Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
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DOI：
10.1164/rccm.201110-1826oc
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发表时间：
2012-07-01
影响因子：
24.7
通讯作者：
Lecanda, Fernando
中科院分区：
文献类型：
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作者：
Anton, Iker;Molina, Eva;Lecanda, Fernando
原理：有效的转移需要肿瘤细胞的存活和适应细胞外环境施加的严格条件。目的：探讨活化蛋白C（APC）及其受体（内皮蛋白C受体[EPCR]）在肺癌转移动物模型和肺腺癌患者中的作用。通过沉默和阻断抗体在无胸腺裸鼠Foxn 1（nu）中的肺癌转移的几种体内模型中评估功能意义。我们使用107名患者的微阵列数据集检查了EPCR水平。免疫组化分析进行了一个独立的队列295例肺adenocarcinoma. Measures和主要结果：APC结合EPCR的影响迅速触发Akt和细胞外信号调节激酶信号通路，导致体外细胞凋亡减弱。在体内，沉默EPCR表达或阻断APC/EPCR相互作用减少了靶器官的浸润，导致促转移活性受损。此外，EPCR过表达诱导靶器官转移活性增加。临床样本的分析表明，高EPCR水平和预后不良，特别是在I期patients.Conclusions：EPCR及其配体APC促进细胞生存，有助于肿瘤细胞的耐力，以支持肺腺癌的促转移活性的压力之间的强大的关联。EPCR/APC是与早期肺癌临床结局相关的新靶点。
Rationale: Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression.Objectives: To investigate the contribution of activated protein C (APC) and its receptor (endothelial protein C receptor [EPCR]) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma.Methods: Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis in athymic nude Foxn1(nu) mice. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma.Measurements and Main Results: The effects of APC binding to EPCR rapidly triggered Akt and extracellular signal-regulated kinase signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced infiltration in the target organ, resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increased metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis, particularly in stage I patients.Conclusions: EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma. EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer.