Data from Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via α<sub>5</sub>-Integrin, which Is a Therapeutic Target

Abstract

<div>Abstract<p>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 α<sub>5</sub>-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 <i>in vitro</i> and <i>in vivo</i> with an α<sub>5</sub>β<sub>1</sub>-integrin–blocking antibody. When E-cadherin is silenced, α<sub>5</sub>-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 α<sub>5</sub>-integrin, i.p. treatment with an α<sub>5</sub>β<sub>1</sub>-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 (<i>P</i> < 0.0005). α<sub>5</sub>-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 α<sub>5</sub>-integrin overexpression, and 39% had some level of α<sub>5</sub>-integrin expression. The median survival for patients with high α<sub>5</sub>-integrin levels was 26 months versus 35 months for those with low integrin expression (<i>P</i> < 0.05). Taken together, we have identified α<sub>5</sub>-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]</p></div>