Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
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

  • Text
  • PDF
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

×

Figure 6

Single pretreatment of OvCa Cells with an MMP-2/-9 inhibitor or an MMP-2 antibody inhibits peritoneal metastases and increases survival.

Options: View larger image (or click on image) Download as PowerPoint
Proposed role of MMP-2 in early OvCa cell metastasis to the omentum and ...
(A) Prevention study. SKOV3ip1 cells (1 × 106) were pretreated with MMPI or cyclic peptide and injected i.p. into nude mice. After 28 days, the number of metastasis and tumor weight were determined. **P < 0.001. (B) Intervention study. SKOV3ip1 cells (1 × 106) were injected i.p. into nude mice. After 14 days of tumor growth, mice were treated with the MMPI 3 times per week for 3 weeks. After 28 days mice were sacrificed, the number of metastasis and tumor weight were determined. The columns represent the mean and the bars the SD. *P < 0.01. (C) Prevention study. SKOV3ip1 cells or HeyA8 cells (1 × 106) were pretreated with an MMP-2 antibody or the isotypic specific control antibody and then injected i.p. into nude mice. After 28 days mice were sacrificed, the number of metastasis and tumor weight were determined. **P < 0.001. (D) Survival in prevention and intervention studies. The treatment courses of the prevention and intervention studies were conducted as described above. Mice were sacrificed once they showed signs of distress, and Kaplan-Meier curves were calculated. (E) Tumor lysates from MMPI or control peptide treated mice were subjected to gelatin zymography as described in Figure 1B. (F) Sections of tumors from MMP-2 antibody or mIgG antibody–treated mice were stained with H&E, a Ki-67-specific antibody to detect proliferation, or a CD31-specific antibody to count microvessels. Scale bar: 100 μm.

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

Sign up for email alerts

Referenced in 6 patents
226 readers on Mendeley
1 readers on CiteULike
See more details