Structure and Types
- VEGFRs are receptor tyrosine kinases found mainly on endothelial cells (cells lining blood vessels).
- There are three main types:
- VEGFR-1 (Flt-1)
- VEGFR-2 (KDR/Flk-1) – the most important for angiogenesis
- VEGFR-3 – mainly involved in lymphangiogenesis (formation of lymphatic vessels)
- Each receptor has:
- An extracellular domain that binds VEGF ligands
- A transmembrane region
- An intracellular tyrosine kinase domain that triggers signaling inside the cell
Role in Angiogenesis
- Angiogenesis = formation of new blood vessels from existing ones.
- VEGFRs, especially VEGFR-2, are activated when VEGF ligands (like VEGF-A) bind to their extracellular domain.
- Binding causes dimerization (pairing) of receptors and activates their kinase domain.
- This triggers downstream signaling that:
- Stimulates endothelial cell proliferation, migration, and survival
- Increases vascular permeability
- Angiogenesis is critical for normal wound healing and growth but also for tumor growth and metastasis.
Relevance in Cancer Biology
- Tumors need blood supply to grow beyond a small size.
- Many cancers produce high levels of VEGF to stimulate angiogenesis via VEGFR.
- Increased VEGFR signaling leads to:
- New blood vessels feeding the tumor
- Enhanced tumor growth and potential for metastasis
Targeting VEGFR in Therapy
- Anti-angiogenic therapies aim to block VEGFR signaling to “starve” tumors.
- Examples:
- Bevacizumab: a monoclonal antibody that binds VEGF ligand, preventing it from activating VEGFR.
- Sunitinib and other TKIs: small molecules that inhibit VEGFR’s tyrosine kinase activity directly.
- These therapies are used in cancers like:
- Renal cell carcinoma
- Colorectal cancer
- Non-small cell lung cancer
- Gastrointestinal stromal tumors (GIST)