首页> 美国卫生研究院文献>Molecular Cellular Proteomics : MCP >Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma
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Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

机译:血清样品的多组学分析表明转移性黑素瘤中通过全身性钙动员和血小板活化对器官功能进行重新编程。

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摘要

Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia.
机译:癌症相关综合征(如恶病质)的病理生理学知之甚少,并且尚未建立常规的生物标志物。使用shot弹枪蛋白质组学,发现转移性黑素瘤患者的已知标记分子(包括PMEL,CRP,SAA和CSPG4)失控。具有多种反应监测功能的58种选定蛋白质的目标分析可用于独立数据验证。在三名患者中,其中两名患有恶病质,确定了一种组织损伤特征,包括九种蛋白质,PLTP,CD14,TIMP1,S10A8,S10A9,GP1BA,PTPRJ,CD44和C4A,以及甘氨酸和天冬酰胺和降低的多不饱和磷脂酰胆碱浓度水平,这是通过目标代谢组学确定的。值得注意的是,已知这些分子与癌症恶病质的关键过程有关。基于这些结果,我们提出了一个模型,即转移性黑素瘤如何通过在氧化条件下从长链多不饱和磷脂酰胆碱形成血小板活化因子并通过系统诱导细胞内钙动员来导致器官功能重编程。血小板中的钙动员被证明可以改变其中一些标记分子的水平。另外,来自黑素瘤患者的血小板被证明处于相当疲惫的状态,并且发现来自三名黑素瘤患者的血液中血小板衍生的类二十烷酸大量增加。因此,血小板被认为是晚期黑色素瘤患者血清蛋白和脂质改变的重要来源。结果,提出的模型描述了脂肪组织的脂解与氧化应激介导的肌肉消瘦之间的串扰,从而导致恶病质的代谢失调。

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