Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production.
BACKGROUND
Although matrix metalloproteinases (MMPs) are implicated in tumourigenesis and cancer progression, the role of MMP-13 in melanoma cell metastases is poorly understood.


METHODS
Lung metastases of mouse melanoma B16BL6 cells were analysed in MMP-13 knockout (KO) and wild-type (WT) mice after intravenous injection. The mRNA and protein expression of MMP-13 in lung tissues was analysed by RT-PCR, real-time PCR, immunoblotting and immunohistochemistry. The expression of SDF-1α, CXCR4 and endostatin, and effects of endostatin to cultured melanoma cells and lung metastases were also studied.


RESULTS
Lung metastases of B16BL6 cells were significantly higher by 2.5-5.7-fold in MMP-13 KO mice than in WT mice. The expression of MMP-13 in WT mouse lung tissue was stimulated on day 1 after intravenous injection of the melanoma cells and MMP-13 was immunolocalised to vascular endothelial cells in the lungs. Endostatin formation, but not degradation of SDF-1α, in the lung tissue was associated with reduced lung metastasis in WT mice. Endostatin significantly inhibited migration of B16BL6 cells in monolayer wounding assay and remarkably suppressed Matrigel invasion and transendothelial invasion of the cells. In addition, lung metastases of melanoma cells in MMP-13 KO mice were reduced by intraperitoneal administration of endostatin.


CONCLUSIONS
Our results suggest that MMP-13 is overproduced by endothelial cells in the lungs with melanoma cells and has a protective role in lung metastasis by local generation of endostatin.
Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
H
H
Fukuda
S
S
Mochizuki
H
H
Abe
H J
HJ
Okano
C
C
Hara-Miyauchi
H
H
Okano
N
N
Yamaguchi
M
M
Nakayama
J
J
D'Armiento
Y
Y
Okada
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D043169:Endostatins / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D008175:Lung Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D043169:Endostatins; D053509:Matrix Metalloproteinase 13