Both authors contributed equally to this work.
Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival
Article first published online: 21 JUL 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 33, Issue 9, pages 1428–1440, October 2013
How to Cite
Liver Int. 2013; 33:1428–1440
- Issue published online: 8 SEP 2013
- Article first published online: 21 JUL 2013
- Accepted manuscript online: 25 JUN 2013 02:06AM EST
- Manuscript Accepted: 15 JUN 2013
- Manuscript Received: 26 FEB 2013
- Deutsche Forschungsgemeinschaft
- hepatocellular carcinoma;
- LSEC ;
- sinusoidal endothelial cell;
- tumour endothelium
Background & Aims
Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC.
The murine inducible albumin-SV40-large T-antigen model and two tissue microarrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b.
LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 μm in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63–95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion.
In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.