The angiopoietin (ANGPT)–TIE system is crucial for the angiogenic switch in tumours, and together with vascular endothelial growth factor A (VEGFA) promotes the initiation of angiogenesis and maturation of new vessels. The ANGPT–TIE system is also involved in inflammation, metastasis and lymphangiogenesis.
ANGPT1 is a TIE2 agonist, and ANGPT2 functions as an antagonist or a partial agonist of TIE2 in different contexts. Both ANGPT1 and ANGPT2 have been shown to promote or inhibit tumorigenesis in various settings.
Agents specifically targeting ANGPT1 and ANGPT2 are currently in Phase II clinical trials and early reports suggest a promising anti-tumour activity and a safety profile distinct from those of anti-VEGFA agents.
Substantial combination benefit of targeting both the ANGPT2 and VEGFA pathways has been demonstrated preclinically.
Angiopoietins (ANGPTs) are ligands of the endothelial cell receptor TIE2 and have crucial roles in the tumour angiogenic switch. Increased expression of ANGPT2 relative to ANGPT1 in tumours correlates with poor prognosis. The biological effects of the ANGPT–TIE system are context dependent, which brings into question what the best strategy is to target this pathway. This Review presents an encompassing picture of what we know about this important axis in tumour biology. The various options for therapeutic intervention are discussed to identify the best path forwards.
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All authors are employees of CovX, a division of Pfizer Inc.
- Adaptive resistance
Tumours that adapt and evade anti-angiogenic therapy.
- Intrinsic non-responsiveness
Tumours that are inherently non-responsive to anti-angiogenic therapy.
- Mural cells
Vascular smooth muscle cells and pericytes, often used interchangeably with perivascular cells.
- Weibel–Palade body
Storage granule of endothelial cells, including ANGPT2, von Willebrand factors, P-selectin and several other chemokines.
Embryonic mesenchymal tissues from which blood cells and blood vessels are formed.
- Adherens junction
Transmembrane clustered adhesive cadherin proteins at cell–cell contacts that connect with a complex network of cytoskeletal proteins through their cytoplasmic domain.
- Tight junction
Also referred to as a zonula occludens, a site where the membranes of two cells join together forming a virtually impermeable barrier.
- Gap junction
Specialized pores made of primarily homo-hexamers or hetero-hexamers of connexin proteins that allow small molecules and ions to pass between cells.
- Allantois explant
Dissected from E8.0 to E8.5 animal embryo, cultured in vitro to study vasculogenesis and angiogenesis.
A biologically active peptide fused to either the N or C terminus of the Fc domain of immunoglobulin.
- Chylous ascites
A milky chyle (fluid) that has leaked into the abdominal cavity.
- Endotoxin shock
Septic shock induced by endotoxins of gram-negative bacteria.
- Rolling leukocyte
White blood cell that moves more slowly in microvessels than red blood cells, and tends to attach and infiltrate vessel walls during inflammation.
Specific covalent fusion between a biologically active pharmacophore, such as a peptide, and a monoclonal antibody through a specifically designed linker.
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Huang, H., Bhat, A., Woodnutt, G. et al. Targeting the ANGPT–TIE2 pathway in malignancy. Nat Rev Cancer 10, 575–585 (2010). https://doi.org/10.1038/nrc2894
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