ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor

Junko Inagaki; Katsuyuki Takahashi; Hiroko Ogawa; Keiichi Asano; Omer Faruk Hatipoglu; Mehmet Zeynel Cilek; Masanari Obika; Takashi Ohtsuki; Matthias Hofmann; Shozo Kusachi; Yoshifumi Ninomiya; Satoshi Hirohata

doi:10.1016/j.yexcr.2014.03.002

ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor

Exp Cell Res. 2014 May 1;323(2):263-75. doi: 10.1016/j.yexcr.2014.03.002. Epub 2014 Mar 11.

Affiliations

¹ Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
² Department of Dermatology, Venereology and Allergology, Goethe University, Frankfurt, Germany.
³ Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
⁴ Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; International Center, Okayama University, Okayama, Japan. Electronic address: hirohas@cc.okayama-u.ac.jp.

PMID: 24631293
DOI: 10.1016/j.yexcr.2014.03.002

Abstract

Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.

Keywords: ADAMTS1; Lymphangiogenesis; Lymphatic endothelial cell; VEGFC; VEGFR-3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins / genetics
ADAM Proteins / metabolism*
ADAMTS1 Protein
Cell Line, Tumor
Cell Movement
Cell Proliferation*
Endothelial Cells / metabolism*
Endothelial Cells / physiology
HEK293 Cells
Humans
Lymphatic Vessels / cytology
Lymphatic Vessels / metabolism
Lymphatic Vessels / physiology*
Phosphorylation
Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

FLT4 protein, human
Vascular Endothelial Growth Factor Receptor-3
ADAM Proteins
ADAMTS1 Protein
ADAMTS1 protein, human