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.
Highlights
The tumor vasculature which supports tumor metabolism, growth, and hematogenic metastasis differs from vessels found in normal tissues
Solid tumors became hemorrhagic within 1–3 hours (Supplementary Figure 1), while no obvious hemorrhage was detectable in other tissues, such as skin, muscle, kidney, or liver
We observed that the NRP1-binding rhodocetin-αβ without the α2β1 integrin-blocking rhodocetin-γδ-subunit, was sufficient for this effect
Summary
The tumor vasculature which supports tumor metabolism, growth, and hematogenic metastasis differs from vessels found in normal tissues. Abnormal tumor blood vessels (ATV) can be classified into at least six distinct types [1], and even tumor cell-lined blood cell-filled conduits have been described in some tumors [3]. Such vasculogenic mimicry (VM) is not found in the healthy body but is unique to tumor tissue where it promotes cancer growth and hematogenic dissemination of detaching tumor cells causing metastasis [4, 5]. VM has been observed in many cancers, such as astrocytoma www.oncotarget.com
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