Angiopoietin-like 4 and its use in modulating cell leakiness

Abstract

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.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit and priority of US Provisional Patent Application Serial No. 61 / 521,031, filed August 8, 2011, the contents of which are incorporated herein by reference. technical field [0003] The present invention relates to the regulation of cell permeability. Background technique [0004] Endothelial cell leakage is a commonly observed phenomenon in tumor vessels and is involved in the pathogenesis of asthma, sepsis and cardiovascular disease. Normally, endothelial cells form a tight monolayer that allows only small molecules such as ions and solutes to pass through. Under pathological conditions, increased endothelial cell permeability or disruption of cell-cell junctions causes endothelial leakage, allowing macromolecules or cells (such as tumor cells and macrophages) to pass through blood vessels more easily. On the other hand, a leaky endothelial cell layer facilitates drug delivery to ...

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Angiopoietin-like 4 (ANGPTL4) protein is implicated in cancer (10), however, its exact role in cancer biology remains controversial

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