Human hepatocellular carcinoma tumor-derived endothelial cells manifest increased angiogenesis capability and drug resistance compared with normal endothelial cells.
OBJECTIVE
Increasing evidence indicates that tumor-derived endothelial cells (TEC) possess a distinct and unique phenotype compared with endothelial cells (NEC) from adjacent normal tissue and may be able to acquire resistance to drugs. The aim of this study was to investigate the angiogenesis activity and response to drug treatment of TECs and NECs derived from human hepatocellular carcinoma (HCC).


METHODS
TECs or NECs were isolated from HCC or adjacent normal liver tissue using anti-CD105 antibody coupled to magnetic beads. The phenotypic and functional properties of endothelial cells were characterized by testing the expression of CD105, CD31, CD144, vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, and von Willebrand factor, and the ability of DiI-Ac-LDL-uptake and tube formations. CD105(+) TECs were compared with CD105(+) NECs and human umbilical vein endothelial cells (HUVEC) by examining their ability to proliferate, motility, ability to adhere to tumor cells, response to tumor conditioned medium, and reactions to the chemotherapy drugs Adriamycin and 5-fluorouracil and the antiangiogenic drug sorafenib.


RESULTS
Compared with CD105(+) NECs and HUVECs, CD105(+) TECs showed increased apoptosis resistance and motility and proangiogenic properties. Meanwhile, CD105(+) TECs had a greater ability to adhere to tumor cells and survive in the tumor environment. Moreover, CD105(+) TECs acquired more resistance to Adriamycin, 5-fluorouracil, and sorafenib than CD105(+) NECs and HUVECs.


CONCLUSIONS
TECs possessed enhanced angiogenic activity and resistance to chemotherapeutic drugs and an angiogenesis inhibitor, and may provide a better tool for studying tumor angiogenesis and antiangiogenesis drugs in HCC.
Xiong
Yu-Quan
YQ
Liver Cancer Institute and Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai, P R China.
Sun
Hui-Chuan
HC
Zhang
Wei
W
Zhu
Xiao-Dong
XD
Zhuang
Peng-Yuan
PY
Zhang
Ju-Bo
JB
Wang
Lu
L
Wu
Wei-Zhong
WZ
Qin
Lun-Xiu
LX
Tang
Zhao-You
ZY
D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001557:Benzenesulfonates / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077157:Sorafenib; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D015820:Cadherins; D004317:Doxorubicin; D000071063:Endoglin; D005472:Fluorouracil; D020929:Mitogen-Activated Protein Kinase Kinases; D009536:Niacinamide; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; D000077157:Sorafenib; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D014841:von Willebrand Factor; D000099152:Cadherin 5; C064206:ENG protein, human; C494086:STAT3 protein, human