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  • Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.

Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.

Clinical cancer research : an official journal of the American Association for Cancer Research (2010-12-15)
Hilary A Kenny, Payton Leonhardt, Andras Ladanyi, S Diane Yamada, Anthony Montag, Hae Kyung Im, Sujatha Jagadeeswaran, David E Shaw, Andrew P Mazar, Ernst Lengyel
ABSTRACT

To understand the functional and preclinical efficacy of targeting the urokinase plasminogen activator receptor (u-PAR) in ovarian cancer. Expression of u-PAR was studied in 162 epithelial ovarian cancers, including 77 pairs of corresponding primary and metastatic tumors. The effect of an antibody against u-PAR (ATN-658) on proliferation, adhesion, invasion, apoptosis, and migration was assessed in 3 (SKOV3ip1, HeyA8, and CaOV3) ovarian cancer cell lines. The impact of the u-PAR antibody on tumor weight, number, and survival was examined in corresponding ovarian cancer xenograft models and the mechanism by which ATN-658 blocks metastasis was explored. Only 8% of all ovarian tumors were negative for u-PAR expression. Treatment of SKOV3ip1, HeyA8, and CaOV3 ovarian cancer cell lines with the u-PAR antibody inhibited cell invasion, migration, and adhesion. In vivo, anti-u-PAR treatment reduced the number of tumors and tumor weight in CaOV3 and SKOV3ip1 xenografts and reduced tumor weight and increased survival in HeyA8 xenografts. Immunostaining of CaOV3 xenograft tumors and ovarian cancer cell lines showed an increase in active-caspase 3 and TUNEL staining. Treatment with u-PAR antibody inhibited α(5)-integrin and u-PAR colocalization on primary human omental extracellular matrix. Anti-u-PAR treatment also decreased the expression of urokinase, u-PAR, β(3)-integrin, and fibroblast growth factor receptor-1 both in vitro and in vivo. This study shows that an antibody against u-PAR reduces metastasis, induces apoptosis, and reduces the interaction between u-PAR and α(5)-integrin. This provides a rationale for targeting the u-PAR pathway in patients with ovarian cancer and for further testing of ATN-658 in this indication.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Integrin β3 Antibody, clone B3A, azide free, clone B3A, Chemicon®, from mouse
Sigma-Aldrich
Anti-Integrin αVβ3 Antibody, clone LM609, clone LM609, Chemicon®, from mouse