Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors.
Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors.
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DOI：
10.1158/1078-0432.ccr-12-3416
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Liotta LA
中科院分区：
文献类型：
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作者：
Chiechi A;Novello C;Magagnoli G;Petricoin EF 3rd;Deng J;Benassi MS;Picci P;Vaisman I;Espina V;Liotta LA
迫切需要降低骨转移患者死亡率的疗法。在这项研究中，我们描绘了人类骨转移微环境的蛋白质信号通路网络。目的是确定与首次诊断骨转移后生存时间相关的相互作用蛋白质组。我们使用反相蛋白芯片技术检测了159例原发性癌和肉瘤患者骨转移组织中88个终点的表达。对于所分析的大多数蛋白质，源自不同原发性肿瘤的转移显示出跨组织类型的相似水平的细胞信号传导，这表明骨微环境强烈影响转移性肿瘤信号传导谱。在训练集（72个样本）中，TNFR 1单独（p=0.0013）或与血清素（p=0.0004）、TNFα（p=0.0214）和RANK（p=0.0226）联合使用与生存率差相关，无论原发肿瘤来源如何。结果得到以下机构的确认：a）独立验证集（71个样品）的分析和B）使用支持向量机学习模型的独立生物信息学分析。斯皮尔曼rho分析显示，在骨转移信号网络中，与ERα S118、血清素、TNFα、RANKL和MMP交叉的相互作用数量非常显著，与原发肿瘤无关。在短期与长期生存者的相互作用网络模式是显着不同的。TNFR 1和神经内分泌调节的蛋白信号通路在骨转移中起重要作用，并可能构成骨转移中种子-土壤串扰的新的药物靶向机制。
There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis. Using Reverse Phase Protein Microarray technology we measured the expression of 88 end-points in the bone microenvironment of159 bone metastasis tissue samples derived from patients with primary carcinomas and sarcomas. Metastases originating from different primary tumors showed similar levels of cell signaling across tissue types for the majority of proteins analyzed, suggesting that the bone microenvironment strongly influences the metastatic tumor signaling profiles. In a training set (72 samples), TNFR1, alone (p=0.0013) or combined with Serotonin (p=0.0004), TNFα (p=0.0214) and RANK (p=0.0226), was associated with poor survival, regardless of the primary tumor of origin. Results were confirmed by: a) analysis of an independent validation set (71 samples) and b) independent bioinformatic analysis using a support vector machine learning model. Spearman’s rho analysis revealed a highly significant number of interactions intersecting with ERα S118, Serotonin, TNFα, RANKL and MMPs in the bone metastasis signaling network, regardless of the primary tumor. The interaction network pattern was significantly different in the short versus long survivors. TNFR1 and neuroendocrine-regulated protein signal pathways appear to play an important role in bone metastasis and may constitute a novel drug-targetable mechanism of seed-soil cross-talk in bone metastasis.