Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target

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

Research output: Contribution to journalArticle

249 Scopus citations

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 α5-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 α5β1- integrin-blocking antibody. When E-cadherin is silenced, α5- 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 A5-integrin, i.p. treatment with an α5β1-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). α5-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 α5-integrin overexpression, and 39% had some level of α5-integrin expression. The median survival for patients with high α5-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified α5-integrin upregulation 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.

Original languageEnglish (US)
Pages (from-to)2329-2339
Number of pages11
JournalCancer Research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sawada, K., Mitra, A. K., Radjabi, A. R., Bhaskar, V., Kistner, E. O., Tretiakova, M., Jagadeeswaran, S., Montag, A., Becker, A., Kenny, H. A., Peter, M. E., Ramakrishnan, V., Yamada, S. D., & Lengyel, E. (2008). Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target. Cancer Research, 68(7), 2329-2339. https://doi.org/10.1158/0008-5472.CAN-07-5167