Orthotopic models of tumor angiogenesis and blood flow

描述（由申请人提供）：需要肿瘤血管生成和血流的临床相关动物模型，这是当前药物评价和开发的两个关键目标。大多数血管生成和血流模型是基于肿瘤的皮下移植或背部皮褶窗模型。这些模型通常不允许转移，这是癌症的一个关键方面。也有证据表明，血管生成可能是器官部位特异性的，因此原位模型将是非常重要的。我们以前已经开发了原位转移模型的癌症，表达绿色荧光蛋白（GFP）。我们已经表明，这些模型能够实现肿瘤生长和转移的高分辨率全身成像，并且在新的发展中，能够实现内部器官上的血管生成（Yang，M.，等人，Direct external imaging of nascent cancer，tumor progression，angiogenesis，and metastasis on internal organs in the fluorescent orthotopic model. 本申请提出开发和验证额外的技术，其将使得能够在原位模型中对原发性和转移性胰腺和乳腺肿瘤中的肿瘤血管生成和血流进行外部定量成像。皮瓣窗口模型将进一步发展，以图像血管生成和血流原位GFP表达肿瘤和转移，使用双光子激光共聚焦显微镜的高分辨率。具体目标包括：1）开发胰腺和乳腺肿瘤和转移瘤中血管生成的定量光学成像模型; 2）开发这些肿瘤和转移瘤的血管中肿瘤血流的定量光学成像模型; 3）用特异性抗血管生成剂测试模型;四、通过比较肿瘤血管生成和血流的光学成像与动态显微磁共振的类似测量来验证模型血管造影（MRA）。该模型的独特之处在于，它是原位的，并且对于血管生成和血液流动是真实的实时光学可成像的。该模型在开发和验证后将用于筛选和评估靶向肿瘤血管生成和血流的关键靶点的药物。

DESCRIPTION (provided by applicant): 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 include: 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.