Epithelial-Mesenchymal Transition in Tumor Metastasis

肿瘤转移中的上皮-间质转化

基本信息

批准号：
7431122
负责人：
Jing Yang
金额：
$ 231.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431122
关键词：
1-Phosphatidylinositol 3-Kinase Address Adherens Junction Adult Affect Age Alleles Animals Antibodies Apoptosis Appearance Area Arts Attention Award Basement membrane Biochemical Biochemical Genetics Biochemical Markers Biological Biological Assay Biological Testing Birth Blood Circulation Blood Vessel Tissue Body Weight Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Model Breast Carcinoma Cancer Biology Cancer Center Cancer Patient Cancer cell line Candidate Disease Gene Carcinoma Cause of Death Cell Adhesion Cell Count Cell Cycle Cell Cycle Regulation Cell Death Cell Proliferation Cell-Cell Adhesion Cells Cellular biology Characteristics Clinical Collaborations Collagen Color Complex Computer software Coupled Creativeness Cues Cultured Cells Cyclin B DNA Sequence Rearrangement DNA biosynthesis DNA chemical synthesis Data Data Analyses Detection Development Diagnostic Neoplasm Staging Digestion Disease Disruption Dissociation Distant Distant Metastasis E-Cadherin Embryo Embryonic Development Endothelial Cells Enhancers Ensure Environment Epigenetic Process Epithelial Epithelial Cells Equipment Erythrocytes Event Exhibits Experimental Designs Extravasation Family Female Fibroblasts Fibronectins Fingers Fluorescence Freezing Frequencies Frozen Sections Future Ganciclovir Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genome Genomics Goals Green Fluorescent Proteins Growth Harvest Heterogeneity Human Hyaluronidase Hyperplasia Image Immigration Immunohistochemistry Implant In Vitro Incidence Individual Infection Infiltration Institutes Internal Ribosome Entry Site Intraperitoneal Injections Invaded Journals Knowledge Label Laboratories Leukocytes Life Localized Lung Magnetism Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Measures Mediating Medicine Membrane Mentors Mesenchymal Mesenchymal Differentiation Mesoderm Messenger RNA Metastatic Carcinoma Metastatic Lesion Metastatic Neoplasm to the Lung Methods Microarray Analysis Micrometastasis Microscope Microscopic Microscopy Minority Mitosis Mitotic Modeling Molecular Molecular Analysis Molecular Profiling Monitor Morphogenesis Morphology Mouse Mammary Tumor Virus Movement Mus Mutation Nasopharynx Carcinoma Nature Neoplasm Metastasis Neural Crest Neuroblastoma Nodule Noise Noninfiltrating Intraductal Carcinoma Numbers Oncogene Proteins Oncogenes Oranges Organ Outcome Paper Partner in relationship Pathogenesis Pathologist Pathway interactions Patients Persons Phenotype Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphotransferases Photons Physiology Play Polyomavirus Population Primary Neoplasm Procedures Process Prognostic Marker Proliferating Promoter Regions Property Protein Overexpression Proteins Proto-Oncogenes Protocols documentation Publications Publishing RNA Range Reporter Reporting Research Research Design Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Risk Role Role playing therapy Route Sampling Science Scientist Score Series Signal Pathway Signal Transduction Signaling Molecule Signaling Pathway Gene Simplexvirus Site Skin Snails Solid Solutions Sorting - Cell Movement Specificity Staging Staining method Stains Structure of parenchyma of lung Suspension substance Suspensions System Tail Techniques Technology Testing Therapeutic Thinking Thymidine Kinase Time Tissues Training Transcription factor genes Transcriptional Activation Transcriptional Regulation Transgenes Transgenic Mice Transgenic Organisms Translations Tumor Cell Invasion Tumor Cell Line Tumor Tissue Tumor stage United States National Institutes of Health Universities Up-Regulation Validation Veins Vimentin Viral Tumor Antigens Week Women&apos s Group Work Xenopus Yang abstracting annexin A5 base c-myc Genes cancer cell cancer type career cdc25 Phosphatase cell motility cell stroma chromatin immunoprecipitation clinical application collagenase day design desire embryonic stem cell epithelial to mesenchymal transition experience extracellular frontier gain of function genome sequencing improved in vivo in vivo Model innovation interest loss of function lymph nodes malignant breast neoplasm malignant stomach neoplasm mammary epithelium mammary tumor virus medical schools melanoma migration mouse model neoplastic cell news novel nucleocytoplasmic transport nucleoside analog outcome forecast plakoglobin programs promoter research study sialosyl-T antigen site-specific integration skills slug small hairpin RNA tool transcription factor transgene expression tumor tumor initiation tumor progression tumorigenesis twist protein two-photon willingness

项目摘要

90% of cancer deaths are caused by metastatic growths in distant organs; however, the molecular basis of tumor metastasis is largely unknown. In a so-called “metastatic” primary tumor mass, only a small minority of carcinoma cells are actually migrating and on their route to disseminate into distant organs. To understand the cellular and molecular machineries that promote carcinoma cell dissemination, it is essential to identify and isolate such rare migrating carcinoma cells for molecular studies. A highly conserved developmental program Epithelial-Mesenchymal Transition (EMT) has been indicated in promoting metastasis progression. A group of embryonic EMT-inducing transcription factors, including Twist, Snail and Slug, are induced in carcinoma cells to promote cell motility and invasion. These transcription factors mainly function during embryogenesis, and they are mostly silent in normal adult tissues. Since activation of EMT is an early event to promote tumor cell dissemination, transcriptional activation of Twist, Snail and Slug provides a very specific and sensitive indicator of carcinoma cells that are undergoing EMT, migrating and disseminating into distant organs. In this study, I propose to use the promoters of Twist, Snail and Slug to drive the expression of a novel EMT detection/selection system, thus marking migrating tumor cells in vivo. Using this strategy, we aim to identify, image and isolate migrating carcinoma cells in primary tumors, to directly test the biological significance of EMT and cell migration in tumor metastasis in vivo, and to explore the signal pathways that promote carcinoma cells to migrate and disseminate into distant organs. If successful, our experiments will, for the first time, generate a molecular definition of the rare migrating carcinoma cells in vivo. The results from this study will not only significantly improve our molecular understanding of cancer metastasis, but also provide potential prognostic markers and specific targets for anti-metastasis therapies.

然而，90% 的癌症死亡是由远处器官的转移性生长引起的；肿瘤转移的基础在很大程度上是未知的，在所谓的“转移性”原发肿瘤块中，只有一小部分。少数癌细胞实际上正在迁移并正在扩散到远处的器官。了解促进癌细胞扩散的细胞和分子机制，至关重要识别和分离这种罕见的迁移癌细胞以进行分子研究。高度保守的发育程序上皮-间质转化（EMT）已被一组胚胎 EMT 诱导转录因子，包括 Twist、Snail 和 Slug，在癌细胞中被诱导以促进细胞运动和侵袭。转录因子主要在胚胎发生过程中发挥作用，在正常成人中大多是沉默的由于 EMT 的激活是促进肿瘤细胞扩散、转录的早期事件。 Twist、Snail 和 Slug 的激活为癌细胞提供了非常特异且敏感的指标经历EMT，迁移并传播到远处的器官。在这项研究中，我建议使用 Twist、Snail 和 Slug 的启动子来驱动新颖的EMT检测/选择系统，从而利用这种策略在体内标记迁移的肿瘤细胞。旨在识别、成像和分离原发性肿瘤中的迁移癌细胞，以直接测试生物学 EMT和细胞迁移在体内肿瘤转移中的意义，并探讨EMT和细胞迁移的信号通路促进癌细胞迁移并扩散到远处器官如果成功，我们的实验将，首次对体内罕见的迁移癌细胞进行分子定义。这项研究不仅将显着提高我们对癌症转移的分子认识，而且为抗转移治疗提供潜在的预后标志物和特定靶点。