There is a need for clinically relevant animal models of tumor angiogenesis and blood flow, two critical targets for current drug evaluation and development. Most models of angiogenesis and blood flow are either based on subcutaneous transplantation of tumors or dorsal skin-fold window models. These models generally do not allow metastasis, which is a critical aspect of cancer. There is also evidence that angiogenesis may be organ-site specific and therefore orthotopic models would be very important. We have previously developed orthotopic metastatic models of cancer, which express green fluorescent protein (GFP). We have shown that these models enable high resolution whole-body imaging of tumor growth and metastasis and, in new developments, angiogenesis on internal organs (Yang, M., et al. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. The present application proposes to develop and validate additional technology that will enable external quantitative imaging of tumor angiogenesis and blood flow in primary and metastatic pancreatic and breast tumors in orthotopic models. Skin-flap window models will be further developed in order to image angiogenesis and blood flow in orthotopic GFP-expressing tumors and metastases using dual-photon laser confocal microscopy for high resolution.
The specific aims i nclude: 1) Develop models for quantitative optical imaging of angiogenesis in pancreatic and breast tumors and metastasis; 2) Develop models for quantitative optical imaging of tumor blood flow in the vessels of these tumors and metastases; 3) Test the model with specific anti-angiogenesis agents; 4) Validate the model by comparison of optical imaging of tumor angiogenesis and blood flow with similar measurements by dynamic micro magnetic resonance angiography (MRA). The model is unique in that it is orthotopic and optically imageable in real time for angiogenesis and blood flow. The model when developed and validated will be used to screen and evaluate drugs that target these critical targets of tumor angiogenesis and blood flow.
