Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

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

doi:10.1186/s12885-017-3404-4

Abstract

BackgroundStudies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.MethodsR-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.ResultsProperdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.ConclusionsProperdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.

Highlights

Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse
Tumors treated with properdistatin or sunitinib showed lower overall vessel density than untreated tumors (Fig. 2a; vehicle vs properdistatin: P = 0.004; vehicle vs sunitinib: P = 0.005), and properdistatin-treated tumors did not differ from sunitinib-treated tumors in overall vessel density (Fig. 2a; P > 0.05)
We demonstrate that antiangiogenic agents targeting different angiogenic pathways affect vascular function and tumor hypoxia distinctly different in the same melanoma model

Summary

Introduction

Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. Antiangiogenic treatments targeting the vascular endothelial growth factor A (VEGF-A) pathway have been shown to improve blood supply and oxygenation in some preclinical tumor models, and to reduce blood supply and induce hypoxia in others [3, 4, 10,11,12]. The reasons for these different effects are not well understood but may have substantial impact on combination therapies where antiangiogenic treatment is applied prior to or concurrent with conventional therapy [13]. Studies comparing microenvironmental effects of antiangiogenic agents targeting different angiogenic pathways have not been reported far

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