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: 8699016
• 负责人: Garson DAVID ROODMAN
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 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/8699016
• 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)的特征是血管生成增加和骨破坏，这两者都会导致肿瘤的加速生长。在临床前模型中，阻断肿瘤相关的血管生成或破骨细胞(OCL)的骨吸收都会显著影响MM的生长。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屈膦酸盐--两种OCL活性的抑制剂--在新诊断的MM患者中与化疗相结合的情况，结果表明，与较弱的双膦酸氯屈膦酸盐相比，唑来膦酸治疗显著延长了5.5个月的存活期，而且这种存活率的提高与骨骼相关事件无关。重要的是，在这项试验中，30%的患者在试验开始时没有溶骨病，仍然受益于唑来膦酸疗法。这些结果表明，阻断OCL活性对肿瘤生长的抑制作用可能超出了对骨吸收的影响。与这种可能性一致，我们最近报道了OCL在体内和体外都是血管生成细胞，提示OCL可能有助于促进MM的血管生成。为了支持这一假说，我们证明了Annexin 2(AxII)是由OCL分泌的，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，导致促进肿瘤生长和骨破坏。然而，OCL来源的AxII在多发性骨髓瘤中的作用尚不清楚。我们的假设是，MM患者中OCL活性的增加促进了肿瘤的生长，这既是通过OCL分泌生长因子和血管生成因子(如AxII)，也是通过从骨基质中释放MM生长因子。此外，从骨髓基质细胞和OCL释放AxII会增加MM细胞产生的细胞因子，从而诱导破骨细胞生成、成骨细胞抑制和血管生成。因此，为了验证这一假说，我们将通过追求以下特定目的来评估微环境衍生的AxII在骨髓瘤骨病(MMBD)中的作用：1)确定骨髓基质细胞和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来源的AxII是否起血管生成因子的作用。3)利用我们新近建立的MMBD体内免疫活性模型，确定骨髓微环境来源的AxII在MM血管生成、肿瘤生长和骨破坏中的作用。作为这一目标的一部分，我们将确定OCL来源的AxII在这些过程中的贡献，以检验OCL在体内对肿瘤生长、骨破坏和MM血管生成增加的多重贡献的假说。因此，在本提案中，我们将确定骨髓基质细胞来源的AxII，尤其是OCL来源的AxII在MMBD中的作用以及它们在调节MM细胞功能(包括成骨细胞抑制、促进破骨细胞生成和产生促血管生成因子)中的各自作用(AIM 1)；确定OCL来源的AxII直接作为血管生成因子作用于内皮细胞的能力(AIM 2)；以及确定微环境来源的AxII(完全敲除)和OCL来源的AxII(条件性敲除)在体内肿瘤生长、骨破坏和血管生成中的作用(AIM 3)。