dll4

Overview

DLL4 is a cell-surface ligand that activates the Notch 1 receptor and performs critical functions in both normal vascular development and pathological angiogenesis.1

DLL4/Notch is a distinct angiogenic pathway from VEGF/VEGFR.2 The VEGF/VEGFR and DLL4/Notch signaling pathways function in coordination to regulate normal and pathological angiogenesis, blood vessel differentiation, and homeostasis.3 DLL4 has also been observed to interact with other VEGF-dependent and -independent pathways.4-7

Implications in cancer

In addition to tumor angiogenesis, DLL4 has also been shown to play a role in the maintenance of tumor-initiating cells or cancer stem cells (CSCs) and chemoresistance.1,8-10

  • There is both preclinical and clinical evidence that DLL4 expression is associated with resistance to VEGF-targeted therapy.11-13

Colorectal Cancer

  • There is substantial evidence that DLL4-Notch signaling plays an important role in a range of tumor cell types, including colorectal cancer.1,14

Breast Cancer

  • In clinical breast cancer samples, DLL4 was expressed by nearly all intratumoral endothelial cells, as well as in cells of ductal carcinomas.15
  • A high intensity of DLL4 endothelial expression was a statistically significant adverse prognostic factor.15
    • This may suggest that breast tumors with high DLL4 expression in the vasculature progressed more rapidly.16

Ovarian Cancer

  • DLL4 overexpression may be an independent predictor of poor survival.17
  • Patients with tumors responding to anti-VEGF therapy had lower levels of DLL4 than patients with stable or progressive disease, suggesting that high levels of DLL4 may contribute to resistance to anti-VEGF therapy.17
  1. Gurney A, Hoey T. Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc Cell. 2011;3:18.
  2. Hernandez SL, Banerjee D, Garcia A, et al. Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. Vasc Cell. 2013;5(1):17.
  3. Li JL, Harris AL. Crosstalk of VEGF and Notch pathways in tumor angiogenesis: therapeutic implications. Front Biosci (Landmark Ed). 2009;14:3094-3110.
  4. Kuhnert F, Kirshner JR, Thurston G. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc Cell. 2011;3(1):20.
  5. Hodkinson PS, Elliott PA, Lad Y, et al. Mammalian NOTCH-1 activates beta1 integrins via the small GTPase R-Ras. J Biol Chem. 2007;82(39):28991-29001.
  6. Thurston G, Kitajewski J. VEGF and Delta-Notch: interacting signaling pathways in tumour angiogenesis. Br J Cancer. 2008;99(8):1204-1209.
  7. Hainaud P, Contreres JO, Villemain A, et al. The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res. 2006;66(17):8501-8510.
  8. Fischer M, Yen WC, Kapoun AM, et al. Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Res. 2010;71(5):1520-1525.
  9. Hoey T, Yen WC, Axelrod F, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5(2):168-177.
  10. Kang M, Jiang B, Xu B, et al. Delta like ligand 4 induces impaired chemo-drug delivery and enhanced chemoresistance in pancreatic cancer. Cancer Lett. 2013;330(1):11-21.
  11. Williams CK, Li JL, Murga M, Harris AL, Tosato G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 2006;107:931-939.
  12. Ridgway J, Zhang G, Wu Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444:1083-1087.
  13. Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 2007;67(23):11244-11253.
  14. Jubb AM, Turley H, Moeller HC, et al. Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Br J Cancer. 2009;101(10):1749-1757.
  15. Jubb AM, Soilleux EJ, Turley H, et al. Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. Am J Pathol. 2010;176(4):2019-2028.
  16. Kontomanolis E, Panteliadou M, Giatromanolaki A, et al. Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis.
    Med Oncol. 2014;31(5):945.
  17. Hu W, Lu C, Dong HH, et al. Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res. 2011;71(18):6030-6039.

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