AXII in the Multiple Myeloma Bone Microenvironment

描述（由申请方提供）：骨髓瘤（MM）细胞与骨髓微环境中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的骨破坏过程中起重要作用。MM细胞的基因表达谱显示，MM细胞高度表达膜联蛋白II（AXII）。 我们最近克隆了AXII受体（AXIR），发现AXIR也在原代MM细胞和MM细胞系中表达。 我们的初步结果表明，AXII/AXIR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。 本申请的主要目的是确定MM细胞和骨髓微环境之间的AXII/AXIR相互作用对MM细胞生长、MM细胞与基质细胞粘附和破骨细胞（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。 我们推测基质细胞上的AXII和MM细胞上的AXIR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的形成中起重要作用。 此外，OCL衍生的AXII与通过骨破坏过程从骨基质释放的生长因子组合刺激MM细胞的生长以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AXIR特异性结合AXII; 2）确定AXII/AXIR对骨髓微环境中MM细胞的粘附和生长的贡献，以及AXII/AXIR信号传导对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/AXIR和MM细胞AXII/AXIR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;和4）AXII/AXIR在体内骨髓中MM细胞归巢、沉积和动员中的作用。 这些研究的结果应确定AXII/AXIR作为MM患者新治疗靶点的潜在效用。 公共卫生相关性：本申请的主要目的是确定骨髓瘤（MM）细胞和骨髓微环境之间AXII/AXIR相互作用对MM细胞生长、MM细胞与基质细胞粘附和破骨细胞（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。

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.