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.