Role of Microenvironmental-Derived AXII in Myeloma Bone Disease

微环境衍生的 AXII 在骨髓瘤骨病中的作用

• 批准号: 8245284
• 负责人: Garson DAVID ROODMAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245284
• 关键词: Affect; African American; Angiogenic Factor; Annexins; Binding; Biological Assay; Bone Diseases; Bone Marrow; Bone Matrix; Bone Regeneration; Bone Resorption; Breeding; Caucasians; Caucasoid Race; Cell Adhesion Molecules; Cell Proliferation; Cell physiology; Cells; Characteristics; Conditioned Culture Media; Data; Development; Dichloromethylene Diphosphonate; Disease; Elderly; Endothelial Cells; Event; Growth; Growth Factor; Health; Human; Immunocompetent; In Vitro; Knock-out; Lead; Lytic; Malignant lymphoid neoplasm; Marrow; Mediating; Medical Research; Messenger RNA; Modeling; Multiple Myeloma; Mus; Newly Diagnosed; Osteoblasts; Osteoclasts; Patients; Plasmin; Plasminogen; Play; Pre-Clinical Model; Process; Production; Property; Protocols documentation; Quality of life; Reporting; Role; Signal Transduction; Source; Stromal Cells; Surface; System; Testing; United States; Veterans; Zoledronic Acid; angiogenesis; bisphosphonate; bone; cell type; chemokine; chemotherapy; cytokine; dimer; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; migration; monomer; novel; osteoclastogenesis; receptor; skeletal; tumor; tumor growth

DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is characterized by increased angiogenesis and bone destruction, which both result in enhanced tumor growth. Blocking either tumor associated angiogenesis or bone resorption by osteoclasts (OCL) significantly impacts MM growth in preclinical models. Further, the recent Medical Research Council Myeloma IX trial, which compared zoledronic acid and clodronate, both inhibitors of OCL activity, in combination with chemotherapy in patients with newly diagnosed MM, showed that zoledronic acid treatment significantly increased survival by 5.5 months compared to the weaker bisphosphonate clodronate, and that this survival benefit was independent of skeletal-related events. Importantly, 30% of the patients in this trial did not have lytic bone disease at the start of the trial and still benefited from zoledronic acid therapy. These results suggest that blocking OCL activity may have additional inhibitory effects on tumor growth beyond effects on bone resorption. Consistent with this possibility, we recently reported that OCL are angiogenic cells both in vivo and in vitro, suggesting that OCL may contribute to the enhanced angiogenesis in MM. In support of this hypothesis, we have demonstrated that Annexin 2 (AXII) is secreted by OCL, is a growth factor for MM cells and can stimulate proliferation of human endothelial cells. These results suggest that OCL have a multiplicity of effects in myeloma that result in enhanced tumor growth and bone destruction. However, the role of OCL-derived AXII in MM is unclear. It is our hypothesis that the increased OCL activity present in MM patients increases tumor growth, both through secretion of growth factors and angiogenic factors such as AXII by OCL and release of MM growth factors from the bone matrix. Further, release of AXII from bone marrow stromal cells and OCL increases production of cytokines by MM cells that induce osteoclastogenesis, osteoblast suppression, and angiogenesis. Therefore, to test this hypothesis, we will assess the role of microenvironment-derived AXII in myeloma bone disease (MMBD) by pursuing the following specific aims: 1) Determine if modulating AXII produced in the MM microenvironment by bone marrow stromal cells and OCL impacts the capacity of MM cells to induce osteoclastogenesis, osteoblast suppression, and angiogenesis. 2) Determine if OCL-derived AXII acts as an angiogenic factor. 3) Determine the role of marrow microenvironment-derived AXII on angiogenesis, tumor growth and bone destruction in MM using our recently developed immunocompetent in vivo model of MMBD. As part of this aim, we will determine the contribution of OCL-derived AXII to these processes to test the hypothesis that OCL make multiple contributions to tumor growth, bone destruction and the increased angiogenesis characteristic of MM in vivo. Thus, In this proposal, we will determine the roles of both bone marrow stromal cell-derived and in particular OCL-derived AXII activity in MMBD and their respective roles in regulating MM cell functions including osteoblast suppression, enhanced osteoclastogenesis, and production of pro-angiogenic factors (AIM 1); determine the capacity of OCL-derived AXII's capacity to act directly as an angiogenic factor on endothelial cells (AIM 2); and determine the role of microenvironment-derived AXII (total knockout) and specifically of OCL-derived AXII (conditional knockout) in tumor growth, bone destruction and angiogenesis in vivo (AIM 3).

描述（由申请人提供）： 多发性骨髓瘤（MM）的特征是血管生成和骨破坏增加，这两者都导致肿瘤生长增强。阻断肿瘤相关的血管生成或破骨细胞（OCL）的骨吸收显著影响临床前模型中的MM生长。此外，最近的医学研究理事会骨髓瘤IX试验比较了唑来膦酸和氯膦酸盐（均为OCL活性抑制剂）联合化疗治疗新诊断的MM患者，结果显示，与较弱的双膦酸盐氯膦酸盐相比，唑来膦酸治疗显著延长了5.5个月的生存期，并且这种生存获益与肿瘤相关事件无关。重要的是，该试验中30%的患者在试验开始时没有溶骨性疾病，仍然从唑来膦酸治疗中获益。这些结果表明，阻断OCL活性可能对肿瘤生长有额外的抑制作用，而不是对骨吸收的影响。与这种可能性相一致，我们最近报道，OCL是血管生成细胞在体内和体外，这表明OCL可能有助于增强MM的血管生成。在支持这一假设，我们已经证明，膜联蛋白2（AXII）是由OCL分泌，是MM细胞的生长因子，可以刺激人内皮细胞的增殖。这些结果表明，OCL在骨髓瘤中具有多种作用，导致肿瘤生长和骨破坏增强。然而，OCL衍生的AXII在MM中的作用尚不清楚。我们的假设是，MM患者中存在的OCL活性增加会增加肿瘤生长，这是通过OCL分泌生长因子和血管生成因子（如AXII）以及MM生长因子从骨基质中释放来实现的。此外，AXII从骨髓基质细胞和OCL的释放增加了MM细胞诱导破骨细胞生成、成骨细胞抑制和血管生成的细胞因子的产生。因此，为了验证这一假设，我们将通过以下具体目标评估微环境来源的AXII在骨髓瘤骨疾病（MMBD）中的作用：1）确定调节骨髓基质细胞和OCL在MM微环境中产生的AXII是否影响MM细胞诱导破骨细胞生成、成骨细胞抑制和血管生成的能力。2)确定OCL衍生的AXII是否作为血管生成因子。3)使用我们最近开发的免疫活性体内MMBD模型，确定骨髓微环境衍生的AXII对MM血管生成、肿瘤生长和骨破坏的作用。作为这一目标的一部分，我们将确定OCL衍生的AXII对这些过程的贡献，以检验OCL对体内MM的肿瘤生长、骨破坏和血管生成特征增加做出多种贡献的假设。因此，在本研究中，我们将确定骨髓基质细胞来源的AXII活性，特别是OCL来源的AXII活性在MMBD中的作用，以及它们各自在调节MM细胞功能中的作用，包括成骨细胞抑制、破骨细胞生成增强和促血管生成因子（AIM 1）的产生;确定OCL衍生的AXII直接作为血管生成因子作用于内皮细胞的能力（AIM 2）;并确定微环境衍生的AXII（完全敲除）和特别是OCL衍生的AXII（条件敲除）在体内肿瘤生长、骨破坏和血管生成中的作用（AIM 3）。