Res Proj 2: Development of PET Imaging Probes for Chemokine Receptors for Head...

研究项目 2：开发头部趋化因子受体 PET 成像探针...

基本信息

批准号：
7287004
负责人：
HYUNSUK SHIM
金额：
$ 5.28万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7287004
关键词：
Animal Model Animals Antibodies Benign Binding Biodistribution Biological Markers Bone Marrow CCL7 gene CXCR4 Receptors CXCR4 gene Cancer Patient Carcinoma Cell Line Cell Surface Proteins Cells Chemotaxis Clinic Clinical Complex Destinations Development Diagnostic Discrimination Disease Progression Distant Metastasis Drug Delivery Systems Early Diagnosis Epidermal Growth Factor Receptor Fluorine Goals Half-Life Head Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hematopoietic High Pressure Liquid Chromatography Homing In Vitro Integrins Kinetics Label Lesion Ligands Literature Liver Lung Malignant - descriptor Malignant Neoplasms Mediating Metabolic Clearance Rate Metastatic Neoplasm to the Lung Micrometastasis Monitor Necrosis Neoplasm Metastasis Nodal Nonmetastatic Normal tissue morphology Numbers Operative Surgical Procedures Organ Outcome Paraffin Embedding Patients Peptides Pertussis Toxin Pharmaceutical Preparations Phase Play Positron Positron-Emission Tomography Primary Neoplasm Process Proteins Quality of life Radiation Rate Rattus Reporting Risk Role Sampling Scintillation Counter Signal Transduction Site Specificity Squamous cell carcinoma Staging Stromal Cell-Derived Factor 1 Surface TN14003 Technology Time Toxic effect Translating Tumor Cell Invasion Xenograft procedure base bone cancer cell chemokine chemokine receptor design imaging probe improved in vivo interest lymph nodes metastatic process migration mortality mouse model neoplastic cell novel outcome forecast prevent receptor response size small molecule synthetic peptide tool tumor uptake

项目摘要

Head and neck cancer mortality would be greatly diminished if it were possible to non-invasively detect small foci of head and neck cancer or micrometastases early on. It would also be of great interest if the same technology could be used to detect (or predict) the metastatic potential of primary tumors in the early stages of disease progression. This would provide the opportunity to prevent further malignant progression of head and neck cancer. Metastasis is the result of several sequential steps and represents an organ-selective process (5). Although a number of mechanisms have been implicated in the metastasis of head and neck cancer, the precise mechanisms determining the directional migration and invasion of tumor cells into specific organs remain elusive. Chemokines are secreted proteins that act in a coordinated fashion with cell-surface proteins, including integrins, to direct the homing of various subsets of hematopoietic cells to specific anatomical sites (6-9). CXCR4 mediates the migration of cancer cells to the lymph nodes, lungs, liver, and bones whereas CCR7 mediates the migration of cancer cells to the lymph nodes exclusively. This migration is mediated through the binding of CXCR4 to its ligand, stromal cell-derived factor 1 (SDF-1) and that of CCR7 to its ligand, CCL7. While the levels of SDF-1 are high at the common destinations of cancer metastasis including the lymph node, lung, liver, and the bone marrow and those of CCL7 are particularly high in the lymph nodes, the expression of CXCR4 and CCR7 is significantly elevated in malignant tumors compared to their normal tissue counterparts. The interactions between SDF-1 and CXCR4 and between CCL7 and CCR7 have been shown to direct cells to organ sites that have high levels of SDF-1 and CCL7 expression, suggesting that these interactions play a key role in the chemotaxis and homing of these metastatic cells. When SDF-1 binds to CXCR4 or CCL7 binds to CCR7, the complex activates the pertussis toxin-sensitive Garprotein-mediated signaling (10). The inhibition of both interactions between CXCR4 and SDF-1 and between CCR7 and CCL7 may therefore provide a means of inhibiting the metastatic process.

如果可以非侵入性检测早期的头颈癌或微量转移的小焦点。如果相同的话，这也将引起极大的兴趣技术可用于检测（或预测）原发性肿瘤在早期的转移性潜力疾病进展。这将为防止头部和颈部癌。转移是几个顺序步骤的结果，代表器官选择过程（5）。尽管许多机制与头颈癌的转移有关，但确定肿瘤细胞定向迁移和侵袭特定器官的精确机制保持难以捉摸。趋化因子是分泌的蛋白质，以与细胞表面蛋白协调的方式作用，包括整联蛋白，将各种造血细胞子集归巢到特定的解剖部位（6-9）。 CXCR4介导癌细胞向淋巴结，肺，肝脏和骨骼的迁移，而 CCR7专门介导癌细胞向淋巴结的迁移。这种迁移是介导的通过CXCR4与其配体的结合，基质细胞衍生的因子1（SDF-1）和CCR7的配体与其配体的结合， CCL7。虽然SDF-1的水平在癌症转移的常见目的地很高，包括淋巴结，肺，肝脏和骨髓以及CCL7的淋巴结淋巴结特别高，在淋巴结中，与正常组织相比，恶性肿瘤的CXCR4和CCR7的表达显着升高同行。 SDF-1和CXCR4之间以及CCL7和CCR7之间的相互作用已显示将细胞引导到具有高水平的SDF-1和CCL7表达的器官位点，这表明这些位点相互作用在这些转移细胞的趋化性和归巢中起关键作用。当SDF-1结合到 CXCR4或CCL7与CCR7结合，该复合物激活百日咳毒素敏感的GARPROTEIN介导信号（10）。 CXCR4与SDF-1之间以及CCR7和CCL7之间的两种相互作用的抑制作用因此，可以提供抑制转移过程的方法。