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Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis
B Fingleton1, T Vargo-Gogola, H C Crawford
1Department of Cancer Biology, Vanderbilt University School of Medicine, PRB 23rd and Pierce, Nashville, TN 37232-6840, USA. barbara.fingleton@mcmail.vanderbilt.edu
Abstract:
The matrix metalloproteinase matrilysin (MMP-7) has been demonstrated to contribute to tumor development. We have shown previously that members of the TNF family of apoptosis-inducing proteins are substrates for this enzyme, resulting in increased death pathway signaling. The goal of the current study was to reconcile the proapoptotic and tumor-promoting functions of matrilysin. In the human HBL100 and murine NMuMG cell lines that represent early stages of tumor progression and that express both Fas ligand and its receptor, exposure to matrilysin results in cell death that can be blocked by FasL neutralizing antibodies. Constitutive expression of matrilysin in these cell lines selects for cells with reduced sensitivity to Fas-mediated apoptosis as demonstrated both with a receptor-activating antibody and with in vitro activated splenocytes. Matrilysin-expressing cells are also significantly less sensitive to chemical inducers of apoptosis. We propose that the expression of matrilysin that has been reported at early stages in various tumor types can act to select cells with a significantly decreased chance of removal due to immune surveillance. As a result, these cells are more likely to acquire additional genetic modifications and develop further as tumors.
Insights
Matrilysin (MMP-7) promotes tumor development by reducing cancer cell sensitivity to apoptosis, allowing cells to evade immune surveillance and acquire mutations for further tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Matrilysin (MMP-7) is implicated in tumor development.
- TNF-family proteins are substrates for MMP-7, influencing apoptosis.
- MMP-7 exhibits both pro-apoptotic and tumor-promoting functions.
Purpose of the Study:
- To reconcile the dual roles of matrilysin (MMP-7) in apoptosis and tumor promotion.
- To investigate MMP-7's impact on cancer cell sensitivity to death receptor-mediated apoptosis.
Main Methods:
- Utilized human HBL100 and murine NMuMG cell lines representing early tumor progression.
- Assessed cell death upon matrilysin exposure, blocked by FasL neutralizing antibodies.
- Evaluated Fas-mediated apoptosis sensitivity in matrilysin-expressing cells using receptor-activating antibodies and splenocytes.
- Tested sensitivity to chemical apoptosis inducers in matrilysin-expressing cells.
Main Results:
- Matrilysin exposure induced cell death in HBL100 and NMuMG cells, inhibited by FasL antibodies.
- Constitutive matrilysin expression selected for cells with reduced sensitivity to Fas-mediated apoptosis.
- Matrilysin-expressing cells demonstrated significantly lower sensitivity to chemical apoptosis inducers.
Conclusions:
- Early-stage tumor expression of matrilysin (MMP-7) selects for apoptosis-resistant cells.
- This resistance may allow cells to evade immune surveillance, promoting tumor progression.
- MMP-7 contributes to tumor development by facilitating the acquisition of further genetic modifications.