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Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival
- Source :
- Liver international : official journal of the International Association for the Study of the Liver. 33(9)
- Publication Year :
- 2013
-
Abstract
- 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. Methods 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. Results 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. Conclusions In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.
- Subjects :
- Sorafenib
Pathology
medicine.medical_specialty
Carcinoma, Hepatocellular
Cell Adhesion Molecules, Neuronal
Receptors, Lymphocyte Homing
Vesicular Transport Proteins
Biology
Vascular remodelling in the embryo
Mice
medicine
Animals
Humans
Intussusceptive angiogenesis
Sprouting angiogenesis
Tissue microarray
Hepatology
Neovascularization, Pathologic
Transdifferentiation
Liver Neoplasms
Receptors, IgG
Endothelial Cells
medicine.disease
Microarray Analysis
Immunohistochemistry
digestive system diseases
Endothelial stem cell
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Liver
Microscopy, Fluorescence
Hepatocellular carcinoma
Cell Transdifferentiation
Biomarkers
medicine.drug
Subjects
Details
- ISSN :
- 14783231
- Volume :
- 33
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Liver international : official journal of the International Association for the Study of the Liver
- Accession number :
- edsair.doi.dedup.....27d5f21e67a4842535b6f3d9747feeaa