Tumor Cell-Microenvironment Interactions in the Molecular Pathogenesis of Multipl

肿瘤细胞-微环境相互作用在多种肿瘤分子发病机制中的作用

基本信息

批准号：
8555168
负责人：
John Damian Shaughnessy
金额：
$ 40.61万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-05 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8555168
关键词：
Alleles Archives Attenuated Benign Binding Biology Bone Diseases Bone Marrow Bone neoplasms Bortezomib CDH1 gene Cadherins Carcinoma Cell Adhesion Cell Line Cell Proliferation Cells Clinical Code Complex Consensus Sequence DNA Modification Process DNA Sequence Data Derivation procedure Disease Disease Progression Down-Regulation Drug resistance E-Cadherin Enhancers Event Exhibits Extracellular Matrix Extramedullary Foundations Gene Expression Gene Expression Profile Gene Expression Profiling Gene Frequency Gene Mutation Genes Genetic Genetic Polymorphism Genetic Transcription Goals Growth Homologous Gene In Vitro Interleukin-9 Length Lesion Link Longitudinal Studies Luciferases Lytic Metastatic Lesion Magnetic Resonance Imaging Malignant Neoplasms Measures Mediating Mesenchymal Stem Cells Messenger RNA Molecular Monoclonal gammopathy of uncertain significance Multiple Myeloma Mutation N-Cadherin Natural History Neoplasm Metastasis Nuclear Nucleotides Osteoblasts Osteolytic Pathogenesis Pathway interactions Patients Plasma Cells Plasmin Protein Isoforms Proteins Publishing Quality of life Recombinants Regulation Resistance Role SCID-hu Mice Sampling Signal Transduction Site Solid Neoplasm Staging TCF Transcription Factor Therapeutic Tissues Tumor Suppressor Proteins Up-Regulation Variant Western Blotting Work Wound Healing angiogenesis base beta catenin bone cell growth chemotherapy chromatin immunoprecipitation epithelial to mesenchymal transition gain of function improved in vivo innovation insight lenalidomide loss of function malignant breast neoplasm mouse model neoplastic cell novel novel therapeutic intervention osteoblast differentiation overexpression programs promoter syndecan therapeutic target transcription factor tumor tumor growth tumor progression

项目摘要

A clinically distinguishing feature of multiple myeloma (MM) is focal tumor growth detectable by MRI as focal lesions; this tumor growth is associated with increased resistance to chemotherapy and often osteolytic bone disease. Our preliminary work suggests that focal lesions, osteolytic bone disease, and dissemination to extramedullary disease are associated with molecular events resulting from suppression of Wnt/Beta-catenin signaling and from interactions between p-catenin and cadherin that mediate cell adhesion. Our long-term objective is to thoroughly understand the relationship between Wnt/Beta-catenin signaling and myeloma pathogenesis, with the ultimate goal of uncovering novel therapeutic approaches to control myeloma growth and improve survival and quality of life of patients with MM. We hypothesize that deregulation of Wnt/Beta-catenin signaling in both the microenvironment and the myeloma tumor cell is a fundamental and critical event in the natural history of MM. Therefore, control of this signaling axis may represent a paradigm shift in myeloma therapy. We will pursue this broad hypothesis through the following specific aims: (Aim 1) Verify that elevated transcription of DKKI in myeloma tumor cells is related to polymorphisms/mutations in the DKKI promoter; (Aim 2) Examine the roles of E- and N-cadherin and their interactions with Beta-catenin in MM pathogenesis and determine if they represent viable therapeutic targets; (Aim 3) Determine whether bone-anabolic effects of bortezomib treatment result from induction of Beta-catenin signaling in mesenchymal stem cells and osteoblasts; (Aim 4) Establish the derivation of a novel CYR61 isoform in MM and determine the in vitro and In vivo effects of this and native CYR61 on myeloma growth and bone disease. Comprehensive understanding of the molecular events surrounding dysregulation of Wnt/Beta-catenin signaling in MM will potentially provide the foundation for innovative therapeutic strategies to control growth of myeloma.

多发性骨髓瘤 (MM) 的一个临床显着特征是 MRI 可检测到局灶性肿瘤生长，表现为局灶性病变；这种肿瘤的生长与化疗耐药性的增加以及通常的溶骨性骨病有关。我们的初步工作表明，局灶性病变、溶骨性骨疾病和播散至髓外疾病与 Wnt/β-连环蛋白信号传导抑制以及介导细胞粘附的 p-连环蛋白和钙粘蛋白之间的相互作用引起的分子事件相关。我们的长期目标是彻底了解 Wnt/β-catenin 信号传导与骨髓瘤发病机制之间的关系，最终目标是发现新的治疗方法来控制骨髓瘤生长并提高 MM 患者的生存率和生活质量。我们假设微环境和骨髓瘤肿瘤细胞中 Wnt/β-catenin 信号传导的失调是 MM 自然史中的一个基本且关键的事件。因此，对该信号轴的控制可能代表骨髓瘤治疗的范式转变。我们将通过以下具体目标来追求这一广泛的假设：（目标 1）验证骨髓瘤肿瘤细胞中 DKKI 转录的升高与 DKKI 启动子中的多态性/突变有关；（目标 2）检查 E- 和 N-钙粘蛋白的作用及其与 β-连环蛋白在 MM 发病机制中的相互作用，并确定它们是否代表可行的治疗靶点；（目标 3）确定硼替佐米治疗的骨合成代谢作用是否是由于间充质干细胞和成骨细胞中β-连环蛋白信号传导的诱导所致；（目标 4）在 MM 中建立新型 CYR61 同工型的衍生，并确定该同工型和天然 CYR61 对骨髓瘤生长和骨疾病的体外和体内影响。全面了解 MM 中 Wnt/β-catenin 信号传导失调的分子事件可能为控制骨髓瘤生长的创新治疗策略奠定基础。