Involvement of specific matrix metalloproteinases during tumor necrosis factor/IFNgamma-based cancer therapy in mice.
The potent antitumor activity of tumor necrosis factor (TNF) in combination with IFN-gamma can only be applied in local regimens due to their strong proinflammatory properties. It has been shown that the broad-spectrum matrix metalloproteinase (MMP) inhibitor BB-94 protects against TNF/IFNgamma-induced toxicity without blocking the antitumor effect. Here, we tried to explain this protective role of BB-94 and sought to assign roles to specific MMPs in TNF/IFNgamma-induced toxicity. By studying the expression of MMP genes in different organs and in the tumor, we observed that the expression levels of MMP-7, MMP-8, MMP-9, and MMP-12 and tissue inhibitor of metalloproteinase-4 are clearly up-regulated in the liver during therapy. MMP-8 and MMP-9 are also up-regulated in the lung and kidney, respectively. In the tumor, most MMP genes are expressed, but only MMP-3 is up-regulated during TNF/IFNgamma treatment. Using MMP-deficient or double-deficient mice, we have shown a mediating role for MMP-3 during TNF/IFNgamma treatment in tumor-free and B16BL6 melanoma-bearing mice. By contrast, MMP-12 seemed to have some protective role in both models. However, because most phenotypes were not extremely outspoken, we have to conclude, based on the set of MMP-deficient mice we have studied, that inhibition of a single MMP will probably not increase the therapeutic value of TNF/IFNgamma, but that rather, broad-spectrum MMP inhibitors will be required.
Van Roy
Maarten
M
Department of Molecular Biomedical Research, VIB, Ghent University, Technologiepark 927, 9052 Ghent (Zwijnaarde), Belgium.
Van Lint
Philippe
P
Van Laere
Ineke
I
Wielockx
Ben
B
Wilson
Carole
C
López-Otin
Carlos
C
Shapiro
Stephen
S
Libert
Claude
C
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000627:therapeutic use*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000502:physiology; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000502:physiology; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000502:physiology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013876:Thiophenes / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000998:Antiviral Agents; D013876:Thiophenes; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; D007371:Interferon-gamma; C080985:batimastat; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12