Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target.
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.
Sawada
Kenjiro
K
Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA.
Mitra
Anirban K
AK
Radjabi
A Reza
AR
Bhaskar
Vinay
V
Kistner
Emily O
EO
Tretiakova
Maria
M
Jagadeeswaran
Sujatha
S
Montag
Anthony
A
Becker
Amy
A
Kenny
Hilary A
HA
Peter
Marcus E
ME
Ramakrishnan
Vanitha
V
Yamada
S Diane
SD
Lengyel
Ernst
E
D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039482:Integrin alpha5 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000556:secondary*; D011379:Prognosis; D014162:Transfection
D014408:Biomarkers, Tumor; D015820:Cadherins; D039482:Integrin alpha5; D039081:Integrin alpha5beta1