Circulating 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. Detection 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. The 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. These 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.

中文翻译：

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转移前的生态位触发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。

循环肿瘤细胞（CTC），尤其是间充质CTC，是转移的重要决定因素，其导致肝细胞癌（HCC）的大多数复发和死亡。然而，关于转移前小生境中CTC定殖的潜在机制知之甚少。使用CanPatrol™系统对患者的CTC进行检测和分类。构建表达靶向Prrx1的shRNA的慢病毒载体，以产生稳定的HCC细胞系，其中Prrx1的表达较低。评估了Prrx1敲低对细胞系干性，迁移和耐药性的影响，包括SDF-1 / CXCR4信号传导的参与。探索了STAT3酪氨酸磷酸化抑制剂，C188-9和CXCR4抗体特异性阻断的有前景的临床应用。血液中间充质CTC的数量与肿瘤的复发或转移密切相关。转移前的利基来源的SDF-1可能下调Prrx1，从而通过STAT3途径诱导HCC细胞的干性，耐药性和CXCR4表达的增加。在体内，携带Prrx1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品中，与原发灶相比，Prrx1的丢失与肺转移部位CXCR4表达的增加呈负相关。这些发现表明，Prrx1的表达降低会刺激SDF-1 / CXCR4信号传导，并有助于HCC中血液CTC的器官定植。