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.

Synergistic Cytotoxic and Anti-invasive Effects of Mitoxantrone and Triterpene Saponins from Lysimachia ciliata on Human Prostate Cancer Cells.

Triterpene saponins are secondary metabolites typical for higher plants. They possess a wide range of pharmaceutical and biological activities. These include anti-inflammatory, vasoprotective, expectorant, and antitumor properties. In particular, the ability of saponins to enhance the cytotoxicity of chemotherapeutic drugs has opened new perspectives for their application in combined cancer chemotherapy. In this study, the biological activity of the saponin fraction isolated from Lysimachia ciliata (denoted as CIL-1/2) was evaluated to assess its chemosensitizing activity in prostate cancer cell lines (DU-145, PC-3). No cytotoxic or cytostatic effect of the CIL-1/2 fraction administered at the concentration of 0.5 µg/mL was observed. In contrast, cocktails of CIL-1/2 and mitoxantrone (a drug commonly used in prostate cancer therapy) exerted synergistic cytostatic and proapoptotic effects. Furthermore, the synergy of proapoptotic activities of the analyzed cocktails is accompanied by their synergistic effects on prostate cancer cell movement and invasiveness. The significantly weaker impact of this cocktail on normal prostate cells additionally adds to the significance of our data and confirms that the CIL-1/2 fraction might be considered a potent adjuvant for prostate cancer chemotherapy.