Orthotopic models of tumor angiogenesis and blood flow

肿瘤血管生成和血流的原位模型

• 批准号: 7292746
• 负责人: MENG YANG
• 金额: $ 37.48万
• 依托单位: ANTICANCER, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292746
• 关键词: Animal Model; Animals; Blood Vessels; Blood flow; Cancer Model; Cell Nucleus; Color; Cytoplasm; Development; Dorsal; Drug Compounding; Drug Evaluation; Engineering; Evaluation; Extravasation; Facility Construction Funding Category; Feasibility Studies; Grant; Green Fluorescent Proteins; Image; Imagery; Implant; Invaded; Label; Libraries; Life; Malignant Neoplasms; Modeling; Mus; Nature; Neoplasm Metastasis; Neoplasm Transplantation; Nuclear; Nude Mice; Numbers; Optics; Organ; Phase; Resolution; Site; Skin; System; Technology; Testing; Transgenic Organisms; Transplantation; Tumor Angiogenesis; angiogenesis; anticancer research; base; cancer cell; clinically relevant; design; fluorescence imaging; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; red fluorescent protein; subcutaneous; technology development; trafficking; tumor; tumor growth; whole body imaging

DESCRIPTION (provided by applicant): There is a need for clinically-relevant imageable animal models of tumor blood flow, intravascular cancer-cell trafficking and extravasation, critical targets for current drug evaluation and development. Most models of tumor cell trafficking and blood flow are either based on subcutaneous transplantation of tumors or dorsal skin- fold window models. These models generally do not allow metastasis. There is also evidence that tumor vascularity 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) (Nature Rev Cancer 5, 796-806, 2005). We have shown that these models enable high resolution whole-body imaging of tumor growth and metastasis and angiogenesis on internal organs (PNAS 97, 1206-11, 2000; 99, 3824-9, 2002). New developments in Phase I include the construction of dual-color cancer cells with GFP in the nucleus and RFP in the cytoplasm (Cancer Res 64, 4251-6, 2004; 65, 4246-52, 2005) that can enable imaging of tumor cell migration, nuclear-cytoplasmic dynamics, and extravasation in the live mouse. Nude mouse models with GFP-expressing blood vessels have also been developed in Phase I which can facilitate imaging of tumor blood flow (Cancer Res 64, 8651-6, 2004; 65, 5352-7, 2005). With these technologies developed during the Phase I grant, the Phase II grant will further develop these technologies in orthotopic models to evaluate inhibitors of tumor blood flow, intravascular tumor cell trafficking and extravasation. The specific aims include: (1) Use of transgenic nude mouse models with GFP blood vessels, orthotopically transplanted with RFP tumor cells for testing agents that target blood flow in the vessels of tumors and their metastasis; (2) Use of dual-color cancer cells with GFP in the nucleus and RFP in the cytoplasm orthotopically implanted in nude mice for in vivo testing of agents that target intravascular trafficking of tumor cells; (3) Use of dual-color cancer cells with GFP in the nucleus and RFP in the cytoplasm orthotopically implanted in nude mice for in vivo testing of agents that target extravasating tumor cells. These orthotopic models are unique in that they will enable visualization tumor blood flow, intravascular tumor-cell trafficking and extravasation at the nuclear-cytoplasmic dynamic level in clinically-relevant mouse models. The newly developed Olympus OV100 whole-mouse imaging system has optics for macro- and high-resolution subcellular imaging along with the models to screen an initial set of potential inhibitors that target these critical steps of metastasis. These models will be used commercially in Phase III to screen and evaluate large numbers of drugs and compound libraries. There is a need for clinically-relevant imageable animal models of tumor blood flow, intravascular cancer-cell trafficking and extravasation, critical targets for current drug evaluation and development. Most models of tumor cell trafficking and blood flow are either based on subcutaneous transplantation of tumors or dorsal skin- fold window models. These models generally do not allow metastasis. There is also evidence that tumor vascularity may be organ-site specific and therefore orthotopic models would be very important. With the technologies developed during the Phase I grant, this Phase II grant will further develop these technologies in orthotopic models to evaluate inhibitors of tumor blood flow, intravascular tumor cell trafficking and extravasation.

描述（由申请人提供）：需要临床相关的肿瘤血流、血管内癌细胞运输和外渗的可成像动物模型，这是当前药物评估和开发的关键靶点。大多数肿瘤细胞运输和血流模型要么基于肿瘤皮下移植，要么基于背侧皮肤折叠窗模型。这些模型通常不允许转移。也有证据表明肿瘤血管分布可能是器官部位特异性的，因此原位模型将是非常重要的。我们之前已经开发出表达绿色荧光蛋白（GFP）的原位转移癌模型（Nature Rev cancer 5,796 -806, 2005）。我们已经证明，这些模型能够实现肿瘤生长、转移和内部器官血管生成的高分辨率全身成像（PNAS 97,1206 - 11,2000; 99,3824 - 9,2002）。I期研究的新进展包括构建细胞核中含有GFP、细胞质中含有RFP的双色癌细胞（cancer Res 64, 4251- 6,2004; 65, 4246- 52,2005），能够在活体小鼠中成像肿瘤细胞迁移、核胞质动力学和外溢。具有表达gfp血管的裸鼠模型也在I期开发，可以促进肿瘤血流成像（Cancer Res 64, 8651- 6,2004; 65, 5352- 7,2005）。随着这些技术在I期资助期间的发展，II期资助将进一步在原位模型中开发这些技术，以评估肿瘤血流抑制剂、血管内肿瘤细胞运输和外渗。具体目的包括：(1)利用转基因GFP血管裸鼠模型，原位移植RFP肿瘤细胞，检测靶向肿瘤血管血流及其转移的药物；(2)利用细胞核中含有GFP，细胞质中含有RFP的双色癌细胞原位植入裸鼠体内，对靶向肿瘤细胞血管内转运的药物进行体内试验；(3)利用细胞核中含有GFP，细胞质中含有RFP的双色癌细胞原位植入裸鼠体内，对外溢肿瘤细胞靶向药物进行体内试验。这些原位模型的独特之处在于，它们将在临床相关小鼠模型的核-细胞质动态水平上可视化肿瘤血流、血管内肿瘤细胞运输和外渗。新开发的奥林巴斯OV100全小鼠成像系统具有用于宏观和高分辨率亚细胞成像的光学器件，以及用于筛选针对转移这些关键步骤的初始潜在抑制剂的模型。这些模型将在III期商业化使用，以筛选和评估大量药物和化合物库。有必要建立与临床相关的肿瘤血流、血管内癌细胞运输和外渗的可成像动物模型，这是当前药物评估和开发的关键靶点。大多数肿瘤细胞运输和血流模型要么基于肿瘤皮下移植，要么基于背侧皮肤折叠窗模型。这些模型通常不允许转移。也有证据表明肿瘤血管分布可能是器官部位特异性的，因此原位模型将是非常重要的。随着I期资助期间开发的技术，该II期资助将进一步在原位模型中开发这些技术，以评估肿瘤血流抑制剂、血管内肿瘤细胞运输和外渗。