dll4

Overview

DLL4 is a cell surface ligand that serves to activate the Notch 1 receptor, and performs many important functions in normal development and tissue homeostasis, including roles in1:

  • Vascular development
  • The immune system
  • Gastrointestinal tract

Due to the importance of Notch signaling in stem cell biology, DLL4 has been investigated for its role in the maintenance and proliferation of cancer stem cells (CSCs).1

Implications in cancer

  • DLL4 plays an important role in CSC maintenance and angiogenesis.1
  • There is both preclinical and clinical evidence that DLL4 expression is associated with resistance to VEGF-targeted therapy.2
    • DLL4 is a distinct angiogenic pathway from VEGF.3
  • Preclinical data suggest that CSCs, which express DLL4, play a role in resistance to chemotherapy.4

Colorectal Cancer

  • There is substantial evidence that DLL4-Notch signaling plays an important role in a range of tumor cell types, including colorectal cancer.1,5

Breast Cancer

  • In clinical breast cancer samples, DLL4 was expressed by nearly all intratumoral endothelial cells, as well as in cells of ductal carcinomas.6
  • A high intensity of DLL4 endothelial expression was a statistically significant adverse prognostic factor.6
    • This may suggest that breast tumors with high DLL4 expression in the vasculature progressed more rapidly.

Ovarian Cancer

  • DLL4 overexpression may be an independent predictor of poor survival.7
  • Patients with tumors responding to anti-VEGF therapy had lower levels of DLL4 than patients with stable or progressive disease.7
  1. Gurney A. Hoey T. Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc Cell. 2011;3:18.
  2. 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.
  3. Hernandez SL, Banerjee D, Garcia A, et al. Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. Vasc Cell. 2013;5:17.
  4. 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.
  5. Mullendore M, Koorstra J-B, Li Y-M, et al. Ligand-dependent notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res. 2009;15:2291-2301.
  6. Brzozowa M, Wojnicz R, Kowalcyzk-Ziomek G, Helewski K. The notch ligand delta-like 4 (DLL4) as a target in angiogenesis-based cancer therapy? Contemp Oncol (Pozn). 2013;17(3):234-237.
  7. Hu W, Lu C, Han HD, 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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