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Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

Author:
  • Yasuhiro Yoshimatsu
  • Yulia G. Lee
  • Yuichi Akatsu
  • Luna Taguchi
  • Hiroshi I. Suzuki
  • Sara I. Cunha
  • Kazuichi Maruyama
  • Yuka Suzuki
  • Tomoko Yamazaki
  • Akihiro Katsura
  • S. Paul Oh
  • Teresa A. Zimmers
  • Se-Jin Lee
  • Kristian Pietras
  • Gou Young Koh
  • Kohei Miyazono
  • Tetsuro Watabe
Publishing year: 2013
Language: English
Pages: 18940-18945
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 110
Issue: 47
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1(ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.

Keywords

  • Cancer and Oncology
  • lymphangiogenesis
  • angiogenesis
  • blood vascular endothelial cells

Other

Published
  • ISSN: 1091-6490
Kristian Pietras
E-mail: kristian.pietras [at] med.lu.se

Professor

Division of Translational Cancer Research

+46 46 222 64 29

MV404 A31B1

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Project manager

Experimental oncology