Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases.
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.
Houghton
A McGarry
AM
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Grisolano
Jay L
JL
Baumann
Mary L
ML
Kobayashi
Dale K
DK
Hautamaki
R Dean
RD
Nehring
Leslie C
LC
Cornelius
Lynn A
LA
Shapiro
Steven D
SD
D043168:Angiostatins / Q000096:biosynthesis; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000201:enzymology* / Q000556:secondary*; D048708:Cell Growth Processes / Q000502:physiology; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D016676:Macrophages, Alveolar / Q000201:enzymology*; D008297:Male; D053508:Matrix Metalloproteinase 12; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D010641:Phenotype
D043168:Angiostatins; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12