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In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.
- Source :
-
The Journal of cell biology [J Cell Biol] 1998 Mar 23; Vol. 140 (6), pp. 1535-41. - Publication Year :
- 1998
-
Abstract
- Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.
- Subjects :
- 9,10-Dimethyl-1,2-benzanthracene
Animals
Breast Neoplasms
Carcinogenicity Tests
Carcinogens
Cloning, Molecular
Extracellular Matrix physiology
Female
Fibroblasts cytology
Fibroblasts enzymology
Humans
Limb Buds cytology
Male
Matrix Metalloproteinase 11
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Nude
Neoplasm Transplantation
Phenotype
Pregnancy
Recombination, Genetic
Tumor Cells, Cultured cytology
Tumor Cells, Cultured enzymology
Epithelial Cells enzymology
Metalloendopeptidases genetics
Metalloendopeptidases metabolism
Paracrine Communication physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9525
- Volume :
- 140
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 9508784
- Full Text :
- https://doi.org/10.1083/jcb.140.6.1535