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Urokinase Receptor Integrin Interactions in Lung Cancer

肺癌中尿激酶受体整合素相互作用

基本信息

批准号：
8079454
负责人：
Harold A Chapman
金额：
$ 28.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2007-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079454
关键词：
Adhesions Amino Acids Apoptosis Binding Biological Assay Carcinoma Cell Adhesion Molecules Cell Line Cell Survival Cell physiology Cells Cessation of life Co-Immunoprecipitations Complex Cytoskeletal Modeling Data Development Diagnosis Diagnostic tests Epithelial Cells Extracellular Matrix Fibronectins Frequencies Growth H1299 Human In Vitro Integrins Invaded Knockout Mice Laminin Lead Ligands Lung Lung Adenocarcinoma Lung Neoplasms MAP Kinase Gene MMP9 gene Malignant - descriptor Malignant Epithelial Cell Malignant neoplasm of lung Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Modeling Molecular Mus Neoplasm Metastasis Nude Mice Operative Surgical Procedures PLAUR gene Pathway interactions Peptide Hydrolases Peptides Plasminogen Activator Inhibitor 1 Point Mutation Primary Neoplasm Recombinant Proteins Research Personnel Retroviridae Role Signal Transduction Site Specimen System Testing Tumor Cell Invasion Tumor Cell Line Up-Regulation Urokinase Urokinase Plasminogen Activator Receptor Work angiogenesis base cancer cell cancer therapy in vivo insight lung Carcinoma malignant phenotype mutant neoplastic cell novel therapeutics programs reconstitution research study therapeutic target tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Critical determinants of cancer progression and death from carcinomas are the capacity of tumor cells to survive, grow, invade their matrix stroma, and metastasize. Invasion and metastasis depend on the coordinated and temporal expression of proteolytic enzymes necessary to degrade the surrounding extracellular matrix and of adhesion molecules to reorganize cell-cell and cell-matrix attachments. Strong circumstantial evidence indicates that the protease urokinase, its receptor (uPAR), and b1 integrins are important to lung cancer progression. And prior work indicates that uPAR is a b1 integrin ligand, modifying integrin matrix engagement and signaling, and promoting tumor cell migration in vitro and in vivo. This proposal will test the hypothesis that uPAR acts as a strong agent of tumor cell survival and metastasis, acting through interactions with b1 integrins to coordinate MMP upregulation and alter cytoskeletal organization favoring matrix invasion. First, extending prior work, critical amino acid residues in uPAR that mediate interactions with the b1 integrins a3b1 and a5b1 will be fully established. Based on this information, peptides which disrupt uPAR/b1 integrin interactions will be exploited as a diagnostic test for uPAR/integrin signaling in primary lung cancer cells. Secondly, using uPAR point mutants unable to bind specific b1 integrins, the molecular mechanisms of altered matrix engagement and MMP upregulation initiated by uPAR/integrin interactions will be defined. Finally, wild type or uPAR silenced, GFP tagged H1299 cells will be injected either orthotopically into lungs of athymic nude mice and lung cancer growth, node metastasis, and angiogenesis quantified and compared. Cells reconstituted with uPAR mutants unable to bind either a3b1 or a5b1 will be examined to determine if uPAR/integrin interactions rather than uPA binding alone is crucial to uPAR-dependent tumor progression in vivo. Together, these experiments should clarify the mechanistic basis for the promoting role of uPAR on tumor progression, establish whether uPAR/integrin interactions are a compelling therapeutic target, and determine whether a diagnostic test for lung cancers dependent on uPAR for their malignant potential can be defined.

描述（由申请人提供）：肿瘤进展和死亡的关键决定因素是肿瘤细胞存活、生长、侵袭基质和转移的能力。侵袭和转移依赖于降解周围细胞外基质所需的蛋白水解酶的协调和时间表达，以及重组细胞-细胞和细胞-基质附着的粘附分子。强有力的间接证据表明，蛋白酶尿激酶及其受体（uPAR）和b1整合素对肺癌的进展很重要。先前的研究表明，uPAR是b1整合素配体，在体外和体内调节整合素基质结合和信号传导，促进肿瘤细胞迁移。该提案将验证uPAR作为肿瘤细胞存活和转移的强因子的假设，uPAR通过与b1整合素的相互作用来协调MMP上调并改变细胞骨架组织，有利于基质入侵。首先，扩展先前的工作，将充分建立uPAR中介导与b1整合素a3b1和a5b1相互作用的关键氨基酸残基。基于这些信息，破坏uPAR/b1整合素相互作用的肽将被用作原发性肺癌细胞中uPAR/整合素信号的诊断测试。其次，使用无法结合特异性b1整合素的uPAR点突变体，将定义由uPAR/整合素相互作用引发的基质结合改变和MMP上调的分子机制。最后，将野生型或uPAR沉默、GFP标记的H1299细胞原位注射到胸腺裸小鼠的肺中，量化并比较肺癌的生长、淋巴结转移和血管生成。用不能结合a3b1或a5b1的uPAR突变体重组的细胞将被检查，以确定uPAR/整合素的相互作用是否比单独的uPA结合对体内uPAR依赖的肿瘤进展至关重要。总之，这些实验应阐明uPAR促进肿瘤进展作用的机制基础，确定uPAR/整合素相互作用是否是一个令人信服的治疗靶点，并确定是否可以定义依赖于uPAR的肺癌恶性潜能的诊断测试。