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.
Author: | Stephan NilandGND, Dorde Komljenovic, Jadranka Macas, Thilo BrachtORCiDGND, Tobias Bäuerle, Stefan LiebnerORCiDGND, Johannes A. EbleORCiDGND |
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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: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
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): | Creative Commons - Namensnennung 3.0 |