Pre-metastatic niche triggers SDF-1/CXCR4 axis and promotes organ colonisation by hepatocellular circulating tumour cells via downregulation of Prrx1
Authors: Lei Luo
Yishi Lu
Mingxin Pan
Bangjian Peng
Wenbin Huang
Yuan Chen
Yujun Tang
Liang Zhao
Lei Cai
Hangyu Liao
Journal: Journal of Experimental & Clinical Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Circulating tumour cells; Liver neoplasms; Neoplasm metastasis.
Affiliations: Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China., Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China., Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China., Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China., Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China. ., Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. ., Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China. ., Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China. .

Abstract:  Background: 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. Methods: 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. Results: 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. Conclusions: 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. 

Retracted: No

PubPeer comments:
 Figure 6C: Areas are more similar than expected. Could authors check this issue please? ![file] , 
 #1 I think the duplicated area is somewhat larger (see below). Closer inspection of the largest available version of this and other image panels shows many oddities indicative of assembly from rectangular patches, unless the authors have some other explanation. ![file] ,