%0 Journal Article
%A Niland, Stephan
%A Komljenovic, Dorde
%A Macas, Jadranka
%A Bracht, Thilo
%A Bäuerle, Tobias
%A Liebner, Stefan
%A Eble, Johannes A
%T Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models.
%J OncoTarget
%V 9
%N 32
%@ 1949-2553
%C [S.l.]
%I Impact Journals LLC
%M DKFZ-2018-02327
%P 22406- 22422
%D 2018
%X The tumor vasculature differs from normal blood vessels in morphology, composition and stability. Here, we describe a novel tumor vessel-disrupting mechanism. In an HT1080/mouse xenograft tumor model rhodocetin-αβ was highly effective in disrupting the tumor endothelial barrier. Mechanistically, rhodocetin-αβ triggered MET signaling via neuropilin-1. As both neuropilin-1 and MET were only lumen-exposed in a subset of abnormal tumor vessels, but not in normal vessels, the prime target of rhodocetin-αβ were these abnormal tumor vessels. Consequently, cells lining such tumor vessels became increasingly motile which compromised the vessel wall tightness. After this initial leakage, rhodocetin-αβ could leave the bloodstream and reach the as yet inaccessible neuropilin-1 on the basolateral side of endothelial cells and thus disrupt nearby vessels. Due to the specific neuropilin-1/MET co-distribution on cells lining such abnormal tumor vessels in contrast to normal endothelial cells, rhodocetin-αβ formed the necessary trimeric signaling complex of rhodocetin-αβ-MET-neuropilin-1 only in these abnormal tumor vessels. This selective attack of tumor vessels, sparing endothelial cell-lined vessels of normal tissues, suggests that the neuropilin-1-MET signaling axis may be a promising drugable target for anti-tumor therapy, and that rhodocetin-αβ may serve as a lead structure to develop novel anti-tumor drugs that target such vessels.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29854288
%2 pmc:PMC5976474
%R 10.18632/oncotarget.25032
%U https://inrepo02.dkfz.de/record/142097