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Notch signaling regulates tumor angiogenesis by diverse mechanisms

Oncogene volume 27, pages 5132–5137 (2008)Cite this article

Abstract

The Notch signaling pathway is fundamental to proper cardiovascular development and is now recognized as an important player in tumor angiogenesis. Two key Notch ligands have been implicated in tumor angiogenesis, Delta-like 4 and Jagged1. We introduce the proteins and how they work in normal developing vasculature and then discuss differing models describing the action of these Notch ligands in tumor angiogenesis. Endothelial Dll4 expression activates Notch resulting in restriction of new sprout development; for instance, in growing retinal vessels. In agreement with this activity, inhibition of Dll4-mediated Notch signaling in tumors results in hypersprouting of nonfunctional vasculature. This Dll4 inhibition may paradoxically lead to increased angiogenesis but poor tumor growth because the newly growing vessels are not functional. In contrast, Jagged1 has been described as a Notch ligand expressed in tumor cells that can have a positive influence on tumor angiogenesis, possibly by activating Notch on tumor endothelium. A novel Notch inhibitor, the Notch1 decoy, which blocks both Dll4 and Jagged1 has been recently shown to restrict tumor vessel growth. We discuss these models and speculate on therapeutic approaches.

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References

  • Alva JA, Iruela-Arispe ML . (2004). Notch signaling in vascular morphogenesis. Curr Opin Hematol 11: 278–283.

    Article  CAS  PubMed  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.

    Article  CAS  PubMed  Google Scholar 

  • Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ et al. (2005). Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA 102: 9884–9889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claxton S, Fruttiger M . (2004). Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns 5: 123–127.

    Article  CAS  PubMed  Google Scholar 

  • Funahashi Y, Hernandez SL, Das I, Ahn A, Huang J, Vorontchikhina M et al. (2008). A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res 68: 4727–4735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM et al. (2004). Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA 101: 15949–15954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A et al. (2003). VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161: 1163–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwald I . (1998). LIN-12/Notch signaling: lessons from worms and flies. Genes Dev 12: 1751–1762.

    Article  CAS  PubMed  Google Scholar 

  • Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P et al. (2007). Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445: 776–780.

    Article  PubMed  Google Scholar 

  • High FA, Epstein JA . (2008). The multifaceted role of Notch in cardiac development and disease. Nat Rev Genet 9: 49–61.

    Article  CAS  PubMed  Google Scholar 

  • High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA . (2008). Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA 105: 1955–1959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iso T, Maeno T, Oike Y, Yamazaki M, Doi H, Arai M et al. (2006). Dll4-selective Notch signaling induces ephrinB2 gene expression in endothelial cells. Biochem Biophys Res Commun 341: 708–714.

    Article  CAS  PubMed  Google Scholar 

  • Jain RK, Duda DG, Clark JW, Loeffler JS . (2006). Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3: 24–40.

    Article  CAS  PubMed  Google Scholar 

  • Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T . (2004). Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18: 2469–2473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP et al. (2000). Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14: 1343–1352.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA et al. (2001). Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128: 3675–3683.

    CAS  PubMed  Google Scholar 

  • Lawson ND, Weinstein BM . (2002). Arteries and veins: making a difference with zebrafish. Nat Rev Genet 3: 674–682.

    Article  CAS  PubMed  Google Scholar 

  • Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK . (2005). Essential role of endothelial Notch1 in angiogenesis. Circulation 111: 1826–1832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD et al. (2007). Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104: 3219–3224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D . (2001). Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69: 135–144.

    Article  CAS  PubMed  Google Scholar 

  • Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW et al. (2006). Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444: 1032–1037.

    Article  CAS  PubMed  Google Scholar 

  • Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K et al. (2006). Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer. Clin Cancer Res 12: 4836–4844.

    Article  CAS  PubMed  Google Scholar 

  • Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL . (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: 8690–8697.

    Article  CAS  PubMed  Google Scholar 

  • Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V et al. (2004). Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167: 215–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reedijk M, Odorcic S, Chang L, Zhang H, Miller N, McCready DR 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: 8530–8537.

    Article  CAS  PubMed  Google Scholar 

  • Reedijk M, Pinnaduwage D, Dickson BC, Mulligan AM, Zhang H, Bull SB et al. (2007). JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat; e-pub ahead of print.

  • Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y et al. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444: 1083–1087.

    Article  CAS  PubMed  Google Scholar 

  • Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R et al. (2007). Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109: 4753–4760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shawber CJ, Das I, Francisco E, Kitajewski J . (2003). Notch signaling in primary endothelial cells. Ann NY Acad Sci 995: 162–170.

    Article  CAS  PubMed  Google Scholar 

  • Siekmann AF, Lawson ND . (2007). Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445: 781–784.

    Article  CAS  PubMed  Google Scholar 

  • Stylianou S, Clarke RB, Brennan K . (2006). Aberrant activation of notch signaling in human breast cancer. Cancer Res 66: 1517–1525.

    Article  CAS  PubMed  Google Scholar 

  • Suchting S, Freitas C, Ie Noble F, Benedito R, Breant C, Duarte A et al. (2007). The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104: 3225–3230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeshita K, Satoh M, Li M, Silver M, Limbourg FP, Mukai Y et al. (2007). Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res 100: 70–78.

    Article  CAS  PubMed  Google Scholar 

  • Thurston G, Noguera-Troise I, Yancopoulos GD . (2007). The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7: 327–331.

    Article  CAS  PubMed  Google Scholar 

  • 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 USA 98: 5643–5648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wang HU, Chen ZF, Anderson DJ . (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93: 741–753.

    Article  CAS  PubMed  Google Scholar 

  • Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C et al. (1999). Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 8: 723–730.

    Article  CAS  PubMed  Google Scholar 

  • Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H et al. (2005). Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8: 13–23.

    Article  CAS  PubMed  Google Scholar 

  • Zhong TP, Childs S, Leu JP, Fishman MC . (2001). Gridlock signalling pathway fashions the first embryonic artery. Nature 414: 216–220.

    Article  CAS  PubMed  Google Scholar 

  • Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC . (2000). gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 287: 1820–1824.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Columbia University Medical Center, New York, NY, USA

    J Dufraine & J Kitajewski

  2. Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY, USA

    J Dufraine & J Kitajewski

  3. Tsukuba Research Laboratories, Eisai Co, Ltd, Ibaraki, Japan

    Y Funahashi

  4. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

    J Kitajewski

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  1. J Dufraine
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Correspondence to J Kitajewski.

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Dufraine, J., Funahashi, Y. & Kitajewski, J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27, 5132–5137 (2008). https://doi.org/10.1038/onc.2008.227

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