Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival

Authors

  • Cyrill Géraud,

    Corresponding author
    • Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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    • Both authors contributed equally to this work.
  • Carolin Mogler,

    1. Institute of Pathology, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany
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    • Both authors contributed equally to this work.
  • Anja Runge,

    1. Joint Research Division of Vascular Biology, Medical Faculty Mannheim, Heidelberg University, and German Cancer Research Center Heidelberg, Heidelberg, Germany
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  • Konstantin Evdokimov,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Shun Lu,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Kai Schledzewski,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Bernd Arnold,

    1. Department of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Günter Hämmerling,

    1. Department of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Philipp S. Koch,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Kai Breuhahn,

    1. Institute of Pathology, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany
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  • Thomas Longerich,

    1. Institute of Pathology, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany
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  • Alexander Marx,

    1. Department of Pathology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Christel Weiss,

    1. Division for Medical Statistics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Friederike Damm,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Astrid Schmieder,

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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  • Peter Schirmacher,

    1. Institute of Pathology, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany
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  • Hellmut G. Augustin,

    1. Joint Research Division of Vascular Biology, Medical Faculty Mannheim, Heidelberg University, and German Cancer Research Center Heidelberg, Heidelberg, Germany
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  • Sergij Goerdt

    1. Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany
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Correspondence

Cyrill Géraud, MD, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Mannheim D-68135 Mannheim, Germany

Tel: +49 (0) 621 383 2280

Fax: +49 (0) 621 383 3815

e-mail: cyrill.geraud@umm.de

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.

Ancillary