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

2018; Impact Journals LLC; Volume: 9; Issue: 32 Linguagem: Inglês

10.18632/oncotarget.25032

1949-2553

Stephan Niland, Dorde Komljenovic, Jadranka Macas, Thilo Bracht, Tobias Bäuerle, Stefan Liebner, Johannes A. Eble,

Cancer Cells and Metastasis

// Stephan Niland 1 , Dorde Komljenovic 2 , Jadranka Macas 3 , Thilo Bracht 1, 4 , Tobias Bäuerle 2 , Stefan Liebner 3 and Johannes A. Eble 1 1 Institute of Physiological Chemistry and Pathobiochemistry, Münster University Hospital, Münster, Germany 2 German Cancer Research Center, Division Medical Physics in Radiology, Heidelberg, Germany 3 Institute of Neurology, Edinger Institute, Johann Wolfgang Goethe University, Frankfurt, Germany 4 Current address: Clinical Proteome Center, Ruhr-University, Bochum, Germany Correspondence to: Johannes A. Eble, email: Johannes.eble@uni-muenster.de Keywords: endothelial barrier; abnormal tumor vasculature; vasculogenic mimicry; rhodocetin-αβ; neuropilin-1 Received: July 21, 2017 Accepted: March 19, 2018 Published: April 27, 2018 ABSTRACT 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.