RÉSUMÉ
With the ever-increasing evidence that the extracellular matrix (ECM) can stimulate tumor growth, it follows that inhibiting the synthesis of tumor-derived stroma may be a potential therapeutic target of cancer progression. The proline analog cis-hydroxyproline (CHP), an inhibitor of collagen deposition, was examined for its effects on the growth of clonal tumor cells that differentially produce type IV collagen and laminin. Two separate clones derived from rat mammary carcinoma cells that produce high and low amounts of type IV collagen and laminin were injected into the flanks of nude mice. Tumors in animals receiving CHP treatment grew faster than tumors in control animals receiving saline, although statistically not significant. Furthermore, upon administration of CHP to these clones in culture, increased proliferation rates of both cell types were observed. These results show that CHP is not useful in preventing stromal development and growth of rat mammary tumor xenografts.
Sujet(s)
Division cellulaire/effets des médicaments et des substances chimiques , Hydroxyproline/pharmacologie , Tumeurs expérimentales de la mamelle/anatomopathologie , Animaux , Collagène/analyse , Relation dose-effet des médicaments , Régulation de l'expression des gènes tumoraux , Humains , Immunohistochimie , Tumeurs expérimentales de la mamelle/génétique , Tumeurs expérimentales de la mamelle/métabolisme , Souris , Souris nude , Transplantation tumorale , Antigène nucléaire de prolifération cellulaire/analyse , Rats , Inhibiteur tissulaire de métalloprotéinase-1/génétique , Transplantation hétérologue , Cellules cancéreuses en cultureSujet(s)
Tumeurs expérimentales de la mamelle/anatomopathologie , Tumeurs expérimentales de la mamelle/prévention et contrôle , Inhibiteur tissulaire de métalloprotéinase-1/sang , 7,12-Diméthyl-benzo[a]anthracène , Vieillissement/sang , Animaux , Test ELISA , Femelle , Gelatinases/antagonistes et inhibiteurs , Humains , Tumeurs expérimentales de la mamelle/induit chimiquement , Matrix metalloproteinase 2 , Acétate de médroxyprogestérone , Metalloendopeptidases/antagonistes et inhibiteurs , Souris , Souris transgéniques , Inhibiteur tissulaire de métalloprotéinase-1/génétiqueRÉSUMÉ
We recently reported enhanced tumor growth and stimulation of vascular endothelial growth factor (VEGF) expression in rat mammary carcinoma cells transfected with a human tissue inhibitor of metalloproteinases-1 (hTIMP-1) cDNA (1). In the present study, we examined if the composition of the stroma was altered in the tumors with the highest hTIMP-1 production. Immunohistological examination revealed increased amounts of the basement membrane (BM) components, type IV collagen and laminin, in the hTIMP-1 overexpressing tumors compared to that of the control. In vitro studies also revealed upregulation of type IV collagen and laminin gene expression associated with the hTIMP-1 overexpression. Endogenous RNA levels of rat TIMP-1 and the rat matrix metalloproteinases (MMPs), MMP-2, MMP-3, and MMP-9, were not affected by the hTIMP-1 transfection, suggesting that the increase in BM deposition was not a result of decreased collagenolytic activity. This is the first report to show an association between overexpression of TIMP-1 and increased tumor BM matrix production through stimulation of type IV collagen and laminin gene expression.