High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma.
OBJECTIVE
To investigate the prognostic values of putative hepatic stem/progenitor cell (HSC/HPC) biomarkers in patients with hepatocellular carcinoma (HCC).


METHODS
Fourteen biomarkers related to HSCs/HPCs or tumour angiogenesis were assessed by qRT-PCR and then validated by tissue microarrays (TMAs) in three independent cohorts of patients with HCC undergoing curative resection (n=67, 314 and 73).


RESULTS
Most of the biomarkers were found to be overexpressed in patients with recurrent HCC by quantitative reverse transcription-PCR (qRT-PCR). The HSC/HPC biomarkers cytokeratin 19, ATP-binding cassette subfamily G member 2 (ABCG2), CD133, Nestin and CD44, and the markers of angiogenesis microvessel density (MVD, determined by CD34 immunostaining), vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were confirmed as significant predictors for overall survival (OS) and/or relapse-free survival (RFS) in TMA analysis. As compared with the low HSC/HPC profile group, patients with a high HSC/HPC profile who had higher VEGF levels (p=0.012) and MVD (p=0.030) in tumours had significantly lower OS and RFS (p<0.0001). Based on Cox regression, a simplified model including CD133, CD44, Nestin and MVD was constructed and confirmed as an independent predictor for OS (p<0.0001) and RFS (p<0.0001), regardless of alpha-fetoprotein level, tumour stage and recurrence time (p<0.0001 for all).


CONCLUSIONS
High expression levels of HSC/HPC biomarkers are related to tumour angiogenesis and poor prognosis of HCC. The simplified model based on the HSC/HPC and tumour angiogenesis profile can be used to classify patients with HCC with a high risk of tumour recurrence after surgery.
Yang
Xin-Rong
XR
Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, 136 Yi Xue Yuan Road, Shanghai, PR China.
Xu
Yang
Y
Yu
Bin
B
Zhou
Jian
J
Qiu
Shuang-Jian
SJ
Shi
Guo-Ming
GM
Zhang
Bo-Heng
BH
Wu
Wei-Zhong
WZ
Shi
Ying-Hong
YH
Wu
Bin
B
Yang
Guo-Huan
GH
Ji
Yuan
Y
Fan
Jia
J
D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004812:Epidemiologic Methods; D005260:Female; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D046888:Tissue Array Analysis / Q000379:methods
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D012334:RNA, Neoplasm