Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein present on the cancer cell plasma membrane, enhances fibroblast synthesis of matrix metalloproteinases (MMPs). The demonstration that peritumoral fibroblasts synthesize most of the MMPs in human tumors rather than the cancer cells themselves has ignited interest in the role of EMMPRIN in tumor dissemination. In this report we have demonstrated a role for EMMPRIN in cancer progression. Human MDA-MB-436 breast cancer cells, which are tumorigenic but slow growing in vivo, were transfected with EMMPRIN cDNA and injected orthotopically into mammary tissue of female NCr nu/nu mice. Green fluorescent protein was used to visualize metastases. In three experiments, breast cancer cell clones transfected with EMMPRIN cDNA were considerably more tumorigenic and invasive than plasmid-transfected cancer cells. Increased gelatinase A and gelatinase B expression (demonstrated by in situ hybridization and gelatin substrate zymography) was demonstrated in EMMPRIN-enhanced tumors. In contrast to de novo breast cancers in humans, human tumors transplanted into mice elicited minimal stromal or inflammatory cell reactions. Based on these experimental studies and our previous demonstration that EMMPRIN is prominently displayed in human cancer tissue, we propose that EMMPRIN plays an important role in cancer progression by increasing synthesis of MMPs.
The DNA sequence of the secA gene, essential for protein export in Escherichia coli, was determined and found to encode a hydrophic protein of 901 amino acid residues with a predicted molecular weight of 101,902, consistent with its previously determined size and subcelular location. Sequence analysis of 9 secA(Ts) mutations conferring general protein export and secA regulatory defects revealed that these mutations were clustered in three specific regions within the first 170 amino acid residues of the SecA protein and were the result of single amino acid changes predicted to be severely disruptive of protein structure and function. The DNA sequence immdtely upstream of secA was shown to encode a previously inferred gene, gene X.
Osteopontin (OPN), a secreted acidic phosphoglycoprotein found in many tissues and body fluids, is produced in increased amounts in response to certain infections and after malignant transformation. In this study we examined the action of OPN on macrophage cytotoxicity and nitric oxide (NO) synthesis. A human OPN cDNA was cloned into the bacteriophage T7-based vector, pET8C, and the encoded protein purified from an induced culture of Escherichia coli carrying the plasmid. Recombinant OPN inhibited NO production by macrophage-like RAW264.7 cells stimulated with lipopolysaccharide plus interferon-gamma. OPN also inhibited the cytolytic activity of the activated macrophages toward NO-sensitive P815 mastocytoma cells, an action that was blocked by the NO synthase inhibitor, NG-monomethyl-L-arginine. Inhibition of NO production correlated with an OPN-dependent decrease in the abundance of inducible NO synthase mRNA. The shape of the dose-response curve, with a maximal effect over a narrow range of OPN concentrations, suggested a complex interaction of OPN with cell surface receptors. Our data support the hypothesis that tumor-cell-derived OPN functions to protect the tumor cells from macrophage-mediated destruction.
Osteopontin (OPN) serves both a cell attachment function and a cell signalling function via the alpha v beta 3 integrin. We have investigated the action on mammalian cells of recombinant OPN made both in E. coli and in human cells. In its cell signalling capacity it initiates a signal transduction cascade that includes changes in the intracellular calcium ion levels and the tyrosine phosphorylation status of several proteins including pp60src and components of focal adhesion complexes. Effects on gene expression include suppression of the induction of nitric oxide synthase by inflammatory mediators. OPN can also reduce cell peroxide levels, promote the survival of cells exposed to hypoxia, and inhibit the killing of tumor cells by activated macrophages.
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