Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis.
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.
Fingleton
B
B
Department of Cancer Biology, Vanderbilt University School of Medicine, PRB 23rd and Pierce, Nashville, TN 37232-6840, USA. barbara.fingleton@mcmail.vanderbilt.edu
Vargo-Gogola
T
T
Crawford
H C
HC
Matrisian
L M
LM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001940:Breast / Q000166:cytology; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D003208:Concanavalin A / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013154:Spleen / Q000166:cytology; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D019014:fas Receptor / Q000502:physiology
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D003208:Concanavalin A; D016685:Mitomycin; D003513:Cycloheximide; D020783:Matrix Metalloproteinase 7; D019311:Staurosporine