Rhodocetin-αβ selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models
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Stephan Niland1, Dorde Komljenovic2, Jadranka Macas3, Thilo Bracht1,4, Tobias Bäuerle2, Stefan Liebner3 and Johannes A. Eble1
1Institute of Physiological Chemistry and Pathobiochemistry, Münster University Hospital, Münster, Germany
2German Cancer Research Center, Division Medical Physics in Radiology, Heidelberg, Germany
3Institute of Neurology, Edinger Institute, Johann Wolfgang Goethe University, Frankfurt, Germany
4Current address: Clinical Proteome Center, Ruhr-University, Bochum, Germany
Johannes A. Eble, email: [email protected]
Keywords: endothelial barrier; abnormal tumor vasculature; vasculogenic mimicry; rhodocetin-αβ; neuropilin-1
Received: July 21, 2017 Accepted: March 19, 2018 Published: April 27, 2018
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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