The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin
Authors
Discussion
Loading...
Member takes
Implication
Preclinical study demonstrates that tumor MMP-2 mediates peritoneal attachment in ovarian cancer models, indicating a therapeutic target to block metastatic colonization.
Key Points
- To determine how matrix metalloproteinase-2 (MMP-2) facilitates the initial attachment and metastatic colonization of ovarian cancer cells within the peritoneal cavity.
- Examined ovarian cancer cell adhesion to 3D organotypic models, human omentum/peritoneum, and mouse tissues following MMP-2 mRNA knockdown or pharmacological inhibition in primary cells and cell lines.
- Assessed the role of host-derived proteases using Mmp2- and Mmp9-null mice, and tested tumor growth and survival in nude mice after intraperitoneal challenge with MMP-2-inhibited ovarian cancer cells.
- MMP-2 expression was upregulated in ovarian cancer cells upon microenvironment attachment, while tumor MMP-2 inhibition reduced cell adhesion across in vitro, ex vivo human, and in vivo murine peritoneal models.
- Host-derived MMP-2 and MMP-9 deficiency failed to alter ovarian cancer cell adhesion, demonstrating that tumor-expressed MMP-2 specifically drives peritoneal attachment.
- Pretreatment of cancer cells with pharmacological inhibitors or neutralizing antibodies against MMP-2 reduced tumor burden and prolonged host survival by preventing MMP-2 cleavage of fibronectin and vitronectin and subsequent binding via alpha5beta1 and alphaVbeta3 integrins.
Cite This Study
Kenny et al. (2008) studied this question.