Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models

  • 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.

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Author:Stephan Niland, Dorde Komljenovic, Jadranka Macas, Thilo Bracht, Tobias Bäuerle, Stefan Liebner, Johannes Andreas Eble
URN:urn:nbn:de:hebis:30:3-465472
DOI:https://doi.org/10.18632/oncotarget.25032
ISSN:1949-2553
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29854288
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/04/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/06/05
Tag:abnormal tumor vasculature; endothelial barrier; neuropilin-1; rhodocetin-αβ; vasculogenic mimicry
Volume:9
Issue:32
Page Number:17
First Page:22406
Last Page:22422
Note:
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HeBIS-PPN:433826576
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0