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 for endothelial cells.
  • VEGF binds to VEGFR-1 and VEGFR-2.2
    • The major pro-angiogenic signal is generated from VEGF-activated VEGFR-2.
    • VEGF binding to VEGFR-2 induces high activity in the MAPK pathway, leading to endothelial proliferation.

Implications in cancer

  • Neovascularization, or sprouting angiogenesis, is required for the growth of most solid tumors and facilitates the spread 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.4
    • The VEGF and DLL4 signaling pathways function in coordination to regulate angiogenesis, blood vessel differentiation, and homeostasis.5
    • 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
      • VEGF also induces DLL4 as a negative feedback regulator of vascular sprouting during tumor angiogenesis.

Colorectal Cancer

  • VEGF is the predominant angiogenic factor in CRC, per evidence from preclinical and clinical studies.1
    • 50% of CRCs express VEGF.
      • Normal colonic mucosa and adenomas express minimal to no VEGF.
    • Increased VEGF is strongly associated with advanced lymph nodes status and distant metastases.
  • Patients with high levels of VEGF expression demonstrate significantly worse survival than those with weak or no expression.1
    • VEGF expression was more common in patients who had progressive disease following 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.6
    • However, acquired resistance to therapy occurs in 90% of patients with metastatic colorectal cancer.7
  1. 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;28:3865-3870.
  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. Mésange P, Poindessous V, Sabbah M, et al. Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget. 2014;5(13):4709-4721.
  4. Li Y, Hickson J, Ambrosi D, et al. Abstract 867: ABT-165 is a first-in-class therapeutic dual variable domain immunoglobulin (DVD-Ig™) that targets DLL4 and VEGF for the treatment of cancer. In: Proceedings: AACR 107th Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract 867.
  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. PNAS. 2007;104(9):3219-3224.
  6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. NEJM. 2004;350(23):2335-2342.
  7. Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Adv Med Oncol. 2016;81(1):57-84.

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