Tumoral angiogenesis and tissue factor expression during hepatocellular carcinoma progression in a transgenic mouse model.
OBJECTIVE
The hypervascularity described in hepatocellular carcinoma varies according to the progression and the differentiation of the tumor, suggesting an angiogenic switch during tumor development.


METHODS
We used a transgenic mouse model of hepatocellular carcinoma induced by the expression of SV40-T antigen, in which male mice developed hepatic tumors at various temporal and histological stages, whereas female mice remained tumor-free. We analyzed, by immunostaining and reverse transcription-polymerase chain reaction, factors involved in tumoral angiogenesis.


RESULTS
We demonstrated that tumoral angiogenesis occurred before the development of diffuse hepatocarcinoma. We showed that some SV40-T-positive cells with an endothelial phenotype are involved in angiogenic processes, suggesting a partial vasculogenic mimicry. This tumoral angiogenesis is associated with platelet activation due to tissue factor expression in endothelial cells and invading macrophages. Normal and transgenic livers exhibited different pattern of expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) mRNA.


CONCLUSIONS
This model of hepatocellular carcinoma displays marked tumoral angiogenesis, with proliferation, remodeling and arterialization of hepatic sinusoids, probably associated with a partial vasculogenic mimicry. Abnormal angiogenesis observed in hepatocarcinoma was associated with platelet activation by tissue factor (TF) produced by endothelial cells and invading macrophages. In this transgenic model, HIF-1alpha, VEGF, and TF play a crucial role in tumoral angiogenesis.
Dupuy
Evelyne
E
Institut des Vaisseaux et du Sang, Hôpital Lariboisière, 8 rue Guy Patin, 75475 Cedex 10, Paris, France. evelyne.dupuy@lrb.ap-hop-paris.fr
Hainaud
Patricia
P
Villemain
Aude
A
Bodevin-Phèdre
Eva
E
Brouland
Jean Philippe
JP
Briand
Pascale
P
Tobelem
Gérard
G
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008113:Liver Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000097:blood / Q000378:metabolism; D015539:Platelet Activation; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin