TY  - JOUR
AU  - Niland, Stephan
AU  - Komljenovic, Dorde
AU  - Macas, Jadranka
AU  - Bracht, Thilo
AU  - Bäuerle, Tobias
AU  - Liebner, Stefan
AU  - Eble, Johannes A
TI  - Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models.
JO  - OncoTarget
VL  - 9
IS  - 32
SN  - 1949-2553
CY  - [S.l.]
PB  - Impact Journals LLC
M1  - DKFZ-2018-02327
SP  - 22406- 22422
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:29854288
C2  - pmc:PMC5976474
DO  - DOI:10.18632/oncotarget.25032
UR  - https://inrepo02.dkfz.de/record/142097
ER  -