In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.
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.
Masson
R
R
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Sant-e et de la Recherche M-edicale, Universit-e Louis Pasteur, Strasbourg, France.
Lefebvre
O
O
Noël
A
A
Fahime
M E
ME
Chenard
M P
MP
Wendling
C
C
Kebers
F
F
LeMeur
M
M
Dierich
A
A
Foidart
J M
JM
Basset
P
P
Rio
M C
MC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001943:Breast Neoplasms; D015197:Carcinogenicity Tests; D002273:Carcinogens; D003001:Cloning, Molecular; D004847:Epithelial Cells / Q000201:enzymology*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006801:Humans; D018878:Limb Buds / Q000166:cytology; D008297:Male; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019899:Paracrine Communication / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy; D011995:Recombination, Genetic; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases