title: ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor.
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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Inagaki
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Asano
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Omer
authors.initials: O
authors.lastname: Faruk Hatipoglu
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Mehmet Zeynel
authors.initials: MZ
authors.lastname: Cilek
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Obika
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohtsuki
authors.affiliation: Department of Dermatology, Venereology and Allergology, Goethe University, Frankfurt, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hofmann
authors.affiliation: Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Kusachi
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ninomiya
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirohata
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human
keywords: ADAMTS1; Lymphangiogenesis; Lymphatic endothelial cell; VEGFC; VEGFR-3