Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target.

Abstract

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 alpha(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 alpha(5)beta(1)-integrin-blocking antibody. When E-cadherin is silenced, alpha(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/beta-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of alpha(5)-integrin, i.p. treatment with an alpha(5)beta(1)-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). alpha(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 alpha(5)-integrin overexpression, and 39% had some level of alpha(5)-integrin expression. The median survival for patients with high alpha(5)-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified alpha(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.

• Authors: Kenjiro Sawada, Anirban K Mitra, A Reza Radjabi, Vinay Bhaskar, Emily O Kistner, Maria Tretiakova, Sujatha Jagadeeswaran, Anthony Montag, Amy Becker, Hilary A Kenny, Marcus E Peter, Vanitha Ramakrishnan, S Diane Yamada, Ernst Lengyel
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 7 Pg. 2329-39 (Apr 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18381440 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Cadherins
• Integrin alpha5
• Integrin alpha5beta1

Topics

• Animals
• Biomarkers, Tumor (biosynthesis, metabolism)
• Blotting, Western
• Cadherins (antagonists & inhibitors, biosynthesis, metabolism)
• Cell Adhesion (physiology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Integrin alpha5 (biosynthesis, genetics, metabolism)
• Integrin alpha5beta1 (metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Ovarian Neoplasms (enzymology, genetics, metabolism, pathology)
• Peritoneal Neoplasms (enzymology, metabolism, secondary)
• Prognosis
• Transfection