Angiopoietin-like 4 and its use in regulating cellular leakiness

Abstract

Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesion proteins on endothelial cells promotes metastasis The role of tumor-secreted angiopoietin-like 4 (cANGPTL4) in vascular leakage and metastasis is controversial due to a lack of understanding of how cANGPTL4 regulates vascular integrity. Here, we show that cANGPTL4 contributes to disruption of endothelial continuity and thus metastasis by directly interacting with 3 novel binding partners integrin α5β1, VE-cadherin and claudin‑5 in a temporally sequential manner. We show that cANGPTL4 binds to and activates integrin α5β1-mediated Rac1 / PAK signaling to attenuate cell–cell contacts. cANGPTL4 subsequently associates with and dissociates VE‑cadherin and claudin‑5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delays vascular destruction. In vivo vascular permeability and metastasis assays using ANGPTL4-knockout and wild-type mice injected with control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induces vascular leakiness and promotes lung metastasis in mice. Thus, our findings explain how cANGPTL4 induces endothelial disruption. Our findings have immediate implications for targeting cANGPTL4 to treat cancer and other vascular lesions.

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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Problems solved by technology

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

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