Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated. Material and methods: Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter. Results: K trans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between v e (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected. Conclusions: This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC.

Six‐dimensional quantitative DCE MR Multitasking of the entire abdomen: Method and application to pancreatic ductal adenocarcinoma

“…Figure contains a bar graph showing the mean and SD measurements of v p , K trans , v e , and K ep from the control, tumor, and nontumoral regions. The results for all categories were in general agreement with published values from literature . An analysis of variance analysis with Holm‐Bonferroni correction indicated that all 4 parameters were significantly different between tumor with non‐tumor ( P = .002, .003, <.001, and .004, respectively) and between tumor and control ( P = .0011, <.001, <.001, and <.001, respectively).…”

“…The estimates of the kinetic parameters v p , K trans , v e , and K ep of control and patient groups are generally in line with the values published in the literature . K trans and v e have been shown to correlate with the microvascular density and fibrosis in PDAC lesions, respectively, and therefore can be used as imaging markers of the perfusion properties of tumor . In the TK model, K trans is dominated by the tissue blood flow and the capillary permeability–surface area and can have different physiological interpretations depending on the balance between the 2 factors .…”

“…Pancreatic ductal adenocarcinoma (PDAC) represents 95% of malignant pancreatic cancers . It has an unusual microenvironment characterized by a highly desmoplastic stroma encompassing up to 90% of the tumor; regions with hypoxic tissue; interstitial hypertension; and heterogeneous vascularization, including low microvascular density and reduced blood flow in the lesion area and high microvascular density in the surrounding area, which is inherently resistant to treatment . Due to technical challenges for early detection, approximately 60% of patients at the first diagnosis are deemed unable to receive macroscopic complete tumor resection, which remains the only curative treatment option for PDAC .…”

“…Dynamic signal enhancement curves are then extracted per pixel or from regions of interest (ROIs) and analyzed with an appropriate pharmacokinetic model to estimate several kinetic parameters, including fractional plasma volume (v p ), transfer constant (K trans ), fractional extravascular extracellular volume (v e ), and rate constant (K ep ). Several investigations have shown that K trans and v e are positively correlated with microvascular density and fibrosis in PDAC, respectively . Other studies have shown that quantitative DCE MRI can characterize PDAC and monitor treatment response …”

Targeting the tumour stroma to improve cancer therapy

“…Interstitial pressure is higher in the TME than in nonmalignant tissue 218–221 . This difference can affect drug diffusion and delivery, as demonstrated in PDAC 222,223 , melanoma 224 or glioma 225 .…”