Abstract 5317: Non-invasive dynamic bioluminescence imaging of tumor functional vascular changes during antiangiogenic therapy in conscious mice

Abstract

Abstract Bioluminescence imaging has been used for several years in oncology research to quantify tumor growth and metastatic spread rather than functional physiological effects. Two recent publications have highlighted the use of non-invasive dynamic bioluminescence imaging (DBLI) in isofluran anesthetized mice to assess vascular changes in subcutaneous xenografts (1) and orthotopic implanted tumors (2) post-treatment. We have previously reported that anesthesia impairs bioluminescence signal intensity (3) and may in turn profoundly affect interpretation of compound activity based on BLI (4). Thus, we decided to investigate DBLI for non-invasive, longitudinal and quantitative monitoring of functional vascular changes (tumor perfusion, blood volume, vascular flow) in conscious mice during antiangiogenic therapy. Subcutaneous xenografts (HCT116 colorectal, U87MG glioblastoma and SJSA-1 osteosarcoma) were treated with a blocking antibody to vascular endothelial growth factor receptor 2 (DC101) and repeatedly examined at bi-weekly intervals. Our results have clearly demonstrated that in all tested models, tumor growth was significantly inhibited (T/C: 0.33, 0.52 and 0.53 for HCT116, U87MG and SJSA-1, respectively) after treatment with DC101 when compared to control. DBLI analysis revealed an initial increase in vascular flow (Day 2 to 3) followed by a gradual decrease after a 2-wk therapy, suggesting early and long-term effects on functional tumor vasculature. Notably, this pattern was more pronounced in highly vascularized (SJSA-1) when compared with less well vascularized (HCT116) tumors. Lastly, very similar decreased microvessel density (MVD) was noted by histological immuno-fluorescence staining following chronic treatment with DC101 in all three tumor models. In conclusion, DBLI measurements in conscious tumor bearing mice offer an optimal and reliable approach for non-invasive functional tumor vessel assessment without the confounding effects of anesthesia. It can be foreseen that with future development of more efficient light-emitting enzyme/substrate systems and the improvement of detection devices it will be possible to increase the sensitivity of this technique allowing the measurement of weaker bioluminescence signals and extending spatial resolution.