vegf

Overview

  • VEGF (also known as VEGF-A) is the most potent angiogenic cytokine involved in the process of neoangiogenesis, which promotes tumor growth and metastasis.1
    • VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic, and vascular permeability–enhancing activities specific to endothelial cells.
  • VEGF binds to VEGFR-1 and VEGFR-2.1,2
    • The major proangiogenic signal is generated from VEGF-activated VEGFR-2.
    • VEGF binding to VEGFR-2 induces high activity in the mitogen-activated protein kinase (MAPK) pathway, leading to endothelial proliferation.

Implications in cancer

  • Neovascularization, or sprouting angiogenesis, is required for the growth of most solid tumors and facilitates metastasis of tumor cells to secondary sites.3
    • VEGF is a key regulator of angiogenesis.3
  • The VEGF/VEGFR axis is known to cooperate with the DLL4/Notch signaling axis during pathological angiogenesis.3,4
    • The VEGF/VEGFR and DLL4/Notch signaling pathways function in coordination to regulate angiogenesis, blood vessel differentiation, and homeostasis.4
    • VEGF is the primary initiator of angiogenesis and upregulates DLL4 expression within the endothelium of angiogenic vessels.5
    • Upregulated DLL4 may act as a negative regulator of VEGF-induced angiogenesis to control excessive vascular sprouting and endothelial cell proliferation.5
      • DLL4 has also been observed to interact with other VEGF-dependent and -independent pathways.6-9

Colorectal Cancer

  • VEGF is the predominant angiogenic factor in colorectal cancer (CRC), per evidence from preclinical and clinical studies.10
    • 50% of CRCs express VEGF.
      • Normal colonic mucosa and adenomas express minimal to no VEGF.
    • Increased VEGF is strongly associated with advanced lymph node status and distant metastases.
  • Patients with high levels of VEGF expression demonstrate significantly worse survival than those with weak or no expression.10
    • VEGF expression was more common in patients who had progressive disease following surgical treatment than in those who showed clinical benefit, suggesting a link between VEGF expression and resistance to therapy.
  • Anti-VEGF therapy has demonstrated clinical efficacy in patients with colorectal cancer when used in combination with standard-of-care chemotherapy.11
    • However, acquired resistance to therapy occurs in 90% of patients with metastatic colorectal cancer.12
  1. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581-611
  2. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097-1105.
  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(1):17.
  4. Li JL, Harris AL. Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications. Front Biosci (Landmark Ed). 2009;14:3094-3110.
  5. Lobov IB, Renard RA, Papadopoulos N, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA. 2007;104(9):3219-3224.
  6. Kuhnert F, Kirshner JR, Thurston G. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc Cell. 2011;3(1):20.
  7. Hodkinson PS, Elliott PA, Lad Y, et al. Mammalian NOTCH-1 activates beta1 integrins via the small GTPase R-Ras. J Biol Chem. 2007;282(39):28991-29001.
  8. Thurston G, Kitajewski J. VEGF and Delta-Notch: interacting signaling pathways in tumour angiogenesis. Br J Cancer. 2008;99(8):1204-1209.
  9. Hainaud P, Contrerés 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.
  10. Bendardaf R, Buhmeida A, Hilska M, et al. VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res. 2008;28(6B):3865-3870.
  11. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.
  12. Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;8(1):57-84.

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