Overexpression of platelet-derived growth factor receptor alpha in endothelial cells of hepatocellular carcinoma associated with high metastatic potential.
OBJECTIVE
Little information is available on the heterogeneity of the vascular endothelium in hepatocellular carcinoma. The aim of this study was to identify the differentially expressed genes in tumor endothelial cells from highly metastatic hepatocellular carcinoma.


METHODS
Magnetic beads conjugated with anti-CD31 antibody were used to isolate vascular endothelial cells from hepatocellular carcinoma xenografts with different metastatic potentials in nude mice. Gene expression profiles for different endothelial cells were compared by use of cDNA microarray. The up-regulated gene was confirmed by reverse transcription-PCR, real-time PCR, and immunohistochemistry.


RESULTS
cDNA microarray analysis revealed differential expression patterns in seven genes consistently presented in endothelial cells isolated from hepatocellular carcinoma with different metastatic potentials. Overexpression of platelet-derived growth factor receptor alpha was found only in the endothelium of highly metastatic hepatocellular carcinoma, which was confirmed by reverse transcription-PCR, real-time PCR, and immunohistochemistry. Oral administration of STI571 (imatinib mesylate or Glivec), a protein tyrosine kinase inhibitor of platelet-derived growth factor receptor, combined with s.c. injection of IFN-alpha not only effectively reduced tumor weight (by 81.8%) and microvessel density (by 70.2%) but also inhibited lung metastasis (by 100%). Furthermore, immunohistochemical analysis of platelet-derived growth factor receptor alpha in human hepatocellular carcinoma tissues revealed its correlation with postoperative recurrence, especially in patients without microvessel invasion.


CONCLUSIONS
The gene expression of hepatocellular carcinoma vascular endothelium is different between tumors with different metastatic potential. Platelet-derived growth factor receptor alpha, which is overexpressed in endothelium of highly metastatic hepatocellular carcinoma, may serve as a biomarker for predicting metastasis and a therapeutic target for highly metastatic hepatocellular carcinoma.
Zhang
Ti
T
Liver Cancer Institute and Zhong Shan Hospital of Fudan University, Shanghai, People's Republic of China.
Sun
Hui-Chuan
HC
Xu
Yang
Y
Zhang
Ke-Zhi
KZ
Wang
Lu
L
Qin
Lun-Xiu
LX
Wu
Wei-Zhong
WZ
Liu
Yin-Kun
YK
Ye
Sheng-Long
SL
Tang
Zhao-You
ZY
D000818:Animals; D001549:Benzamides; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics* / Q000556:secondary*; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015533:Transcriptional Activation
D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha