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Clinical Cancer Research Vol. 9, 6497-6503, December 15, 2003
© 2003 American Association for Cancer Research


Experimental Therapeutics, Preclinical Pharmacology

Adipocyte-Derived Leucine Aminopeptidase Suppresses Angiogenesis in Human Endometrial Carcinoma via Renin-Angiotensin System

Yoshiteru Watanabe1, Kiyosumi Shibata1, Fumitaka Kikkawa1, Hiroaki Kajiyama1, Kazuhiko Ino1, Akira Hattori2, Masafumi Tsujimoto2 and Shigehiko Mizutani1

1 Department of Obstetrics and Gynecology, Nagoya Graduate University School of Medicine, Nagoya, Japan, and
2 RIKEN (Laboratory of Cellular Biochemistry, Institute of Physical and Chemical Research), Saitama, Japan

Purpose: Angiotensin (Ang) II was reported to induce vascular endothelial growth factor (VEGF) expression in various cells. Adipocyte-derived leucine aminopeptidase (A-LAP) is a novel member of the M1 family of zinc metallopeptidases. Enzymatic characterization demonstrated that A-LAP hydrolyzes Ang II. This study examined the role of A-LAP in angiogenesis of human endometrial carcinoma.

Experimental Design: We investigated whether Ang II induces VEGF expression in human endometrial carcinoma cells. To investigate the possible function of A-LAP in angiogenesis of endometrial carcinoma, we transfected A-LAP cDNA into HEC-1A cells, showing the lowest expression of A-LAP.

Results: In the present study, we showed that Ang II enhanced VEGF expression in a dose-dependent manner in endometrial carcinoma cells (HEC-1A cells). Overexpression of A-LAP attenuated Ang II-induced VEGF expression in HEC-1A cells. In addition, Human umbilical vascular endothelial cell migration was increased in conditioned media from Ang II-treated wild-type cells, but not in conditioned media from Ang II-treated A-LAP-overexpressing cells (HEC-1A-A-LAP cells). In an in vivo study, we showed that A-LAP overexpression in endometrial carcinoma cells results in a reduction of VEGF immunoreactivity and the number of blood vessels within tumors.

Conclusions: Our study demonstrates that it is feasible to overexpress Ang II-degrading enzymes in cultured cells and that this overexpression attenuated some effects of exogenous and endogenous Ang II. These experiments are a first step toward the development of novel strategies to selectively antagonize locally generated Ang II and suppress VEGF-induced angiogenesis in endometrial carcinoma.


Commentary

Of Peptides and Peptidases: The Role of Cell Surface Peptidases in Cancer
David M. Nanus
Clin. Cancer Res. 2003 9: 6307-6309. [Full Text] [PDF]



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