Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma.
BACKGROUND
We investigated the distribution and clinical significance of mobilized endothelial progenitor cells (EPCs) in hepatocellular carcinoma (HCC). We found that many more EPCs were recruited to nonmalignant liver tissue (especially into adjacent non-tumor tissues (AT)) than to tumor vessels. These results suggest that the mechanism underlying the recruitment of EPCs into microvessels in AT merits further investigation


METHODS
Angiogenic factors were detected in three tissue microarrays comprising normal liver, paired tumor tissue (TT) and AT from 105 patients (who had undergone hepatectomy for HCC) using immunohistochemistry. Also, the number of EPCs (positive for Sca-1, Flk-1 and c-Kit) in the blood and liver of cirrhotic mice were determined by flow cytometry and immunohistochemistry. The distribution of these labeled EPCs in tumor and non-tumor tissues was then studied.


RESULTS
The results from the tissue microarrays showed that the expression levels of VEGF-A, bFGF, TGF-β, MCP-1, TSP-1, MMP-9, TIMP-2, and endostatin were significantly higher in AT than in either normal liver or TT (p < 0.05), but no significant difference was found in the expression levels of COX-2 and NOS-2 between AT and TT. The expression of VEGF-A, bFGF, TGF-β, MCP-1, TSP-1, MMP-9, TIMP-2, endostatin, COX-2, and NOS-2 in normal liver tissue was weaker than that in AT or TT. In cirrhotic mice, the number of circulating endothelial progenitor cells gradually increased, before decreasing again. In this mouse model, increased numbers of EPCs were recruited and homed specifically to the cirrhotic liver.


CONCLUSIONS
Both liver cirrhosis and HCC led to increased expression of pro-angiogenic factors, which resulted in the recruitment of EPCs into AT. Also, EPCs were mobilized, recruited and homed to cirrhotic liver. The unique pathology of HCC coupled with liver cirrhosis may, therefore, be associated with the distribution and function of EPCs.
Yu
De-cai
DC
Institute of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
Chen
Jun
J
Sun
Xi-tai
XT
Zhuang
Lin-yuan
LY
Jiang
Chun-ping
CP
Ding
Yi-tao
YT
D043925:Angiogenesis Inducing Agents; D000818:Animals; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis
D043925:Angiogenesis Inducing Agents; D014408:Biomarkers, Tumor