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The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin
Hilary A. Kenny, … , Lisa M. Coussens, Ernst Lengyel
Hilary A. Kenny, … , Lisa M. Coussens, Ernst Lengyel
Published March 13, 2008
Citation Information: J Clin Invest. 2008;118(4):1367-1379. https://doi.org/10.1172/JCI33775.
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Research Article Oncology Article has an altmetric score of 6

The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin

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Abstract

Most patients (80%) with ovarian cancer (OvCa) present with metastatic disease. Attachment of OvCa cells to peritoneum and omentum represents the first rate-limiting step for metastatic spread. Therefore, identifying factors regulating cell attachment in the abdominal cavity is critical to the development of therapeutic agents. We show here that MMP-2 expression was upregulated in OvCa cells upon attachment to their microenvironment. Downregulation of MMP-2 mRNA or pharmacological inhibition of MMP-2 proteolytic function, in both human OvCa primary cells and cell lines, reduced attachment of OvCa cells to a 3D organotypic model of metastatic OvCa, full human omentum or peritoneum, and in vivo to mouse peritoneum and omentum. Absence of MMP-2 in the host did not alter OvCa adhesion, as determined utilizing mice harboring homozygous null mutations in either the Mmp2 or Mmp9 genes. Conversely, adhesion induced upregulation of MMP-2 mRNA in OvCa cells. MMP-2 inhibition in OvCa cells through pharmacological or antibody treatment prior to i.p. dissemination in nude mice significantly decreased tumor growth and metastasis and extended survival. MMP-2 enhanced peritoneal adhesion of OvCa cells through cleavage of ECM proteins fibronectin (FN) and vitronectin (Vn) into small fragments and increased binding of OvCa cells to these FN and Vn fragments and their receptors, α5β1 and αVβ3 integrin. These findings indicate that MMP-2 expressed by metastatic OvCa cells functionally regulates their attachment to peritoneal surfaces.

Authors

Hilary A. Kenny, Swayamjot Kaur, Lisa M. Coussens, Ernst Lengyel

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Figure 2

An MMPI inhibits adhesion of OvCa cells to a 3D culture of human omentum, full human omentum and peritoneum, and mouse omentum.

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An MMPI inhibits adhesion of OvCa cells to a 3D culture of human omentum...
SKOV3ip1, HeyA8, or primary human OvCa cells (50,000) were fluorescently labeled and added to the 3D culture (A), a piece of full human omentum (B), or full human peritoneum (C). The 3D culture, the human omentum, and the human peritoneum were washed with PBS, adherent cells on the omentum were lysed with NP-40, and fluorescence intensity was measured with a fluorescence spectrophotometer. (D) SKOV3ip1 cells were fluorescently labeled and 4 × 106 were cells injected i.p. into nude mice (n = 3). The mice were sacrificed after 4 hours, omentum and peritoneum were lysed with NP-40, and fluorescence was measured. **P < 0.001. Each bar represents the mean of 3 wells and SD. Each graph is representative of at least 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 6 patents
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