Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (approximately 10-fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, amongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were approximately 10-fold and approximately 15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immunoreactive PAI-1 was considerably elevated (> 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only approximately 2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (approximately 10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer.
Clin Exp Metastasis 1998 Apr
PMID:Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells. 956 38

The principal cause of death from most forms of cancer is metastatic disease. Cancer cells appear to grow quickly out of the control of the normal host regulatory mechanisms. Many factors contribute to this unrestrained proliferation, including increased metalloproteinase activity causing degradation of the extracellular matrix surrounding cancer cells, angiogenesis permitting easy access of the cells to the bloodstream and decrease or loss of programmed cell death, or apoptosis, an important mechanism for removal of abnormal or senescent cells. Treatment modalities targeted towards arresting cancer cell proliferation and spread are needed to improve the survival of patients with cancer. Vitamin D3, 1,25-dihydroxychole-calciferol D3, has been shown to induce apoptosis in the human breast cancer cell line, MCF-7. We have studied the effects of three concentrations of vitamin D3 on the human breast cancer cell line, MDA-MB-435, the human prostate cancer cell line, LNCaP, and a human osteosarcoma cell line, U20S. We report here that vitamin D3 strikingly inhibits cell proliferation and induces apoptosis in all three cell lines.
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PMID:Effects of vitamin D3 on proliferation of cancer cells in vitro. 957 Mar 87

The occurrence of solid tumors spreading through the body is a major concern for the clinicians. Moreover, in numerous cases, metastases exhibit a multidrug resistant (MDR) pattern. This dual characteristic still remains supported by few biological explanations. The purpose of our study was to compare invasive properties of sensitive and MDR MCF-7 cells. Spheroids were chosen as experimental model since they exhibit a number of characteristics (i.e. tridimensional structure) close to the growth of an in vivo tumor. MDR spheroids formed more compact structures compared to sensitive ones. In every experiment, spheroids made from sensitive cells were more resistant to doxorubicin than the same cells grown as monolayers, a characteristic not observed with MDR cells. On an other hand, a form of multicellular resistance appeared in spheroids of sensitive cells, a fact which was not present in MDR spheroids. Incubation of MDR spheroids in Boyden's chambers put in evidence increased motility and invasive properties through Matrigel which were not present in sensitive MCF-7 cells. Zymograms of culture media and membrane extracts were performed in polyacrylamide gels. Two metalloproteases, progelatinases A et B were detected in culture media conditioned by monolayers and spheroids of both sensitive and resistant cells. In contrast, 2 unidentified serine proteases were detected only in media conditioned by spheroids of both cell types. An intense band of pro-MMP2 was present only in membrane extracts from MDR spheroids. Taken altogether, these results demonstrate that spheroids of MDR cells exhibit a number of properties which could lead to an increased ability to form metastases.
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PMID:[Detection of metastatic activity of the MCF-7 multidrug resistant cell line cultured in spheroids]. 967 58

Breast cancer cell lines vary in invasive behavior and one highly invasive cell line (MDA-MB-231) proteolytically degrades extracellular matrix with invadopodia (Thompson et al. 1992, J Cell Physiol, 150, 534-44; Chen et al 1994, Breast Cancer Res Treat, 31, 217-26). Invadopodial proteolysis of extracellular matrix is thought to be necessary for invasion; however, this has not been demonstrated directly. To obtain such evidence, normal (HBL-100) and malignant (MCF-7, MDA-MB-231) breast cells were evaluated for invadopodial proteolysis of extracellular matrix and invasive behavior. We report that invadopodial proteolysis of immobilized fibronectin is positively correlated with invasion of cells into type I collagen gels. Moreover, reducing the proteolytic activity of invadopodia with the metalloproteinase inhibitor, batimastat (BB-94), also decreases invasion indicating that breast cancer cell invasion is dependent upon proteolytically active invadopodia.
Clin Exp Metastasis 1998 Aug
PMID:Proteolysis of extracellular matrix by invadopodia facilitates human breast cancer cell invasion and is mediated by matrix metalloproteinases. 987 98

The human cell-surface antigen epithelial glycoprotein-2 recognized by the monoclonal antibody MOC-31 is an epithelial tumour-associated glycoprotein expressed in non-squamous carcinomas. MOC-31 immunoreactivity was investigated in human breast, colon, ovarian and lung cancer cell lines, grown either in vitro or in severe combined immunodeficient (SCID) mice as solid tumours and/or metastases. Three of four small-cell lung cancer cell lines (NCI-H69, OH3 and SW2) and three of four ovarian cancer cell lines (SoTu 1, 3 and 4) expressed epithelial glycoprotein-2. In contrast, all three breast (MCF-7, BT20, T47D) and all three colon (HT29, CACO2, SW480) cancer cell lines strongly reacted with monoclonal antibody MOC-31. A notable difference in MOC-31 immunoreactivity was observed in spontaneously formed lung metastases of HT29 colon cancer cells. Whereas larger metastases (> 30 cells) reacted with a similar staining pattern to the primary tumour, smaller metastases did not. These findings indicate that differentiation processes during the epithelial-mesenchymal transition occur in metastases, which lead to a transient loss of epithelial glycoprotein-2 expression during the migratory and early post-migratory period. This loss of antigen expression indicates that the process of metastases formation is a regulatory event, and this transient loss of antigen expression might represent a potential obstacle to antibody-based therapy in the setting of minimal residual disease.
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PMID:Epithelial glycoprotein-2 expression is subject to regulatory processes in epithelial-mesenchymal transitions during metastases: an investigation of human cancers transplanted into severe combined immunodeficient mice. 987 99

Carcinoma of the breast is a leading hormone-dependent malignancy, resulting in a high rate of morbidity and mortality. During the complex multi-step process of tumor promotion, this common cancer is initiated as hormone-responsive (HR), non-metastatic cancer, followed by a gradual transition into a highly metastatic hormone-insensitive (HI) variety which lacks the functional estrogen receptor. This transition of cancer cells causes them to become refractory to hormonal treatment. Urokinase (uPA), a member of the serine protease family has been implicated in the progression of several malignancies including breast cancer. In the current study, we have examined the correlation between hormone sensitivity and uPA expression in HR normal mammary epithelial cells (HMEC) and in MCF-7 and T-47D breast cancer cell lines. Comparison was made with HI breast cancer cells MDA-231. uPA mRNA expression was seen only in the highly invasive, HI breast cancer cells MDA-231. Lack of uPA expression in HR normal (HMEC) and in minimally invasive, HR cells (MCF-7 and T-47D) was due to transcriptional suppression of uPA gene expression as determined by nuclear run-off assays. Since alteration of the DNA methylation status of CpG island in the 5' sequence of oncogenes and tumor suppressor genes has been demonstrated to change their expression, we examined DNA methylation as a potential molecular mechanism for regulating uPA gene transcription in these cancer cells. Southern blot analysis using methylation sensitive enzymes revealed that CpG island of uPA gene are methylated in HR, HMEC, MCF-7 and T-47D cells, whereas they are hypomethylated in HI and MDA-231 cells. Treatment of HR MCF-7 cells with cytosine DNA methyltransferase inhibitor 5' azacytidine caused a dose-dependent induction of uPA mRNA due to demethylation of the CpG island of the uPA gene which led to increased invasive ability of these HR cancer cells. Our results demonstrate that DNA methylation can regulate the transcription of the uPA gene to alter the invasive behaviour of these HR breast cancer cells.
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PMID:Transcriptional regulation of urokinase (uPA) gene expression in breast cancer cells: role of DNA methylation. 1020 60

Although in the past 10 years paclitaxel has emerged as a successful drug in cancer therapy, the overall response rate to this drug in patients with advanced metastatic disease remains low. Therefore, an understanding of the mechanism of the effect of paclitaxel on inducing apoptosis and the discovery of new ways to enhance the effect of paclitaxel will be critical to improving the therapeutic efficiency of this drug. In the present studies, we have determined that the cyclin-dependent kinase inhibitor flavopiridol significantly enhances paclitaxel-induced apoptosis in the human gastric and breast cancer cell lines MKN-74 and MCF-7. Flavopiridol enhances paclitaxel-induced apoptosis only when administered after paclitaxel treatment. The activation of caspases, specifically caspase 3, is enhanced by flavopiridol on paclitaxel-treated cells. In accordance with this, poly(ADP-ribose) polymerase cleavage is enhanced in combination therapy relative to single-agent paclitaxel. The induction of apoptosis, activation of caspase 3, and poly(ADP-ribose) polymerase cleavage in treatment regimens with paclitaxel and paclitaxel followed by flavopiridol were reversed by treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which supports the notion that caspases are the executioners of apoptosis in these processes. Paclitaxel alone causes transient mitotic arrest with activation of cdc-2 kinase. Cells exit mitosis in a specific time window without cytokinesis, with a decrease in cdc-2 kinase activity and MPM-2 labeling. Flavopiridol accelerates the mitotic exit when administered after paclitaxel treatment in association with a more rapid decrease in MPM-2 labeling. In contrast, pretreatment with flavopiridol prevents cells from entering mitosis by inhibiting cdc-2 kinase activity, thus antagonizing the paclitaxel effect. Therefore, in this study we show that potentiation of paclitaxel-induced apoptosis by flavopiridol is highly sequence dependent, such that mitotic entry and cdc-2 kinase activation by paclitaxel must precede flavopiridol therapy, and the synergistic effect of flavopiridol on paclitaxel-treated cells is due to enhancement in caspase activation.
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PMID:Sequential dependent enhancement of caspase activation and apoptosis by flavopiridol on paclitaxel-treated human gastric and breast cancer cells. 1043 95

We have investigated the role of sialylation on cell-cell adhesion mediated by E-cadherin. Two MCF-7 human breast cancer cell variants were studied: MCF-7/AZ cells showed a spontaneous cell-cell adhesion in the fast and slow aggregation assay. whereas the adhesion deficient MCF-7/6 cell variant failed to form larger aggregates, suggesting that E-cadherin was not functional under the conditions of both assays. We measured the sialyltransferase activities using Galbeta1-3GalNAcalpha-O-benzyl and Galbeta1-4GlcNAcalpha-O-benzyl as acceptor substrates as well as mRNA levels of four sialyltransferases, ST3Gal I, ST3Gal III, ST3Gal IV, ST6Gal I, using multiplex RT-PCR in MCF-7 cell variants. The alpha2-6 and alpha2-3 sialylation of E-cadherin was investigated by immuno-blot using Sambucus nigra agglutinin and Maackia amurensis agglutinin. Compared to the adhesion-proficient MCF-7/AZ cells, the adhesion-deficient MCF-7/6 cell line apparently lacks ST6Gal I mRNA, has a lower ST3Gal I mRNA, a lower ST3Gal I sialyltransferase activity, and no alpha2-3 linked sialic acid moieties on E-cadherin. The potential anti-cancer drug 1-O-octadecyl-2-O-methylglycero-3-phosphocholine (ET-18-OMe, 48 h, 25 microg/ml) belonging to the class of alkyllysophospholipids restored the E-cadherin function in the adhesion-deficient MCF-7/6 cells as evidenced by an increased aggregation. ET-18-OMe caused loss of ST6Gal I mRNA in MCF-7/AZ cells but no changes of sialyltransferase activities or sialic acid moieties on E-cadherin could be observed. We conclude that Ca2+-dependent, E-cadherin-specific homotypic adhesion of MCF-7/AZ or MCF-7/6 cells treated with ET-18-OMe was not affected by sialylation of E-cadherin.
Clin Exp Metastasis 1999 May
PMID:Sialylation of E-cadherin does not change the spontaneous or ET-18-OMe-mediated aggregation of MCF-7 human breast cancer cells. 1043 10

Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption. Recently the osteoclast differentiation factor (ODF), better termed RANKL (receptor activator of NF-kappaB ligand), expressed by osteoblasts has been cloned as well as its cognate signaling receptor, receptor activator of NFkappaB (RANK), and a secreted decoy receptor osteoprotegerin (OPG) that limits RANKL's biological action. We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as surrogate osteoblasts to support osteoclast formation in coculture experiments, a result consistent with the fact that they do not express RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were added to cocultures of murine osteoblasts and hematopoietic cells, osteoclast formation resulted without the addition of any osteotropic agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo required exogenous agents for osteoclast formation. When MCF-7 cells overexpressing PTHrP were cultured with murine osteoblasts, osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no effect on RANKL or OPG mRNA levels when cultured with osteoblastic cells. Using a murine model of breast cancer metastasis to bone, we established that MCF-7 cells that overexpress PTHrP caused significantly more bone metastases, which were associated with increased osteoclast formation, elevated plasma PTHrP concentrations and hypercalcaemia compared with parental or empty vector controls.
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PMID:Breast cancer cells interact with osteoblasts to support osteoclast formation. 1049 98

The anticancer activity of the boronic acid dipeptide proteasome inhibitor PS-341 was examined in vitro and in vivo. PS-341 was a potent cytotoxic agent toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 microM on 24 h of exposure to the drug. In the EMT-6 tumor cell survival assay, PS-341 was equally cytotoxic administered p.o. or by i.p. injection up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colony-forming unit-granulocyte macrophage. PS-341 increased the tumor cell killing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Parent tumor, but was not able to overcome the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP tumors. In the tumor growth delay assay, PS-341 administered p.o. had antitumor activity against the Lewis lung carcinoma, both primary and metastatic disease. In combination, regimens with 5-fluorouracil, cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily additive tumor growth delays against the s.c. tumor and was highly effective against disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants continued investigation in cancer therapy.
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PMID:The proteasome inhibitor PS-341 in cancer therapy. 1049 43


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