Oncotarget

Research Papers:

Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression

Jon-Vidar Gaustad _, Trude G. Simonsen, Lise Mari K. Andersen and Einar K. Rofstad

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Oncotarget. 2016; 7:76806-76815. https://doi.org/10.18632/oncotarget.12695

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Abstract

Jon-Vidar Gaustad1, Trude G. Simonsen1, Lise Mari K. Andersen1, Einar K. Rofstad1

1Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

Correspondence to:

Jon-Vidar Gaustad, email: [email protected]

Keywords: malignant melanoma, thrombospondin-1, properdistatin, tumor vasculature, intravital microscopy

Received: August 11, 2016     Accepted: October 12, 2016     Published: October 15, 2016

ABSTRACT

In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function.


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