The Study Of Impact Of Liver Cirrhosis On The Invasion And Metastasis Of Circulating Tumor Cells

Objective The aim of this study is to explore the impact of liver cirrhosis on the livermetastasis caused by circulating hepatocellular carcinoma cells and reveal the mechanismof recurrence of hepatocellular carcinoma（HCC）.Methods Intraperitoneal injection of20%carbon tetrachloride to build mice model of livercirrhosis.Use the method of hydrodynamic cell delivery to establish liver metastatic micemodel of circulating hepatocellular carcinoma cells. Apply the mice model have beenestablished to explore the impact of liver cirrhosis on the liver metastasis caused bycirculating hepatocellular carcinoma cells. Retrospective analysis the disease free survivaltime of238cases of curative resection HCC patients to explore the effect of circulatinghepatocellular carcinoma cells and liver cirrhosis on postoperative disease free survivaltime.Results In the experiment of building liver cirrhosis mouse model,100%mice have livercirrhosis formation. In the experiment of building liver metastatic mice model ofcirculating hepatocellular carcinoma cells，the tumor formation rate of C57BL/6J andBALB/C mice was100%. The mean number and area of liver metastases of cirrhosis groupmice(12.40,22.080mm2)were higher than non-cirrhotic groups(6.60,15.280mm2, P <0.05).In liver cirrhosis group,the tumor cells PCNA expression in liver metastasis (78.4%) washigher than non-cirrhotic groups(52.2%, P <0.05). Clinical retrospective analysis foundthat background of liver cirrhosis was correlative to Postoperative recurrence, the1-,2-,and3-year disease-free survival rates were69.8%,34.3%,23.4%in cirrhotic patients, and78.6%,48.3%,33.6%in noncirrhotic patients respectively(P＜0.05). Univariate analysis show that liver cirrhosis is a risk factor for tumor recurrence（RR=1.378，P＜0.05）. Thelevel of preoperative circulating hepatocellular carcinoma cells was correlative topostoperative recurrence, the1-,2-, and3-year disease-free survival rates were70.4%,36.4%,22.6%in CTC positive patients, and93.8%,71.2%,55.2%in CTC negative patients,respectively(P＜0.001). Univariate analysis show that CTC positive is a risk factor fortumor recurrence（RR=2.617，P＜0.001）. The1-,2-, and3-year disease-free survival rateswere64.5%,23.7%,17.8%in CTC positive cirrhotic patients, and77.6%、42.9%、28.4%，in CTC negative cirrhotic patients, respectively（P＜0.05）. Liver cirrhosis is a risk factorfor tumor recurrence in the patients of CTC positive（RR=1.484，P=0.013）. The1-,2-, and3-year disease-free survival rates were90.9%,81.0%,64.1%in CTC negative cirrhoticpatients, and93.2%,68.8%,50.2%in CTC negative noncirrhotic patients, respectively（P＜0.05）.Conclusion Our study have applied the method of hydrodynamic cell delivery to establishmetastatic mice model of CTC for the first time and the mice model will provide animportant platform for the study of CTC. Residual CTC is a important source of recurrenceand metastasis of hepatocellular carcinoma after radical resection. Background of livercirrhosis can promote the formation of liver metastasis caused by circulating hepatocellularcarcinoma cells. Further research of the mechanism of specific microenvironment factorsin the background of liver cirrhosis promoting the growth and colonization of circulatinghepatocellular carcinoma cells will have a great significance for revealling themechanism of recurrence of HCC patients with cirrhosis.