Abstract
Sustained angiogenesis is essential for the development of solid tumors and metastatic disease. Disruption of signaling pathways that govern tumor vascularity provide a potential avenue to thwart cancer progression. Through phage display-based functional proteomics, immunohistochemical analysis of human pancreatic ductal carcinoma (PDAC) specimens, and in vitro validation, we reveal that hornerin, an S100 fused-type protein, is highly expressed on pancreatic tumor endothelium in a vascular endothelial growth factor (VEGF)-independent manner. Murine-specific hornerin knockdown in PDAC xenografts results in tumor vessels with decreased radii and tortuosity. Hornerin knockdown tumors have significantly reduced leakiness, increased oxygenation, and greater apoptosis. Additionally, these tumors show a significant reduction in growth, a response that is further heightened when therapeutic inhibition of VEGF receptor 2 (VEGFR2) is utilized in combination with hornerin knockdown. These results indicate that hornerin is highly expressed in pancreatic tumor endothelium and alters tumor vessel parameters through a VEGF-independent mechanism.
Highlights
Sustained angiogenesis is essential for the development of solid tumors and metastatic disease
To elucidate peptides that bind to tumor endothelium, an in vivo phage display screen was performed in mice bearing orthotopically implanted human pancreatic ductal carcinoma (PDAC) cells
The immunofluorescent images indicate that the fluorescein isothiocyanate (FITC)-phage remained bound to the luminal surface of the blood vessels even after vigorous perfusion
Summary
The discovery of vascular endothelial growth factor (VEGF), originally called vascular permeability factor, in 19835 dramatically increased the knowledge of angiogenesis in many fields, including tumor angiogenesis Since it is extensively studied and highly overexpressed in cancer as well as other pathologies, the VEGF pathway was a natural initial target when developing antiangiogenesis therapies. Hornerin knockdown combined with VEGF inhibition produced additive tumor volume and angiogenesis abatement, providing further evidence that compensatory pathways exist in tumor-associated endothelial cells. The discovery of elevated hornerin expression in tumor vasculature, the functional consequences of hornerin targeted knockdown on tumor vascularity and growth, and the additive effect of hornerin depletion with VEGFR signaling inhibition directs the potential creation of a novel anti-angiogenesis strategy that targets multiple signaling pathways in tumor endothelial cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
