ABSTRACT
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.
Subject(s)
Cell Division/drug effects , Hydroxyproline/pharmacology , Mammary Neoplasms, Experimental/pathology , Animals , Collagen/analysis , Dose-Response Relationship, Drug , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/metabolism , Mice , Mice, Nude , Neoplasm Transplantation , Proliferating Cell Nuclear Antigen/analysis , Rats , Tissue Inhibitor of Metalloproteinase-1/genetics , Transplantation, Heterologous , Tumor Cells, CulturedSubject(s)
Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/prevention & control , Tissue Inhibitor of Metalloproteinase-1/blood , 9,10-Dimethyl-1,2-benzanthracene , Aging/blood , Animals , Enzyme-Linked Immunosorbent Assay , Female , Gelatinases/antagonists & inhibitors , Humans , Mammary Neoplasms, Experimental/chemically induced , Matrix Metalloproteinase 2 , Medroxyprogesterone Acetate , Metalloendopeptidases/antagonists & inhibitors , Mice , Mice, Transgenic , Tissue Inhibitor of Metalloproteinase-1/geneticsABSTRACT
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.
