DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts

Abstract

The purpose of this study was dual: to investigate (a) whether sunitinib may induce changes in tumor microvasculature and hypoxia in pancreatic ductal adenocarcinoma (PDAC) and (b) whether any changes can be detected by DCE-MRI. Sunitinib-treated and untreated control tumors of two PDAC xenograft models (BxPC-3 and Panc-1) were subjected to DCE-MRI before the imaged tumors were prepared for quantitative analysis of immunohistochemical preparations. Pimonidazole was used as a hypoxia marker, and fraction of hypoxic tissue (HF_Pim), density of CD31-positive microvessels (MVD_CD31), and density of αSMA-positive microvessels (MVD_αSMA) were measured. Parametric images of K^trans and v_e were derived from the DCE-MRI data by using the Tofts pharmacokinetic model. BxPC-3 tumors showed increased HF_Pim, decreased MVD_CD31, unchanged MVD_αSMA, and increased vessel maturation index (VMI = MVD_αSMA/MVD_CD31) after sunitinib treatment. The increase in VMI was seen because sunitinib induced selective pruning rather than maturation of αSMA-negative microvessels. Even though the microvessels in sunitinib-treated tumors were less abnormal than those in untreated tumors, this microvessel normalization did not improve the function of the microvascular network or normalize the tumor microenvironment. In Panc-1 tumors, HF_Pim, MVD_CD31, MVD_αSMA, and VMI were unchanged after sunitinib treatment. Median K^trans increased with increasing MVD_CD31 and decreased with increasing HF_Pim, and the correlations were similar for treated and untreated BXPC-3 and Panc-1 tumors. These observations suggest that sunitinib may induce significant changes in the microenvironment of PDACs, and furthermore, that K^trans may be an adequate measure of tumor vascular density and hypoxia in untreated as well as sunitinib-treated PDACs.