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Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via ₅-Integrin, which Is a Therapeutic Target

¹ Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology, ² Health Studies, ³ Pathology, ⁴ Ben May Department for Cancer Research, and ⁵ Committee on Cancer Biology, University of Chicago, Chicago, Illinois and ⁶ PDL BioPharma, Fremont, California

Requests for reprints: Ernst Lengyel, University of Chicago, Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, MC 2050, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: 773-7026722; Fax: 773-7025411; E-mail: elengyel{at}uchicago.edu.

Key Words: ovarian cancer • prognosis • metastasis • 5β1-integrin • E-cadherin • EGFR

E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of ₅-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an ₅β₁-integrin–blocking antibody. When E-cadherin is silenced, ₅-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1–mitogen-activated protein kinase–dependent signaling pathway and not through the canonical E-cadherin/β-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of ₅-integrin, i.p. treatment with an ₅β₁-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). ₅-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had ₅-integrin overexpression, and 39% had some level of ₅-integrin expression. The median survival for patients with high ₅-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified ₅-integrin up-regulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients. [Cancer Res 2008;68(7):2329–39]

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