Abstract
The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.
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References
Agrawal N, Frederick MJ, Pickering CR et al (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333(6046):1154–1157. https://doi.org/10.1126/science.1206923
Agrawal N, Jiao Y, Bettegowda C et al (2012) Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov 2(10):899–905. https://doi.org/10.1158/2159-8290.CD-12-0189
Andrawes MB, Xu X, Liu H et al (2013) Intrinsic selectivity of notch 1 for delta-like 4 over delta-like 1. J Biol Chem 288(35):25477–25489. https://doi.org/10.1074/jbc.M113.454850
Ashworth TD, Pear WS, Chiang MY et al (2010) Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 116(25):5455–5464. https://doi.org/10.1182/blood-2010-05-286328
Aster JC, Pear WS, Blacklow SC (2017) The varied roles of notch in cancer. Annu Rev Pathol Mech Dis 12:245–275. https://doi.org/10.1146/annurev-pathol-052016-100127
Ayyanan A, Civenni G, Ciarloni L et al (2006) Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism. Proc Natl Acad Sci 103:3799–3804. https://doi.org/10.1073/pnas.0600065103
Bayin NS, Frenster JD, Sen R et al (2017) Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells. Oncotarget 28(6):1019–1029. https://doi.org/10.18632/oncotarget.18117
Benedito R, Hellström M (2013) Notch as a hub for signaling in angiogenesis. Exp Cell Res 319(9):1281–1288
Benedito R, Roca C, Sörensen I et al (2009) The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135. https://doi.org/10.1016/j.cell.2009.03.025
Biktasova AK, Dudimah DF, Uzhachenko RV et al (2015) Multivalent forms of the notch ligand DLL-1 enhance antitumor T-cell immunity in lung cancer and improve efficacy of EGFR-targeted therapy. Cancer Res 75(22):4728–4741. https://doi.org/10.1158/0008-5472.CAN-14-1154
Boareto M, Jolly MK, Lu M et al (2015) Jagged-delta asymmetry in Notch signaling can give rise to a sender/receiver hybrid phenotype. Proc Natl Acad Sci U S A 101:38–47. https://doi.org/10.1073/pnas.1416287112
Boelens MC, Wu TJ, Nabet BY et al (2014) Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159(3):499–513. https://doi.org/10.1016/j.cell.2014.09.051
Cao Z, Bi-Sen D, Guo P et al (2014) Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance. Cancer Cell 25(3):350–365. https://doi.org/10.1016/j.ccr.2014.02.005
Chen HF, Huang CH, Liu CJ et al (2014) Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat Commun 5:4697. https://doi.org/10.1038/ncomms5697
Cho OH, Shin HM, Miele L et al (2009) Notch regulates cytolytic effector function in CD8 + T cells. J Immunol 182(6):3380–3389. https://doi.org/10.4049/jimmunol.0802598
Colombo M, Galletti S, Bulfamante G et al (2016) Multiple myeloma-derived Jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. Oncotarget 7(35):56013–56029. https://doi.org/10.18632/oncotarget.10820
Dameron KM, Volpert OV, Tainsky MA, Bouck N (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265(5178):1582–1584. https://doi.org/10.1126/science.7521539
Demehri S, Kopan R (2009) Notch signaling in bulge stem cells is not required for selection of hair follicle fate. Development 136(6):891–896. https://doi.org/10.1242/dev.030700
Demehri S, Turkoz A, Kopan R (2009) Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16(1):55–66. https://doi.org/10.1016/j.ccr.2009.05.016
Denekamp J (1993) Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 66(783):181–196
Dufraine J, Funahashi Y, Kitajewski J (2008) Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27:5132–5137
Ellisen LW, Bird J, West DC et al (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4):649–661
Folkman J (1974) Tumor angiogenesis factor. Cancer Res 34:2109–2113
Folkman J, Judah F (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186. https://doi.org/10.1056/NEJM197111182852108
Franklin RA, Liao W, Sarkar A et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344(6186):921–925. https://doi.org/10.1126/science.1252510
Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14(12):717–734
Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022
Gascard P, Tlsty TD (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30(9):1002–1019
George J, Lim JS, Jang SJ et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524(7563):47–53. https://doi.org/10.1038/nature14664
Ghajar CM, Peinado H, Mori H et al (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 5(7):807–817. https://doi.org/10.1038/ncb2767
Gurney A, Hoey T (2011) Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc Cell 3:18
Hao L, Rizzo P, Osipo C et al (2010) Notch-1 activates estrogen receptor-alpha-dependent transcription via IKKalpha in breast cancer cells. Oncogene 29:201–213. https://doi.org/10.1038/onc.2009.323
Hellström M, Phng L-K, Gerhardt H (2007) VEGF and Notch signaling. Cell Adhes Migr 1:133–136. https://doi.org/10.1038/nature05571
Hoey T, Yen WC, Axelrod F et al (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5:168–177. https://doi.org/10.1016/j.stem.2009.05.019
Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1(2):149–153. https://doi.org/10.1038/nm0295-149
Hovinga KE, Shimizu F, Wang R et al (2010) Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28(6):1019–1029. https://doi.org/10.1002/stem.429
Hu B, Castillo E, Harewood L et al (2012) Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149(6):1207–1220. https://doi.org/10.1016/j.cell.2012.03.048
Huang Y, Lin L, Shanker A et al (2011) Resuscitating cancer immunosurveillance: selective stimulation of DLL1-notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res 71(19):6122–6131. https://doi.org/10.1158/0008-5472.CAN-10-4366
Indraccolo S, Minuzzo S, Masiero M, Amadori A (2010) Ligand-driven activation of the notch pathway in T-ALL and solid tumors: why not(ch)? Cell Cycle 9(1):80–85
Karamboulas C, Ailles L (2013) Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta 1830:2481–2495. https://doi.org/10.1016/j.bbagen.2012.11.008
Kim W, Khan SK, Gvozdenovic-Jeremic J et al (2017) Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 127(1):137–152. https://doi.org/10.1172/JCI88486
Klinakis A, Szabolcs M, Politi K et al (2006) Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci 103:9262–9267. https://doi.org/10.1073/pnas.0603371103
Klinakis A, Lobry C, Abdel-Wahab O et al (2011) A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473(7346):230–233. https://doi.org/10.1038/nature09999
Kuhnert F, Chen G, Coetzee S et al (2015) Dll4 blockade in stromal cells mediates antitumor effects in preclinical models of ovarian cancer. Cancer Res 75(19):4086–4096. https://doi.org/10.1158/0008-5472.CAN-14-3773
Kulic I, Robertson G, Chang L et al (2015) Loss of the Notch effector RBPJ promotes tumorigenesis. J Exp Med 212(1):37–52. https://doi.org/10.1084/jem.20121192
Lin JT, Wang JY, Chen MK et al (2013) Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6. Exp Cell Res 319(14):2216–2229. https://doi.org/10.1016/j.yexcr.2013.06.003
Liu H, Wang J, Zhang M et al (2017) Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. Breast Cancer Res Treat 166(1):95–107. https://doi.org/10.1007/s10549-017-4394-2
Liu C, Liu L, Chen X et al (2018) LSD1 stimulates cancer-associated fibroblasts to drive Notch3-dependent self-renewal of liver cancer stem–like cells. Cancer Res 78(4):938–949. https://doi.org/10.1158/0008-5472.CAN-17-1236
Lobry C, Oh P, Aifantis I (2011) Oncogenic and tumor suppressor functions of Notch in cancer: It’s NOTCH what you think. J Exp Med 208(10):1931–1935
Lowell S, Jones P, Le Roux I et al (2000) Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters. Curr Biol 10(9):491–500. https://doi.org/10.1016/S0960-9822(00)00451-6
Lu J, Ye X, Fan F 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. https://doi.org/10.1016/j.ccr.2012.12.021
Meurette O, Mehlen P (2018) Notch signaling in the tumor microenvironment. Cancer Cell 34(4):536–548
Mosquera JM, Sboner A, Zhang L et al (2013) Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosom Cancer 52(11):1075–1087. https://doi.org/10.1002/gcc.22102
Muthukkaruppan VR, Kubai L, Auerbach R (1982) Tumor-induced neovascularization in the mouse eye. J Natl Cancer Inst 69(3):699–708. https://doi.org/10.1093/jnci/69.3.699
Nakata T, Shimizu H, Nagata S et al (2017) Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors. Biochem Biophys Res Commun 482(4):1296–1303. https://doi.org/10.1016/j.bbrc.2016.12.031
Nguyen BC, Lefort K, Mandinova A et al (2006) Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20(13):3427–3436. https://doi.org/10.1101/gad.1406006
Nicolas M, Wolfer A, Raj K et al (2003) Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33(3):416–421. https://doi.org/10.1038/ng1099
Ohnuki H, Jiang K, Wang D et al (2014) Tumor-infiltrating myeloid cells activate Dll4/Notch/TGF-β signaling to drive malignant progression. Cancer Res 74(7):2038–2049. https://doi.org/10.1158/0008-5472.CAN-13-3118
Patenaude A, Woerher S, Umlandt P et al (2015) A novel population of local pericyte precursor cells in tumor stroma that require Notch signaling for differentiation. Microvasc Res 101:38–47. https://doi.org/10.1016/j.mvr.2015.05.004
Pedrosa AR, Graça JL, Carvalho S et al (2016) Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development. Prostate 76:80–96. https://doi.org/10.1002/pros.23102
Peng Y, Lei Z, Yang P et al (2014) Direct contacts with colon cancer cells regulate the differentiation of bone marrow mesenchymal stem cells into tumor associated fibroblasts. Biochem Biophys Res Commun 451(1):68–73. https://doi.org/10.1016/j.bbrc.2014.07.074
Procopio MG, Laszlo C, Al Labban D et al (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol 7(9):1193–1204. https://doi.org/10.1038/ncb3228
Proweller A, Tu L, Lepore JJ et al (2006) Impaired notch signaling promotes De novo squamous cell carcinoma formation. Cancer Res 66(15):7438–7444. https://doi.org/10.1158/0008-5472.CAN-06-0793
Radtke F, MacDonald HR, Tacchini-Cottier F (2013) Regulation of innate and adaptive immunity by Notch. Nat Rev Immunol 13(6):427–437
Rampias T, Vgenopoulou P, Avgeris M et al (2014) A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med 20(10):1199–1205. https://doi.org/10.1038/nm.3678
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(13):3427–3436. https://doi.org/10.1093/emboj/20.13.3427
Ribatti D, Crivellato E (2012) Sprouting angiogenesis, a reappraisal. Dev Biol 372:157–165. https://doi.org/10.1016/j.ydbio.2012.09.018
Rodilla V, Villanueva A, Obrador-Hevia A et al (2009) Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci U S A 106(15):6315–6320. https://doi.org/10.1073/pnas.0813221106
Saito T, Chiba S, Ichikawa M et al (2003) Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18(5):675–685. https://doi.org/10.1016/S1074-7613(03)00111-0
Sanguinetti A, Santini D, Bonafè M et al (2015) Interleukin-6 and pro inflammatory status in the breast tumor microenvironment. World J Surg Oncol 13:129. https://doi.org/10.1186/s12957-015-0529-2
Schepers GE, Teasdale RD, Koopman P (2002) Twenty pairs of Sox: extent, homology, and nomenclature of the mouse and human Sox transcription factor gene families. Dev Cell 3(2):167–170
Shutter JR, Scully S, Fan W et al (2000) D114, a novel Notch ligand expressed in arterial endothelium. Genes Dev 14:1313–1318. https://doi.org/10.1101/gad.14.11.1313
Sonoshita M, Aoki M, Fuwa H et al (2011) Suppression of colon cancer metastasis by AES through inhibition of notch signaling. Cancer Cell 19(1):125–123. https://doi.org/10.1016/j.ccr.2010.11.008
Stephens PJ, Davies HR, Mitani Y et al (2013) Whole exome sequencing of adenoid cystic carcinoma. J Clin Invest 123(7):2965–2968. https://doi.org/10.1172/JCI67201
Stransky N, Egloff AM, Tward AD et al (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333(6046):1157–1160. https://doi.org/10.1126/science.1208130
Studebaker AW, Storci G, Werbeck JL et al (2008) Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner. Cancer Res 68(21):9087–9095. https://doi.org/10.1158/0008-5472.CAN-08-0400
Su Q, Zhang B, Zhang L et al (2017) Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 36(5):618–627. https://doi.org/10.1038/onc.2016.232
Sugimoto K, Maekawa Y, Kitamura A et al (2010) Notch2 signaling is required for potent antitumor immunity in vivo. J Immunol 184(9):4673–4678. https://doi.org/10.4049/jimmunol.0903661
Takebe N, Miele L, Harris PJ et al (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12(8):445–464
Tonon G, Modi S, Wu L et al (2003) t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33(2):208–213. https://doi.org/10.1038/ng1083
Tsuyada A, Chow A, Wu J et al (2012) CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res 72(11):2768–2779. https://doi.org/10.1158/0008-5472.CAN-11-3567
Viatour P, Ehmer U, Saddic LA et al (2011) Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 208(10):1963–1976. https://doi.org/10.1084/jem.20110198
Wang YC, He F, Feng F et al (2010) Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70(12):4840–4849. https://doi.org/10.1158/0008-5472.CAN-10-0269
Wang NJ, Sanborn Z, Arnett KL et al (2011) Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci U S A 108(43):17761–17766. https://doi.org/10.1073/pnas.1114669108
Wang K, Zhang Q, Li D et al (2015) PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor. Clin Cancer Res 21:1487–1496. https://doi.org/10.1158/1078-0432.CCR-14-1348
Weng AP, Ferrando AA, Lee W et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271. https://doi.org/10.1126/science.1102160
Wieland E, Rodriguez-Vita J, Liebler SS et al (2017) Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31:355–367. https://doi.org/10.1016/j.ccell.2017.01.007
Xiong S, Wang R, Chen Q et al (2018) Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res 8(2):302–316
Yu W, Wang Y, Guo P (2018) Notch signaling pathway dampens tumor-infiltrating CD8+ T cells activity in patients with colorectal carcinoma. Biomed Pharmacother 97:535–542. https://doi.org/10.1016/j.biopha.2017.10.143
Zage PE, Nolo R, Fang W et al (2012) Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr Blood Cancer 58(5):682–689. https://doi.org/10.1002/pbc.23202
Zhao JL, Huang F, He F et al (2016) Forced activation of notch in macrophages represses tumor growth by upregulating MIR-125a and disabling tumor-associated macrophages. Cancer Res 76(6):1403–1415. https://doi.org/10.1158/0008-5472.CAN-15-2019
Zhu TS, Costello MA, Talsma CE et al (2011) Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71(18):6061–6072. https://doi.org/10.1158/0008-5472.CAN-10-4269
Zweidler-McKay PA, He Y, Xu L et al (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. https://doi.org/10.1182/blood-2005-01-0355
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Fasoulakis, Z. et al. (2021). The Relevance of Notch Signaling in Cancer Progression. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 1287. Springer, Cham. https://doi.org/10.1007/978-3-030-55031-8_11
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