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：
7884926
负责人：
Garson DAVID ROODMAN
金额：
$ 15.1万
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 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884926
关键词：
ANXA2 gene Adherence Adhesions Adhesives Alteplase Annexin A1 Annexins Antibodies Binding Biological Assay Bone Diseases Bone Marrow Bone Matrix Bone Resorption 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 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 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的细胞之间的粘附相互作用在肿瘤细胞归巢、沉积和生长以及MM中的骨破坏过程中发挥重要作用。 MM 细胞的基因表达谱显示 MM 细胞高度表达annexin II (AXII)。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发挥重要作用。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、MM 细胞与基质细胞的粘附和破骨细胞 (OCL) 形成的生物学影响，以及 OCL- 的影响。 MM 细胞和 OCL 上衍生的 AXII。我们假设基质细胞上的 AXII 和 MM 细胞上的 AXIIR 之间的相互作用在 MM 细胞在骨髓中的沉积、MM 细胞的生长和 OCL 形成中发挥重要作用。此外，OCL 衍生的 AXII 与骨破坏过程中从骨基质释放的生长因子相结合，刺激 MM 细胞的生长，从而扩大骨中的肿瘤负荷。为了检验这一假设：1）我们将确定 MM 细胞是否通过 AXIIR 特异性结合 AXII； 2)确定AXII/AXIIR对骨髓微环境中MM细胞粘附和生长的贡献，以及AXII/AXIIR信号对MM细胞和基质细胞关键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 MM 细胞归巢、定位和动员中发挥的作用。这些研究的结果应确定 AXII/AXIIR 作为 MM 患者新治疗靶点的潜在效用。公共健康相关性：本申请的主要目标是确定骨髓瘤 (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以及破骨细胞 (OCL) 形成的生物学影响，如下所示：以及 OCL 衍生的 AXII 对 MM 细胞和 OCL 的影响。