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Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3-/- mice.
- Source :
-
Oncogene [Oncogene] 2006 Oct 19; Vol. 25 (49), pp. 6489-96. Date of Electronic Publication: 2006 May 15. - Publication Year :
- 2006
-
Abstract
- Identifying versatile inhibitors of metastasis that operate in multiple sites against distinct cancer cell types is important for designing novel therapeutics for metastasis. We show that multiple tissues of timp-3-/- mice are more susceptible to metastatic colonization. Overall, a 5-14-fold increase in liver and kidney colonization occurred by EL-4 lymphoma cells, and a twofold increase upon targeting B16F10 melanoma cells to the bone or lung of timp-3-/- mice. There was a general lack of macrophage or neutrophil localization to metastases in the liver, kidney and lung, and of osteoclasts to bone in both genotypes. Analysis of lung showed that proliferation or angiogenesis were unaltered within the metastatic colonies. Lung-trap assays revealed that initial tumor cell trapping was similar in the lung vasculature of timp-3-/- and wild-type mice. However, more tumor cells were found in timp-3-/- lungs at 48 and 96 h after tumor cell injection indicating more efficient extravasation and initial proliferation. Activation of pro-MMP-2 was greater in timp-3-/- lungs at these time points. These data demonstrate TIMP-3 functions to inhibit metastatic dissemination of diverse cancer cells to multiple organs. TIMP-3 regulates MMP-2 activation to limit tumor cell extravasation and subsequent colonization of the lung, without augmenting inflammatory cell response.
- Subjects :
- Animals
Cell Proliferation
Genetic Predisposition to Disease
Inflammation pathology
Kidney pathology
Kidney Neoplasms genetics
Kidney Neoplasms pathology
Lung metabolism
Lung pathology
Lung Neoplasms pathology
Matrix Metalloproteinase 2 metabolism
Melanoma, Experimental pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Invasiveness pathology
Neovascularization, Pathologic mortality
Skin Neoplasms pathology
Skin Neoplasms secondary
Lymphoma pathology
Melanoma, Experimental secondary
Neoplasm Metastasis genetics
Tissue Inhibitor of Metalloproteinase-3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 25
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 16702949
- Full Text :
- https://doi.org/10.1038/sj.onc.1209663