title: Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Géraud
authors.forename: Carolin
authors.initials: C
authors.lastname: Mogler
authors.forename: Anja
authors.initials: A
authors.lastname: Runge
authors.forename: Konstantin
authors.initials: K
authors.lastname: Evdokimov
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.forename: Kai
authors.initials: K
authors.lastname: Schledzewski
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Günter
authors.initials: G
authors.lastname: Hämmerling
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Koch
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx
authors.forename: Christel
authors.initials: C
authors.lastname: Weiss
authors.forename: Friederike
authors.initials: F
authors.lastname: Damm
authors.forename: Astrid
authors.initials: A
authors.lastname: Schmieder
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D054338:Cell Transdifferentiation / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D017452:Receptors, IgG / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; C080571:Fc gamma receptor IIB; C119248:LYVE1 protein, human; D017452:Receptors, IgG; D016201:Receptors, Lymphocyte Homing; C449926:STAB1 protein, human; C449927:STAB2 protein, human; D033921:Vesicular Transport Proteins
keywords: CD32; LSEC; Lyve-1; Stabilin; hepatocellular carcinoma; sinusoidal endothelial cell; tumour endothelium