Tumor growth inhibitory effect of ADAMTS 1 is accompanied by the inhibition of tumor angiogenesis

• Published in: Cancer science Vol. 103; no. 10; pp. 1889 - 1897
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: 01-10-2012
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2012.02381.x

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.