MRI and US imaging reveal evolution of spatial heterogeneity of murine tumor vasculature.

The tumor microenvironment, especially the vasculature, undergoes dynamic remodeling during tumor growth and progression. The aim of this study was to investigate changes in the structure and function of tumor microenvironment (TME), with a special focus on vasculature, during the growth of the Lewis Lung Carcinoma tumor (LLC). We have used several MRI techniques and ultrasound imaging of live animals to assess how heterogenous TME features change in time. Lewis lung carcinoma bearing C57BL/6 mice were examined for three weeks. During this time, assessment of tumor vasculature was performed with Time of Flight (TOF) angiography, Dynamic Contrast Enhanced (DCE) MRI and Power Doppler Ultrasound. Additionally, diffusion and perfusion were analyzed using Diffusion Weighted MRI (DWI). Consecutive measurements of the same animals revealed an approximately twofold decrease in the density of LLC vessels in time. Heterogeneity of vasculature was best uncovered by changes in histogram based DCE analysis and revealed deterioration of tumor vessels during its progression. The tumor vasculature became less dense and with slower blood flow, with larger and more permeable vessels. As a rule, tumor tissue perfusion and diffusion parameters decreased in time, but locally increase was observed. Time- and spatial heterogeneity of tumor microenvironment, including vasculature, was revealed by 3D imaging, demonstrating that local changes are often contradictory to parameters averaged over the whole tumor volume.