AXII in the Multiple Myeloma Bone Microenvironment

描述(申请人提供)：骨髓瘤(MM)细胞与骨髓微环境中的细胞之间的黏附相互作用在肿瘤细胞的归宿、生长以及MM的骨破坏过程中起着重要作用。MM细胞的基因表达谱表明MM细胞高表达膜联蛋白II(AxII)。我们最近克隆了AxII受体(AXIIR)，发现AXIIR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/AXIIR相互作用在多发性骨髓瘤、前列腺癌、骨转移和正常造血中发挥着重要作用。本应用的主要目的是确定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细胞与基质细胞的黏附和破骨细胞(OCL)形成的生物学影响，以及OCL来源的AxII对MM细胞和OCL的影响。我们推测，基质细胞上的AXII与MM细胞上的AXIIR的相互作用在MM细胞在骨髓中的停留、MM细胞的生长和OCL的形成中起着重要的作用。此外，OCL来源的AxII与骨破坏过程中从骨基质中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担。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AxII/AXIIR在骨髓微环境中对MM细胞黏附和生长的贡献，以及AxII/AXIIR信号对MM细胞和基质细胞表达关键细胞因子和黏附分子的贡献。此外，我们将评估内源性基质细胞AxII/AXIIR和MM细胞AxII/AXIIR对MM细胞生长和黏附的贡献；3)我们将确定OCL来源的AxII对MM细胞生长的贡献；以及4)AxII/AXIIR在体内MM细胞归巢、倒伏和动员中的作用。这些研究的结果应该确定AxII/AXIIR作为MM患者新的治疗靶点的潜在用途。 公共卫生相关性：本应用的主要目标是确定AXII/AXIIR在骨髓瘤(MM)细胞和骨髓微环境之间的相互作用对MM细胞生长的生物学效应、MM细胞与基质细胞的黏附和破骨细胞(OCL)的形成，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.