This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Roy, M. Articles by Libert, C. Search for Related Content PubMed PubMed Citation Articles by Van Roy, M. Articles by Libert, C.

Research Articles: Therapeutics, Targets, and Development

Involvement of specific matrix metalloproteinases during tumor necrosis factor/IFN–based cancer therapy in mice

¹ Department of Molecular Biomedical Research, VIB, ² Department of Molecular Biology, Ghent University, Ghent, Belgium; ³ University of Washington School of Medicine, Seattle, Washington; ⁴ Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain; and ⁵ Harvard Medical School, Boston, Massachusetts

Requests for reprints: Claude Libert, Department for Molecular Biomedical Research, VIB-Ghent University, Technologiepark 927, 9052 Ghent (Zwijnaarde), Belgium. Fax: 32-9-331-3609. E-mail: Claude.Libert{at}dmbr.ugent.be

Abstract

The potent antitumor activity of tumor necrosis factor (TNF) in combination with IFN- 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/IFN-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/IFN-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/IFN treatment. Using MMP-deficient or double-deficient mice, we have shown a mediating role for MMP-3 during TNF/IFN 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/IFN, but that rather, broad-spectrum MMP inhibitors will be required. [Mol Cancer Ther 2007;6(9):2563–71]

Grant support: Fund for Scientific Research (FWO)–Flanders, Interuniversity Attraction Poles (IUAP) Program of the Belgian Science Policy, Vereniging voor Kankerbestrijding, Belgium, the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen), CICYT-Spain, Fundacion M. Botín, and European Union (Cancer Degradome-FP6).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B. Wielockx is currently at the Department of Pathology, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Received 1/ 9/07; revised 5/ 8/07; accepted 7/12/07.

This article has been cited by other articles:

				A. Gutierrez-Fernandez, A. Fueyo, A. R. Folgueras, C. Garabaya, C. J. Pennington, S. Pilgrim, D. R. Edwards, D. L. Holliday, J. L. Jones, P. N. Span, et al. Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion Cancer Res., April 15, 2008; 68(8): 2755 - 2763. [Abstract] [Full Text] [PDF]