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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.

如果能够非侵入性地检测出头颈部癌症，头部和颈部癌症或微转移的早期小病灶。如果同样的技术可用于检测（或预测）原发性肿瘤的转移潜力在早期阶段，疾病进展。这将提供机会，以防止进一步恶性进展的头部和颈部癌症转移是几个连续步骤的结果，并代表器官选择性过程（五）、虽然有许多机制与头颈癌的转移有关，决定肿瘤细胞定向迁移和侵入特定器官的精确机制仍然难以捉摸。趋化因子是与细胞表面蛋白以协调方式起作用的分泌蛋白，包括整联蛋白，以指导造血细胞的各种亚群归巢到特定的解剖学部位（6-9）。CXCR 4介导癌细胞向淋巴结、肺、肝和骨的迁移，而 CCR 7仅介导癌细胞向淋巴结的迁移。这种迁移是通过通过CXCR 4与其配体基质细胞衍生因子1（SDF-1）的结合以及CCR 7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（包括肿瘤）是高的，但在肿瘤转移的常见目的地，淋巴结、肺、肝和骨髓中CCL 7的水平特别高， CXCR 4和CCR 7在恶性肿瘤中的表达与其正常组织相比显著升高同行SDF-1与CXCR 4之间以及CCL 7与CCR 7之间的相互作用已被证实将细胞引导到SDF-1和CCL 7表达水平高的器官部位，这表明这些相互作用在这些转移性细胞的趋化性和归巢中起关键作用。当SDF-1与 CXCR 4或CCL 7与CCR 7结合，该复合物激活百日咳毒素敏感的Garprotein介导的信令（10）。抑制CXCR 4和SDF-1之间以及CCR 7和CCL 7之间的相互作用因此可以提供抑制转移过程的手段。