Host-derived adiponectin is tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease
Host-derived adiponectin is tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease
复制标题
DOI：
10.1182/blood-2011-01-330407
复制
发表时间：
2011-11-24
期刊：
影响因子：
20.3
通讯作者：
Edwards, Claire M.
中科院分区：
文献类型：
--
作者：
Fowler, Jessica A.;Lwin, Seint T.;Edwards, Claire M.
宿主微环境对多发性骨髓瘤发病机制的作用，包括从意义未明的单克隆丙种球蛋白病这一非恶性疾病的进展过程，人们知之甚少。在本研究中，对一种需要独特宿主微环境来促进骨髓瘤发展的小鼠模型进行的基因芯片分析发现，与正常小鼠相比，宿主来源的脂联素减少。作为佐证，临床分析显示，在那些随后进展为骨髓瘤的意义未明的单克隆丙种球蛋白病患者中，血清脂联素浓度降低。我们利用脂联素缺乏的小鼠以及通过药物提高循环脂联素水平，研究了脂联素在骨髓瘤发病机制中的作用以及作为一种治疗方法的可行性。在患有骨髓瘤的脂联素缺乏小鼠中观察到肿瘤负荷增加和骨病加重，并且发现脂联素可诱导骨髓瘤细胞凋亡。载脂蛋白肽模拟物L - 4F被用于药物提高脂联素水平。L - 4F降低了肿瘤负荷，提高了患有骨髓瘤小鼠的存活率，并预防了骨髓瘤骨病。总之，我们的研究确定了一种新的机制，即宿主来源的脂联素减少促进骨髓瘤肿瘤生长和骨质溶解。此外，我们已经确定了提高脂联素对治疗骨髓瘤及相关骨病的潜在治疗益处。（《血液》2011年；118(22):5872 - 5882）
The contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease. (Blood. 2011;118(22):5872-5882)