Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis.

Content Provider	Semantic Scholar
Author	Kenny, Hilary A. Leonhardt, Payton T. Ladanyi, Andras Yamada, S. Diane Montag, Anthony C. Im, Hae Kyung Jagadeeswaran, Sujatha Shaw, David Elliot Mazar, Andrew P. Lengyel, Ernst
Copyright Year	2011
Abstract	PURPOSE To understand the functional and preclinical efficacy of targeting the urokinase plasminogen activator receptor (u-PAR) in ovarian cancer. EXPERIMENTAL DESIGN 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. RESULTS 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. CONCLUSIONS 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.
Starting Page	2846
Ending Page	2851
Page Count	6
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/17/3/459.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2011/01/21/1078-0432.CCR-10-2258.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2010/12/11/1078-0432.CCR-10-2258.full.pdf
PubMed reference number	21149615v1
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-10-2258
DOI	10.1158/1078-0432.ccr-10-2258
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume Number	17
Issue Number	3
Language	English
Access Restriction	Open
Subject Keyword	ATN-658 Apoptosis Cultured Cell Line Extracellular Matrix Fibroblast Growth Factor Receptors In Situ Nick-End Labeling Leukemia, B-Cell Malignant neoplasm of ovary Neoplasm Metastasis Neoplasms Omentum Patients Staining method Urokinase Plasminogen Activator Receptor Xenograft procedure Xenograft type of graft cancer cell caspase-3 cellular targeting ovarian neoplasm
Content Type	Text
Resource Type	Article