Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.
Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.
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DOI：
10.1158/1078-0432.ccr-10-2258
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Lengyel E
中科院分区：
文献类型：
--
作者：
Kenny HA;Leonhardt P;Ladanyi A;Yamada SD;Montag A;Im HK;Jagadeeswaran S;Shaw DE;Mazar AP;Lengyel E
To understand the functional and preclinical efficacy of targeting 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 three (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 cells 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 α5-integrin and u-PAR colocalization on primary human omental ECM. Anti-u-PAR treatment also decreased the expression of urokinase, u-PAR, β3-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 α5-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.
