Vascular disruption induced by interactions between tumor-secreted permeability factors and
adhesive proteins on endothelial cells facilitates
metastasis. The role of tumor secreted
angiopoietin-like 4 (cANGPTL4) in vascular leakiness and
metastasis is controversial due to the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with three novel binding partners,
integrin [alpha]5[beta]1, VEcadherin and
claudin-5, in a temporally sequential manner, thus facilitating
metastasis. We showed that cANGPTL4 binds and activates
integrin [alpha]5[beta]1-mediated Rac1 / PAK signaling to weaken
cell-
cell contacts. Subsequently, cANGPTL4 is associated with and declusters VE-
cadherin and
claudin-5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delayed vascular disruption.
In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated
lung metastasis in mice. Therefore, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat
cancer and other vascular pathologies.