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AXII in the Multiple Myeloma Bone Microenvironment

多发性骨髓瘤骨微环境中的 AXII

基本信息

批准号：
8036058
负责人：
Garson DAVID ROODMAN
金额：
$ 10.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2011-11-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8036058
关键词：
ANXA2 gene Adherence Adhesions Adhesives Alteplase Annexin A1 Annexin A3 Annexins Antibodies Binding Biological Assay Bone Diseases Bone Marrow Bone Matrix Bone Resorption CXCR4 gene Cell Adhesion Molecules Cell Line Cells Clinical Coculture Techniques Competitive Binding Conditioned Culture Media Confocal Microscopy Dominant-Negative Mutation Flow Cytometry Future Gene Expression Profiling Goals Growth Growth Factor Hematopoiesis Hematopoietic stem cells Home environment Homing In Vitro Integrins Interleukin-3 Interleukin-6 Macrophage Inflammatory Protein-1 Malignant neoplasm of prostate Marrow Mediating Membrane Metastatic Neoplasm to the Bone Multiple Myeloma Mus Oryctolagus cuniculus Osteoblasts Osteoclasts Patients Play Process Production Receptor Signaling Relative (related person)Reporting Role Signal Pathway Small Interfering RNA Specificity Stromal Cell-Derived Factor 1 Stromal Cells TNF gene TNFSF11 gene Testing Therapeutic Tumor Burden autocrine base bone bone growth factor cancer cell cell growth chemokine cytokine in vivo inhibitor/antagonist knock-down neoplastic cell new therapeutic target paracrine peripheral blood polyclonal antibody public health relevance receptor receptor binding receptor expression research study response small hairpin RNA tumor growth

项目摘要

DESCRIPTION (provided by applicant): Adhesive interactions between myeloma (MM) cells and cells in the marrow microenvironment play an important role in tumor cell homing, lodgment and growth, as well as the bone destructive process in MM. Gene expression profiling of MM cells has shown that annexin II (AXII) is highly expressed by MM cells. We have recently cloned the AXII receptor (AXIIR) and found that AXIIR is also expressed by primary MM cells and MM cell lines. Our preliminary results suggest that AXII/AXIIR interactions play an important role in MM as well as prostate cancer bone metastasis and normal hematopoiesis. The primary goals of this application are to determine the biologic effects of AXII/AXIIR interactions between MM cells and the marrow microenvironment on MM cell growth, adhesion of MM cells to stromal cells and osteoclast (OCL) formation as well as the effects of OCL-derived AXII on MM cells and OCLs. It is our hypothesis that interactions between AXII on stromal cells and AXIIR on MM cells play an important role in lodgment of MM cells in the marrow, growth of MM cells and OCL formation. Further, OCL-derived AXII combined with growth factors released from the bone matrix by the bone destructive process stimulate the growth of MM cells to expand tumor burden in bone. To test this hypothesis: 1) we will determine if MM cells specifically bind AXII via AXIIR; 2) determine the contribution of AXII/AXIIR to adhesion and growth of MM cells in the bone marrow microenvironment, as well as the contribution of AXII/AXIIR signaling on expression of key cytokines and adhesion molecules by MM cells and stromal cells. In addition, we will assess the contribution of endogenous stromal cell AXII/AXIIR and MM cell AXII/AXIIR on the growth and adhesion of MM cells; 3) we will determine the contribution of OCL-derived AXII on the growth of MM cells; and 4) the role that AXII/AXIIR plays in MM cell homing, lodgment, and mobilization in the marrow in vivo. Results of these studies should determine the potential utility of AXII/AXIIR as a novel therapeutic target for patients with MM. PUBLIC HEALTH RELEVANCE: The primary goals of this application are to determine the biologic effects of AXII/AXIIR interactions between myeloma (MM) cells and the marrow microenvironment on MM cell growth, adhesion of MM cells to stromal cells and osteoclast (OCL) formation as well as the effects of OCL-derived AXII on MM cells and OCLs.

描述（由申请人提供）：骨髓瘤（MM）细胞与骨髓微环境中细胞之间的黏附相互作用在骨髓瘤细胞的归巢、沉积和生长以及骨破坏过程中起着重要作用。MM细胞的基因表达谱显示，膜联蛋白II （AXII）在MM细胞中高表达。我们最近克隆了AXII受体（AXIIR），发现原代MM细胞和MM细胞系也表达AXIIR。我们的初步结果表明，AXII/AXIIR相互作用在MM以及前列腺癌骨转移和正常造血中起重要作用。本应用程序的主要目的是确定MM细胞与骨髓微环境之间的AXII/AXIIR相互作用对MM细胞生长、MM细胞与基质细胞的粘附和破骨细胞（OCL）形成的生物学效应，以及OCL衍生的AXII对MM细胞和OCL的影响。我们假设基质细胞上的AXII和MM细胞上的AXIIR相互作用在MM细胞在骨髓中的沉积、MM细胞的生长和OCL的形成中起重要作用。此外，ocl衍生的AXII与骨破坏过程中骨基质释放的生长因子结合，刺激MM细胞生长，扩大骨内肿瘤负荷。为了验证这一假设：1)我们将确定MM细胞是否通过AXIIR特异性结合AXII；2)确定axi /AXIIR对MM细胞在骨髓微环境中粘附和生长的贡献，以及axi /AXIIR信号对MM细胞和基质细胞表达关键细胞因子和粘附分子的贡献。此外，我们将评估内源性基质细胞AXII/AXIIR和MM细胞AXII/AXIIR对MM细胞生长和粘附的贡献；3)我们将确定ocl衍生的AXII对MM细胞生长的贡献；4) AXII/AXIIR在骨髓内MM细胞的归巢、沉积和动员中的作用。这些研究的结果将确定AXII/AXIIR作为MM患者新的治疗靶点的潜在效用。