Table 1.
PTKs and their role in lymphatic biology
| Gene | Role in lymphatic vessels | Inhibitors available* | Effect of pathway inhibition | References |
|---|---|---|---|---|
| VEGFR-2 | Receptor for the VEGF family of ligands. Can also heterodimerize with VEGFR-3. | Yes | Secreted VEGFR-2 is a naturally occurring inhibitor of lymphatic vessel growth. However, Sorafenib† did not block VEGF-C/D induced tumor lymphangiogenesis. |
[132,133] |
| VEGFR-3 | Predominant receptor for the lymphangiogenic growth factors VEGF-C and VEGF-D, transduces survival, proliferation and migration signals. | Yes | Cediranib‡ blocks VEGFR-3 activity and inhibits lymphangiogenesis. Anti-VEGFR-3 antibody prevented tumor lymphangiogenesis with no effect on preexisting vessels. |
[32,33,88,134-136] |
| Tie1 | Not critical for lymphatic cell commitment during development, and no ligand has been shown. | None reported | Tie1 knockout mouse has lymphatic vascular abnormalities that precede the blood vessel phenotype. | [55] |
| Tie2 | Receptor for Ang-1 and Ang-2, appears to control vessel maturation. | Yes |
Tie2-/- mice are embryonic lethal due to vascular defects. Inhibition of Ang-2 leads to tumor blood vessel normalization. |
[49,50,137] |
| EphB4 | Expressed on lymphatic capillary vessels, involved in vascular patterning, binds to the ephrinB2 ligand. | Yes | Mice expressing a mutant form of ephrinB2 lacking the PDZ binding domain show major lymphatic defects in capillary vessels and collecting vessel valve formation. | [60] |
| SRC | Signal transduction downstream from receptors. | Yes | Src inhibitor AZM475271 was effective at blocking VEGF-C driven lymphangiogenesis in vivo. | [103] |
| FGFR3 | The ligands FGF-1 and FGF-2 promote proliferation, migration, and survival of cultured LECs. FGFR3 is direct transcriptional target of Prox1. | Yes | Knockdown of FGFR3 reduced LEC proliferation. | [47] |
| IGF1R | Both of the IGF1R ligands, IGF-1 and IGF-2, significantly stimulated proliferation and migration of primary lymphatic endothelial cells. | Yes | None reported. | [48] |
| PDGFRβ | The ligand PDGF-BB stimulated MAP kinase activity and cell motility of isolated lymphatic endothelial cells. | Yes | None reported. | [138] |
| MET | The ligand for c-Met, hepatocyte growth factor has lymphangiogenic effect, but it is unclear if c-Met is expressed on LECs. | Yes | May be indirect effect. | [45,46] |