in Biology, 5(1), a007898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Batlle, E., et al. (2002). Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell, 111(2), 251–263.

    Article  CAS  PubMed  Google Scholar 

  79. van de Wetering, M., et al. (2002). The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell, 111(2), 241–250.

    Article  PubMed  Google Scholar 

  80. Sancho, E., Batlle, E., & Clevers, H. (2004). Signaling pathways in intestinal development and cancer. Annual Review of Cell and Developmental Biology, 20, 695–723.

    Article  CAS  PubMed  Google Scholar 

  81. Korinek, V., et al. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science, 275(5307), 1784–1787.

    Article  CAS  PubMed  Google Scholar 

  82. Morin, P. J., et al. (1997). Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 275(5307), 1787–1790.

    Article  CAS  PubMed  Google Scholar 

  83. Rubinfeld, B., et al. (1993). Association of the APC gene product with beta-catenin. Science, 262(5140), 1731–1734.

    Article  CAS  PubMed  Google Scholar 

  84. Su, L. K., Vogelstein, B., & Kinzler, K. W. (1993). Association of the APC tumor suppressor protein with catenins. Science, 262(5140), 1734–1737.

    Article  CAS  PubMed  Google Scholar 

  85. Hinck, L., et al. (1994). Beta-catenin: A common target for the regulation of cell adhesion by Wnt-1 and Src signaling pathways. Trends in Biochemical Sciences, 19(12), 538–542.

    Article  CAS  PubMed  Google Scholar 

  86. Cortina, C., et al. (2007). EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nature Genetics, 39(11), 1376–1383.

    Article  CAS  PubMed  Google Scholar 

  87. Dow, L. E., et al. (2015). Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell, 161(7), 1539–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Feng, Y., et al. (2011). Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology, 141(3), 1003–1013.e1–10.

    Article  CAS  PubMed  Google Scholar 

  89. Luo, F., et al. (2007). Conditional expression of mutated K-ras accelerates intestinal tumorigenesis in Msh2-deficient mice. Oncogene, 26(30), 4415–4427.

    Article  CAS  PubMed  Google Scholar 

  90. Luo, F., et al. (2011). Synergism between K-rasVal12 and mutant Apc accelerates murine large intestinal tumourigenesis. Oncology Reports, 26(1), 125–133.

    CAS  PubMed  Google Scholar 

  91. Drost, J., et al. (2015). Sequential cancer mutations in cultured human intestinal stem cells. Nature, 521(7550), 43–47.

    Article  CAS  PubMed  Google Scholar 

  92. Sui, X., et al. (2015). p53 controls colorectal cancer cell invasion by inhibiting the NF-kappaB-mediated activation of Fascin. Oncotarget, 6(26), 22869–22879.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Benhattar, J., et al. (1996). p53 mutations as a possible predictor of response to chemotherapy in metastatic colorectal carcinomas. International Journal of Cancer, 69(3), 190–192.

    Article  CAS  PubMed  Google Scholar 

  94. Fearon, E. R. (2011). Molecular genetics of colorectal cancer. Annual Review of Pathology, 6, 479–507.

    Article  CAS  PubMed  Google Scholar 

  95. Guinney, J., et al. (2015). The consensus molecular subtypes of colorectal cancer. Nature Medicine, 21(11), 1350–1356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Clevers, H. (2011). The cancer stem cell: Premises, promises and challenges. Nature Medicine, 17(3), 313–319.

    Article  CAS  PubMed  Google Scholar 

  97. Dick, J. E. (2008). Stem cell concepts renew cancer research. Blood, 112(13), 4793–4807.

    Article  CAS  PubMed  Google Scholar 

  98. Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nature Reviews Cancer, 8(10), 755–768.

    Article  CAS  PubMed  Google Scholar 

  99. Colak, S., & Medema, J. P. (2014). Cancer stem cells – Important players in tumor therapy resistance. The FEBS Journal, 281(21), 4779–4791.

    Article  CAS  PubMed  Google Scholar 

  100. O’Brien, C. A., et al. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445(7123), 106–110.

    Article  PubMed  CAS  Google Scholar 

  101. Ricci-Vitiani, L., et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature, 445(7123), 111–115.

    Article  CAS  PubMed  Google Scholar 

  102. Dalerba, P., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10158–10163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Todaro, M., et al. (2014). CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell, 14(3), 342–356.

    Article  CAS  PubMed  Google Scholar 

  104. Huang, E. H., et al. (2009). Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Research, 69(8), 3382–3389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Pang, R., et al. (2010). A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell, 6(6), 603–615.

    Article  CAS  PubMed  Google Scholar 

  106. Merlos-Suarez, A., et al. (2011). The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell, 8(5), 511–524.

    Article  CAS  PubMed  Google Scholar 

  107. Schepers, A. G., et al. (2012). Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science, 337(6095), 730–735.

    Article  CAS  PubMed  Google Scholar 

  108. Asfaha, S., et al. (2015). Krt19(+)/Lgr5(-) cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell, 16(6), 627–638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jung, P., et al. (2015). Isolation of human colon stem cells using surface expression of PTK7. Stem Cell Reports, 5(6), 979–987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Barker, N., et al. (2009). Crypt stem cells as the cells-of-origin of intestinal cancer. Nature, 457(7229), 608–611.

    Article  CAS  PubMed  Google Scholar 

  111. Zhu, L., et al. (2009). Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature, 457(7229), 603–607.

    Article  CAS  PubMed  Google Scholar 

  112. Fre, S., et al. (2009). Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proceedings of the National Academy of Sciences of the United States of America, 106(15), 6309–6314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sonoshita, M., et al. (2011). Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell, 19(1), 125–137.

    Article  CAS  PubMed  Google Scholar 

  114. Sonoshita, M., et al. (2015). Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discovery, 5(2), 198–211.

    Article  CAS  PubMed  Google Scholar 

  115. Lopez-Arribillaga, E. (2018). Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells. Nature Communications, 9(1), 2992.

    Google Scholar 

  116. Zheng, H., et al. (2017). Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell, 32(6), 731–747 e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Reedijk, M., et al. (2008). Activation of Notch signaling in human colon adenocarcinoma. International Journal of Oncology, 33(6), 1223–1229.

    PubMed  Google Scholar 

  118. Zhang, Y., et al. (2010). Notch1 regulates the growth of human colon cancers. Cancer, 116(22), 5207–5218.

    Article  CAS  PubMed  Google Scholar 

  119. Lu, J., et al. (2013). Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell, 23(2), 171–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dai, Y., et al. (2014). Silencing of Jagged1 inhibits cell growth and invasion in colorectal cancer. Cell Death & Disease, 5, e1170.

    Article  CAS  Google Scholar 

  121. Hoey, T., et al. (2009). DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell, 5(2), 168–177.

    Article  CAS  PubMed  Google Scholar 

  122. Mailhos, C., et al. (2001). Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation, 69(2–3), 135–144.

    Article  CAS  PubMed  Google Scholar 

  123. Ghaleb, A. M., et al. (2008). Notch inhibits expression of the Kruppel-like factor 4 tumor suppressor in the intestinal epithelium. Molecular Cancer Research, 6(12), 1920–1927.

    Article  CAS  PubMed  Google Scholar 

  124. Zhao, W., et al. (2004). Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene, 23(2), 395–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Timmerman, L. A., et al. (2004). Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes & Development, 18(1), 99–115.

    Article  CAS  Google Scholar 

  126. Fender, A. W., et al. (2015). Notch-1 promotes stemness and epithelial to mesenchymal transition in colorectal cancer. Journal of Cellular Biochemistry, 116(11), 2517–2527.

    Article  CAS  PubMed  Google Scholar 

  127. Candy, P. A., et al. (2013). Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients. British Journal of Cancer, 109(4), 1023–1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fernandez-Majada, V., et al. (2007). Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America, 104(1), 276–281.

    Article  CAS  PubMed  Google Scholar 

  129. Margalef, P., et al. (2015). BRAF-induced tumorigenesis is IKKalpha-dependent but NF-kappaB-independent. Science Signaling, 8(373), ra38.

    Article  PubMed  CAS  Google Scholar 

  130. Van Cutsem, E., et al. (2009). Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. The New England Journal of Medicine, 360(14), 1408–1417.

    Article  PubMed  Google Scholar 

  131. Cunningham, D., et al. (2004). Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. The New England Journal of Medicine, 351(4), 337–345.

    Article  CAS  PubMed  Google Scholar 

  132. Lenz, H. J., et al. (2006). Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Journal of Clinical Oncology, 24(30), 4914–4921.

    Article  CAS  PubMed  Google Scholar 

  133. Boland, P. M., & Fakih, M. (2014). The emerging role of neoadjuvant chemotherapy for rectal cancer. Journal of Gastrointestinal Oncology, 5(5), 362–373.

    PubMed  PubMed Central  Google Scholar 

  134. Pita-Fernandez, S., et al. (2015). Intensive follow-up strategies improve outcomes in nonmetastatic colorectal cancer patients after curative surgery: A systematic review and meta-analysis. Annals of Oncology, 26(4), 644–656.

    Article  CAS  PubMed  Google Scholar 

  135. Hassan, K. A., et al. (2013). Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clinical Cancer Research, 19(8), 1972–1980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kalen, M., et al. (2011). Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion. PLoS One, 6(4), e18709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Miyamoto, S., Nakanishi, M., & Rosenberg, D. W. (2013). Suppression of colon carcinogenesis by targeting Notch signaling. Carcinogenesis, 34(10), 2415–2423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Palagani, V., et al. (2012). Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by gamma-secretase inhibitor IX. PLoS One, 7(10), e46514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Meng, R. D., et al. (2009). gamma-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity. Cancer Research, 69(2), 573–582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zhang, X., et al. (2014). A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of gamma-secretase. The Journal of Biological Chemistry, 289(50), 34851–34861.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Ponnurangam, S., et al. (2016). Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget, 7(3), 3217–3232.

    Article  PubMed  Google Scholar 

  142. Real, P. J., & Ferrando, A. A. (2009). NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia, 23(8), 1374–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Real, P. J., et al. (2009). Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nature Medicine, 15(1), 50–58.

    Article  CAS  PubMed  Google Scholar 

  144. Samon, J. B., et al. (2012). Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Molecular Cancer Therapeutics, 11(7), 1565–1575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wei, P., et al. (2010). Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Molecular Cancer Therapeutics, 9(6), 1618–1628.

    Article  CAS  PubMed  Google Scholar 

  146. Wu, Y., et al. (2010). Therapeutic antibody targeting of individual Notch receptors. Nature, 464(7291), 1052–1057.

    Article  CAS  PubMed  Google Scholar 

  147. Lafkas, D., et al. (2015). Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature, 528(7580), 127–131.

    CAS  PubMed  Google Scholar 

  148. Tran, I. T., et al. (2013). Blockade of individual Notch ligands and receptors controls graft-versus-host disease. The Journal of Clinical Investigation, 123(4), 1590–1604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Tiyanont, K., et al. (2013). Insights into Notch3 activation and inhibition mediated by antibodies directed against its negative regulatory region. Journal of Molecular Biology, 425(17), 3192–3204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Falk, R., et al. (2012). Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells. Methods, 58(1), 69–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Aste-Amezaga, M., et al. (2010). Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One, 5(2), e9094.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Smith, D. C., et al. (2014). A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clinical Cancer Research, 20(24), 6295–6303.

    Article  CAS  PubMed  Google Scholar 

  153. Fischer, M., et al. (2011). Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Research, 71(5), 1520–1525.

    Article  CAS  PubMed  Google Scholar 

  154. Miles, K. M., et al. (2014). Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts. PLoS One, 9(11), e112371.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Ridgway, J., et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 444(7122), 1083–1087.

    Article  CAS  PubMed  Google Scholar 

  156. Yan, M., et al. (2010). Chronic DLL4 blockade induces vascular neoplasms. Nature, 463(7282), E6–E7.

    Article  CAS  PubMed  Google Scholar 

  157. Klose, R., et al. (2015). Soluble Notch ligand and receptor peptides act antagonistically during angiogenesis. Cardiovascular Research, 107(1), 153–163.

    Article  CAS  PubMed  Google Scholar 

  158. Yan, X., et al. (2015). Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis. Science China Life Sciences, 58(5), 425–431.

    Article  CAS  PubMed  Google Scholar 

  159. Weng, A. P., et al. (2003). Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Molecular and Cellular Biology, 23(2), 655–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Moellering, R. E., et al. (2009). Direct inhibition of the NOTCH transcription factor complex. Nature, 462(7270), 182–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work has been supported by grants 20131210 from the Fundació la Marató de TV3; PI16/00437, PIE15/00008, and RD12/0036/0054 from the Instituto de Salud Carlos III/FEDER; and 2017 SGR 135 from the Agència de Gestió Ajuts Universitaris de Recerca.

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Authors and Affiliations

  1. Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain

    Lluís Espinosa, Erika López-Arribillaga & Anna Bigas

  2. Department of Biomedical Sciences, (CIBERONC), University of Barcelona, Barcelona, Spain

    Oriol Bachs

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  1. Lluís Espinosa
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  2. Erika López-Arribillaga
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  3. Oriol Bachs
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  4. Anna Bigas
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Correspondence to Lluís Espinosa .

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Editors and Affiliations

  1. Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Lucio Miele

  2. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    Spyros Artavanis-Tsakonas

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Espinosa, L., López-Arribillaga, E., Bachs, O., Bigas, A. (2018). Notch Signaling in the Normal Intestine and Intestinal Cancer. In: Miele, L., Artavanis-Tsakonas, S. (eds) Targeting Notch in Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-8859-4_13

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