Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1
Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1
复制标题
转移前生态位触发 SDF-1/CXCR4 轴，并通过下调 Prrx1 促进肝细胞循环肿瘤细胞的器官定植
DOI：
10.1186/s13046-019-1475-6
复制
发表时间：
2019-11-21
影响因子：
11.3
通讯作者：
Pan, Mingxin
中科院分区：
文献类型：
--
作者：
Tang, Yujun;Lu, Yishi;Pan, Mingxin
背景循环肿瘤细胞（Circulating tumor cells，CTC），尤其是间充质CTC，是肝细胞癌（hepatocellular carcinoma，HCC）转移的重要决定因素，而转移是导致HCC复发和死亡的主要原因。然而，很少有人知道CTC定植在转移前niches.MethodsDetection和CTCs在患者中的分类使用CanPatrol™系统进行的潜在机制。构建表达Prrx 1靶向shRNA的慢病毒载体，以产生具有低表达Prrx 1的稳定的HCC细胞系。评估了Prrx 1敲低对细胞系的干性、迁移和耐药性的影响，包括SDF-1/CXCR 4信号传导的参与。有前途的临床应用的抑制剂STAT 3酪氨酸磷酸化，C188-9，和特异性封锁与CXCR 4抗体explored.ResultsThe数量间充质CTC在血液中与肿瘤复发或转移密切相关。转移前小生境来源的SDF-1可下调Prrx 1，从而诱导肝癌细胞的干细胞性、耐药，并通过STAT 3途径增加CXCR 4的表达。在体内，携带Prrx 1低表达细胞肿瘤的小鼠的生存期明显缩短。在异种移植肿瘤和临床样本中，Prrx 1的损失与CXCR 4在肺转移部位的表达增加呈负相关，与在原发灶相比。ConclusionsThese研究结果表明，Prrx 1的表达减少刺激SDF-1/CXCR 4信号传导，并有助于器官定植与血液CTC在HCC。STAT 3抑制和CXCR 4特异性阻断具有消除晚期HCC器官转移的临床潜力。
BackgroundCirculating tumour cells (CTCs), especially mesenchymal CTCs, are important determinants of metastasis, which leads to most recurrence and mortality in hepatocellular carcinoma (HCC). However, little is known about the underlying mechanisms of CTC colonisation in pre-metastatic niches.MethodsDetection and classification of CTCs in patients were performed using the CanPatrol™ system. A lentiviral vector expressing Prrx1-targeting shRNA was constructed to generate a stable HCC cell line with low expression of Prrx1. The effect of Prrx1 knockdown on stemness, migration, and drug resistance of the cell line was assessed, including involvement of SDF-1/CXCR4 signalling. Promising clinical applications of an inhibitor of STAT3 tyrosine phosphorylation, C188–9, and specific blockade with CXCR4 antibody were explored.ResultsThe number of mesenchymal CTCs in blood was closely associated with tumour recurrence or metastasis. Pre-metastatic niche-derived SDF-1 could downregulate Prrx1, which induced the stemness, drug resistance, and increased expression of CXCR4 in HCC cells through the STAT3 pathway in vitro. In vivo,mice bearing tumours of Prrx1 low-expressing cells had significantly shorter survival. In xenograft tumours and clinical samples, loss of Prrx1 was negatively correlated with increased expression of CXCR4 in lung metastatic sites compared with that in the primary foci.ConclusionsThese findings demonstrate that decreased expression of Prrx1 stimulates SDF-1/CXCR4 signalling and contributes to organ colonisation with blood CTCs in HCC. STAT3 inhibition and specific blockade of CXCR4 have clinical potential as therapeutics for eliminating organ metastasis in advanced HCC.