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 Houghton, A. M. Articles by Shapiro, S. D. Search for Related Content PubMed PubMed Citation Articles by Houghton, A. M. Articles by Shapiro, S. D.

Macrophage Elastase (Matrix Metalloproteinase-12) Suppresses Growth of Lung Metastases

¹ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts and Departments of ² Pediatrics, ³ Medicine, and ⁴ Dermatology, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Steven D. Shapiro, Division of Pulmonary and Critical Care, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-7599; Fax: 617-732-7421; E-mail: sshapiro{at}rics.bwh.harvard.edu.

Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in macrophage elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely macrophage derived in this model, being expressed by tumor-associated macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics. (Cancer Res 2006; 66(12): 6149-55)

This article has been cited by other articles:

				K. Almholt, A. Juncker-Jensen, O. D. Laerum, K. Dano, M. Johnsen, L. R. Lund, and J. Romer Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model Mol. Cancer Ther., September 1, 2008; 7(9): 2758 - 2767. [Abstract] [Full Text] [PDF]

				P. M. McGowan and M. J. Duffy Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database Ann. Onc., September 1, 2008; 19(9): 1566 - 1572. [Abstract] [Full Text] [PDF]

				A. Nocito, F. Dahm, W. Jochum, J. H. Jang, P. Georgiev, M. Bader, R. Graf, and P.-A. Clavien Serotonin Regulates Macrophage-Mediated Angiogenesis in a Mouse Model of Colon Cancer Allografts Cancer Res., July 1, 2008; 68(13): 5152 - 5158. [Abstract] [Full Text] [PDF]

				B. Borghese, J.-D. Chiche, D. Vernerey, C. Chenot, O. Mir, G. Bijaoui, C. Bonaiti-Pellie, and C. Chapron Genetic polymorphisms of matrix metalloproteinase 12 and 13 genes are implicated in endometriosis progression Hum. Reprod., May 1, 2008; 23(5): 1207 - 1213. [Abstract] [Full Text] [PDF]

				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]

				R. A. Dean, G. S. Butler, Y. Hamma-Kourbali, J. Delbe, D. R. Brigstock, J. Courty, and C. M. Overall Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis Mol. Cell. Biol., December 15, 2007; 27(24): 8454 - 8465. [Abstract] [Full Text] [PDF]

				J. J. Partridge, M. A. Madsen, V. C. Ardi, T. Papagiannakopoulos, T. A. Kupriyanova, J. P. Quigley, and E. I. Deryugina Functional Analysis of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Differentially Expressed by Variants of Human HT-1080 Fibrosarcoma Exhibiting High and Low Levels of Intravasation and Metastasis J. Biol. Chem., December 7, 2007; 282(49): 35964 - 35977. [Abstract] [Full Text] [PDF]

				M. Llamazares, A. J. Obaya, A. Moncada-Pazos, R. Heljasvaara, J. Espada, C. Lopez-Otin, and S. Cal The ADAMTS12 metalloproteinase exhibits anti-tumorigenic properties through modulation of the Ras-dependent ERK signalling pathway J. Cell Sci., October 15, 2007; 120(20): 3544 - 3552. [Abstract] [Full Text] [PDF]

				J. S. Fridman, E. Caulder, M. Hansbury, X. Liu, G. Yang, Q. Wang, Y. Lo, B.-B. Zhou, M. Pan, S. M. Thomas, et al. Selective Inhibition of ADAM Metalloproteases as a Novel Approach for Modulating ErbB Pathways in Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1892 - 1902. [Abstract] [Full Text] [PDF]