Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production

H. Fukuda, S. Mochizuki, H. Abe, H. J. Okano, C. Hara-Miyauchi, Hideyuki Okano, N. Yamaguchi, M. Nakayama, J. D'Armiento, Y. Okada

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1615-1624
Number of pages10
JournalBritish Journal of Cancer
Volume105
Issue number10
DOIs
Publication statusPublished - 2011 Nov 8

Fingerprint

Endostatins
Matrix Metalloproteinase 13
Melanoma
Neoplasm Metastasis
Lung
Knockout Mice
Intravenous Injections
Endothelial Cells
Matrix Metalloproteinases
Immunoblotting
Cell Movement
Real-Time Polymerase Chain Reaction
Cultured Cells

Keywords

  • endostatin
  • matrix metalloproteinase-13
  • melanoma
  • metastasis
  • migration
  • SDF-1a

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production. / Fukuda, H.; Mochizuki, S.; Abe, H.; Okano, H. J.; Hara-Miyauchi, C.; Okano, Hideyuki; Yamaguchi, N.; Nakayama, M.; D'Armiento, J.; Okada, Y.

In: British Journal of Cancer, Vol. 105, No. 10, 08.11.2011, p. 1615-1624.

Research output: Contribution to journalArticle

Fukuda, H, Mochizuki, S, Abe, H, Okano, HJ, Hara-Miyauchi, C, Okano, H, Yamaguchi, N, Nakayama, M, D'Armiento, J & Okada, Y 2011, 'Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production', British Journal of Cancer, vol. 105, no. 10, pp. 1615-1624. https://doi.org/10.1038/bjc.2011.431
Fukuda, H. ; Mochizuki, S. ; Abe, H. ; Okano, H. J. ; Hara-Miyauchi, C. ; Okano, Hideyuki ; Yamaguchi, N. ; Nakayama, M. ; D'Armiento, J. ; Okada, Y. / Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production. In: British Journal of Cancer. 2011 ; Vol. 105, No. 10. pp. 1615-1624.
@article{27edabda3cc7472d889085288e0f9c18,
title = "Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production",
abstract = "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. Conclusion: 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.",
keywords = "endostatin, matrix metalloproteinase-13, melanoma, metastasis, migration, SDF-1a",
author = "H. Fukuda and S. Mochizuki and H. Abe and Okano, {H. J.} and C. Hara-Miyauchi and Hideyuki Okano and N. Yamaguchi and M. Nakayama and J. D'Armiento and Y. Okada",
year = "2011",
month = "11",
day = "8",
doi = "10.1038/bjc.2011.431",
language = "English",
volume = "105",
pages = "1615--1624",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Host-derived MMP-13 exhibits a protective role in lung metastasis of melanoma cells by local endostatin production

AU - Fukuda, H.

AU - Mochizuki, S.

AU - Abe, H.

AU - Okano, H. J.

AU - Hara-Miyauchi, C.

AU - Okano, Hideyuki

AU - Yamaguchi, N.

AU - Nakayama, M.

AU - D'Armiento, J.

AU - Okada, Y.

PY - 2011/11/8

Y1 - 2011/11/8

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

KW - endostatin

KW - matrix metalloproteinase-13

KW - melanoma

KW - metastasis

KW - migration

KW - SDF-1a

UR - http://www.scopus.com/inward/record.url?scp=80755163534&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80755163534&partnerID=8YFLogxK

U2 - 10.1038/bjc.2011.431

DO - 10.1038/bjc.2011.431

M3 - Article

VL - 105

SP - 1615

EP - 1624

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 10

ER -