Expression of platelet-derived growth factor receptor β is maintained by Prox1 in lymphatic endothelial cells and is required for tumor lymphangiogenesis

Authors

  • Hideki Miyazaki,

    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
    2. Department of Human Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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    • These authors contributed equally to this work.
  • Yasuhiro Yoshimatsu,

    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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    • These authors contributed equally to this work.
  • Yuichi Akatsu,

    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Koichi Mishima,

    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Masashi Fukayama,

    1. Department of Human Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Tetsuro Watabe,

    Corresponding author
    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
    2. Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
    3. PRESTO, Japan Science Technology Agency, Kawaguchi, Japan
    • correspondence: Tetsuro Watabe, Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji-city, 192-0392 Tokyo, Japan.

      Tel: +81-426-76-5246; Fax: +81-426-76-5246;

      E-mail: t-watabe@umin.ac.jp

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  • Kohei Miyazono

    1. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Funding Information

    Ministry of Education, Science, Sports, and Culture of Japan; Japan Society for the Promotion of Science

Abstract

The lymphatic system plays important roles not only in the physiological processes, such as maintenance of tissue fluid homeostasis, but also in pathological processes including the lymph node metastasis of tumor cells. Therefore, understanding of the molecular mechanisms underlying lymphatic vessel formation is crucial. Previous studies have shown that proliferation and migration of lymphatic endothelial cells (LECs) are activated by multiple types of signals mediated by tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR) 3. Although signals mediated by platelet-derived growth factor receptor β (PDGFRβ) have been implicated in lymphangiogenesis, the mechanisms explaining how PDGFRβ expression is maintained in LECs remain to be fully elucidated. In the present study, we show that PDGFRβ expression in LECs is maintained by Prox1 transcription factor. Knockdown of Prox1 expression in human dermal LECs decreased the expression of PDGFRβ, leading to the lowered migration of human dermal LECs towards PDGF-BB. Furthermore, we found that PDGF signals play important roles in inflammatory lymphangiogenesis in a chronic aseptic peritonitis model. Intraperitoneal administration of imatinib, a potent inhibitor of PDGFRβ, and transduction of PDGFRβ/Fc chimeric protein by an adenoviral system both reduced inflammatory lymphangiogenesis induced by thioglycollate in mice. We also found that the expression of PDGFRβ/Fc reduced tumor lymphangiogenesis in a BxPC3 human pancreatic cancer xenograft model. These findings suggest that PDGFRβ is one of the key mediators of lymphatic vessel formation acting downstream of Prox1.

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