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

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

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

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,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,

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.

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

K Sawada,AK Mitra,AR Radjabi,V Bhaskar,EO Kistner,M Tretiakova,S Jagadeeswaran,A Montag,A Becker,HA Kenny,ME Peter,V Ramakrishnan,SD Yamada,E Lengyel,K Sawada,AK Mitra,AR Radjabi,V Bhaskar,EO Kistner,M Tretiakova,S Jagadeeswaran,A Montag,A Becker,HA Kenny,ME Peter,V Ramakrishnan,SD Yamada,E Lengyel,

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

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 68

Page Numbers: 2329-39

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Apr

YEAR: 2008

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

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LANGUAGE: eng

NlmUniqueID: 2984705

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

AFFILIATION: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA111882

ACRONYM: CA

MEDLINETA: Cancer Res

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