Open AccessTumor growth inhibitory effect of ADAMTS 1 is accompanied by the inhibition of tumor angiogenesis
Author(s) -
Obika Masanari,
Ogawa Hiroko,
Takahashi Katsuyuki,
Li Jiayi,
Hatipoglu Omer Faruk,
Cilek Mehmet Zeynel,
Miyoshi Toru,
Inagaki Junko,
Ohtsuki Takashi,
Kusachi Shozo,
Ninomiya Yoshifumi,
Hirohata Satoshi
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2012.02381.x
Subject(s) - angiogenesis , adamts , chemistry , endothelial stem cell , cancer research , transfection , thrombospondin , microbiology and biotechnology , matrix metalloproteinase , biology , in vitro , metalloproteinase , gene , biochemistry
Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 ( ADAMTS 1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS 1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo . We examined the effects of the transfection of ADAMTS 1 using two constructs, full‐length ADAMTS 1 (full ADAMTS 1) and catalytic domain‐deleted ADAMTS 1 (delta ADAMTS 1). Transfection of both the full ADAMTS 1 and delta ADAMTS 1 gene constructs demonstrated the secretion of tagged‐ ADAMTS 1 protein into the conditioned medium, so we examined the effects of ADAMTS 1‐containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS 1 on endothelial cell apoptosis. Both conditioned media increased the number of A nnexin V ‐positive endothelial cells and caspase‐3 activity and this effect was attenuated when z‐vad was added. These results indicated that ADAMTS 1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS 1 gene transfer into tumor‐bearing mice. Both full ADAMTS 1 and delta ADAMTS 1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS 1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS 1 that occurs independent of the protease activity.