DCE-MRI–Based Quantification of Tumor Transport and Microenvironment Heterogeneity Using the Cross-Voxel Exchange Model
Abstract
Purpose
Tumor heterogeneity within and across tumors contributes to variable therapeutic response by altering biophysical transport barriers in the tumor microenvironment (TME). Elevated interstitial fluid pressure (IFP) and reduced hydraulic conductivity (K) generate outward convection that impedes drug delivery and influences radiation response. This study evaluated the capability of the Cross-Voxel eXchange Model (CVXM) applied to DCE-MRI to quantify transport properties across distinct TME, characterize intra- versus intertumoral heterogeneity, and detect radiation-induced TME changes.
Methods
ME180 cervical carcinoma xenografts were established orthotopically, intramuscularly (IM), and subcutaneously in immunodeficient NRG mice. CVXM was applied to 7T DCE-MRI to generate voxel-wise maps of tracer extravasation, velocity, diffusion, and tumor hydraulic conductivity (CVXM-derived K). Direct IFP measurements and ex-vivo hydraulic conductivity assays were used for validation of CVXM-derived K. A subset of orthotopic tumors received fractionated radiotherapy (5×5Gy), with post-treatment DCE-MRI acquired five days later. Kruskal-Wallis and Dunn’s tests were performed across implant types to statistically assess intra- versus intertumoral heterogeneity.
Results
Significant differences were observed between tumor implant sites, with orthotopic versus IM and subcutaneous versus IM tumors showing statistically significant differences in velocity, diffusion, IFP, and CVXM-derived K (p < 0.05). CVXM-derived K correlated strongly with velocity (R² = 0.49–0.65, p < 0.001) and agreed with ex vivo measurements. Within the IM model, CVXM captured distinct tumor microenvironments at the lobular level (p < 0.001), with intratumoral heterogeneity (ICC=0.46) comparable to intertumoral heterogeneity (ICC=0.54). Following radiotherapy, orthotopic tumors demonstrated reduced IFP accompanied by decreased velocity and hydraulic conductivity, consistent with previously reported radiation-induced changes in transport.
Conclusion
CVXM enables non-invasive, spatially resolved quantification of tumor transport properties, distinguishes intra- and intertumoral heterogeneity, and is sensitive to radiation-induced biophysical changes. This imaging framework provides a translational tool for evaluating TME-mediated transport barriers relevant to both drug delivery and radiation therapy response.