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）：骨髓微环境中的骨髓瘤（MM）细胞与细胞之间的粘合性相互作用在肿瘤细胞的饲养，群和生长以及MM中的骨破坏过程中起着重要作用。 MM细胞的基因表达分析表明，膜联蛋白II（AXII）由MM细胞高度表达。我们最近克隆了Axii受体（Axiir），发现Axiir也由原代MM细胞和MM细胞系表示。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作用中起着重要作用。该应用的主要目标是确定MM细胞与骨髓微环境之间AXII/AXIIR相互作用对MM细胞生长的生物学作用，MM细胞对基质细胞和骨细胞（OCL）形成的粘附以及OCL衍生的Axii对MM细胞和OCL的影响。我们的假设是，在基质细胞上的Axii与MM细胞上的Axiir之间的相互作用在MM细胞的群体中起重要作用，MM细胞的生长和OCL形成。此外，OCL衍生的AXII与骨基质释放的生长因子相结合，骨骼破坏性过程刺激了MM细胞的生长，从而扩大了骨骼中的肿瘤负担。为了检验这一假设：1）我们将确定MM细胞是否特异性通过Axiir结合了Axii； 2）确定Axii/Axiir对骨髓微环境中MM细胞的粘附和生长的贡献，以及AxiI/Axiir信号对MM细胞和基质细胞的钥匙细胞因子和粘附分子表达的贡献。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在体内骨髓中的MM细胞归巢和动员中扮演的作用。这些研究的结果应确定Axii/Axiir作为MM患者的新型治疗靶标的潜在效用。公共卫生相关性：该应用的主要目标是确定骨髓瘤（MM）细胞与骨髓微环境之间AXII/AXIIR相互作用对MM细胞生长的生物学影响，MM细胞对基质细胞和骨细胞（OCL）形成的粘附粘附，以及OCL Axii Axii oxii of-dderded Axii of-MMMMMMMMMMMM MM和OCLS的影响。