PubMed · 14241138
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D D EVANS, D E EVANS, G S LEWIS, P J PALMER, D J WEYELL. 1964. GENOTROPIC AGENTS: STEROID BASIC ETHERS.. https://doi.org/10.1111/j.2042-7158.1964.tb07395.x
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Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. The cell adhesion molecule E-cadherin is frequently down-regulated or mutated in tumors. In addition to down-regulation of cell adhesion, degradation of the extracellular matrix by matrix metalloproteinases is necessary for tumor cell spread. To investigate a possible link between E-cadherin and matrix metalloproteinase 3 (MMP-3), we examined expression of MMP-3 in human MDA-MB-435S cells transfected with wild-type (wt) or three different tumor-associated mutant E-cadherin variants with alterations in exons 8 or 9, originally identified in gastric carcinoma patients. In the presence of wt E-cadherin, the MMP-3 protein level was decreased in cellular lysates and in the supernatant where a secreted form of the protein is detectable. Down-regulation of MMP-3 was not found in MDA-MB-435S transfectants expressing mutant E-cadherin variants which indicates that E-cadherin mutations interfere with the MMP-3 suppressing function of E-cadherin. The mechanism of regulation of MMP-3 by E-cadherin is presently not clear. We have previously found that cell motility is enhanced by expression of the mutant E-cadherin variants used in this study. Here, we found that application of the synthetic inhibitor of MMP-3 NNGH and small interfering RNA (siRNA) directed against MMP-3 reduce mutant E-cadherin-enhanced cell motility. Taken together, our results point to a functional link between MMP-3 and E-cadherin. MMP-3 is differentially regulated by expression of wt or mutant E-cadherin. On the other hand, MMP-3 plays a role in the enhancement of cell motility by mutant E-cadherin. Both observations may be highly relevant for tumor progression since they concern degradation of the extracellular matrix and tumor cell spread.
Ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Overexpression and high activity of matrix metalloproteinase-2 (MMP-2) are frequently associated with metastatic breast cancers and serve as a prognostic indicator of clinical outcome. MMP-2 is predominantly expressed in stromal fibroblasts and plays a pivotal role in regulating the invasive behavior of breast tumor cells. We hypothesized that ethanol may enhance the invasion of breast tumor cells by modulating the activity of fibroblastic MMP-2. With in vitro models (HS68 and CCD1056SK human fibroblasts), we showed that ethanol at physiologically relevant concentrations (50-200 mg/dl) activated MMP-2; conversely, at a higher concentration (400 mg/dl), it inhibited the MMP-2 activity. Consistently, conditioned medium collected from ethanol (50-200 mg/dl)-exposed fibroblasts markedly enhanced the invasive potential of breast cancer cells and mammary epithelial cells overexpressing ErbB2/HER2 (BT474, SKBR-3 and HB2(ErbB2) cells) but had little effect on cells with low ErbB2 levels (BT20 and HB2 cells). In contrast, conditioned medium obtained from ethanol (400 mg/dl)-treated fibroblasts inhibited cell invasion. Selective inhibitors of MMP-2 (SB-3CT and OA-Hy) eliminated ethanol-stimulated invasion, indicating that the effect of ethanol was mediated by MMP-2. Ethanol activated conventional PKCs and JNKs in fibroblasts; inhibitors of PKC (Go6850 and Go6976) and JNKs (SP600125) significantly inhibited ethanol-mediated MMP-2 activation as well as cell invasion, indicating that PKCs and JNKs play a role in ethanol-induced MMP-2 activation and cell invasion in vitro. Thus, ethanol-promoted breast cancer cell invasion may be mediated by the modulation of fibroblastic MMP-2.
The objective of this study was to determine the concentrations of an extended series of polycyclic aromatic hydrocarbons (PAHs) and nitrated PAHs in outdoor air samples collected in low-contaminated urban areas, affected mainly by traffic emissions, and to estimate in vitro mutagenic and dioxin-like toxicity of extracts from these samples. Data on concentrations of PAHs and toxic in vitro potencies were compared in extracts obtained by different sampling methods. PAHs and their derivatives were analysed by high performance liquid chromatography with diode array and fluorescence detection, as well as gas chromatography with mass spectrometry. The total sum of 39 PAHs under study ranged from 6.7 to 62.7 ng.m(-3); of this, the sum of 16 U.S. EPA priority PAHs in urban air samples ranged from 3.2 to 6.2 ng.m(-3). Phenanthrene was the prevalent PAH in all air samples tested, with concentrations up to 17.6 ng.m(-3), followed by fluorene, fluoranthene and pyrene present mostly in the gaseous phase. Also, other low molecular weight PAHs (with MW up to 228) were distributed mostly in gaseous phase. The particulate phase contained mostly carcinogenic PAHs, among which, benzo[a]pyrene, indeno[1,2,3-cd]pyrene and benzofluoranthenes were predominant compounds (with benzo[a]pyrene reaching levels up to 1.57 ng.m(-3)). Traffic emissions were confirmed as the major source of PAHs in the airborne samples due to the presence of elevated concentrations of benzo[ghi]perylene and coronene. The most abundant nitrated PAH derivatives were nitronaphthalenes, which were present exclusively in the vapor phase; 9-nitroanthracene, 9-nitrophenantrene and 3-nitrofluoranthene were associated mostly with particulate matter (PM(10)). Bioassays for detection of the Ah receptor-mediated activity and mutagenicity in vitro were used as a screen of potential adverse effects of air pollutants emitted from traffic. The major part of mutagenic and aryl hydrocarbon receptor (AhR)-mediated activities was found to be present in the PM(10) fraction. Although the PM(10) sampling technique was found to be a suitable method regarding the subsequent determination of mutagenic and AhR-mediated activities in vitro, relative toxic potencies, associated with low molecular weight PAHs (such as tumor promotion and other adverse effects), could be underestimated.