TY - JOUR
T1 - ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor
AU - Inagaki, Junko
AU - Takahashi, Katsuyuki
AU - Ogawa, Hiroko
AU - Asano, Keiichi
AU - Faruk Hatipoglu, Omer
AU - Zeynel Cilek, Mehmet
AU - Obika, Masanari
AU - Ohtsuki, Takashi
AU - Hofmann, Matthias
AU - Kusachi, Shozo
AU - Ninomiya, Yoshifumi
AU - Hirohata, Satoshi
N1 - Funding Information:
The authors are grateful to Drs. Toshitaka Oohashi, Tomoko Yonezawa, and Aiji Ohtsuka and other members of our department for their stimulating discussions and suggestions. This work was supported in part by a Grant-in-Aid ( 23612004 to J.I. and 23390366 to S.H.) for Scientific Research and an Invitation Fellowship (S13731 to M.H.) from the Japan Society for the Promotion of Science .
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
KW - ADAMTS1
KW - Lymphangiogenesis
KW - Lymphatic endothelial cell
KW - VEGFC
KW - VEGFR-3
UR - http://www.scopus.com/inward/record.url?scp=84897543417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897543417&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2014.03.002
DO - 10.1016/j.yexcr.2014.03.002
M3 - Article
C2 - 24631293
AN - SCOPUS:84897543417
VL - 323
SP - 263
EP - 275
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 2
ER -
