VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma

Authors

  • Armin Thelen,

    Corresponding author
    1. Department of General, Visceral and Transplantation Surgery, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    • Department of General, Visceral and Transplantation Surgery, Charité Universitaetsmedizin Berlin, Campus Virchow-Klinikum,Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
    • Armin Thelen and Arne Scholz contributed equally to this work.

    • Fax: +49-30-450-552900.

  • Arne Scholz,

    1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
    • Armin Thelen and Arne Scholz contributed equally to this work.

  • Christoph Benckert,

    1. Department of General, Visceral and Transplantation Surgery, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Zofia von Marschall,

    1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Maik Schröder,

    1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Bertram Wiedenmann,

    1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Peter Neuhaus,

    1. Department of General, Visceral and Transplantation Surgery, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Stefan Rosewicz,

    1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author
  • Sven Jonas

    1. Department of General, Visceral and Transplantation Surgery, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
    Search for more papers by this author

Abstract

Lymphatic spread is an important clinical determinant for the prognosis of hepatocellular carcinoma (HCC), but little is known about the control of lymphangiogenesis in HCC. We addressed expression and biological role of the pro-(lymph), angiogenic protein VEGF-D in this tumor entity. Using immunohistochemistry and in situ hybridization on specimens of HCC, cirrhotic and normal liver we found abundant expression of VEGF-D exclusively in the tumor cells. The cognate receptor VEGFR-3 was detected on blood and lymphatic vessels. By clinicopathological analysis VEGF-D expression was correlated with pT-stage of the primary, lymph node metastasis and lymphangiosis carcinomatosa. Three out of 4 human HCC cell lines expressed and secreted VEGF-D. To approach its biological function, VEGF-D deficient SKHep-1 cells were stably transfected with VEGF-D cDNA and effects on tumor progression were determined in vivo. Compared to mock-transfected controls, subcutaneous tumors derived from VEGF-D expressing cells were larger and more frequently metastasized to regional lymph nodes. VEGF-D expressing tumors exhibited increased microvessel density and increased abundance of peri- and intratumoral lymphatics, as assessed by immunostaining for CD31 and for LYVE-1 and/or podoplanin, respectively. Furthermore, coexpression of the soluble extracellular VEGFR-3 domain blocked VEGF-D-induced tumor growth and lymphatic spread via reduction of angiogenesis and lymphangiogenesis. In the orthotopic approach, VEGF-D expression resulted in an increased rate of intra- and extrahepatic as well as lymph node metastasis. In conclusion, our study suggests that expression of VEGF-D is involved in growth and lymphatic spread of HCC. Therefore, VEGF-D might represent a therapeutic target in HCC. © 2008 Wiley-Liss, Inc.

Ancillary