Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine the effects of single unsaturated fatty acids (UFAs) or combinations on establishment of lung metastatic colonies, UFAs were administered orally to CDF1 mice bearing s.c. implants of the highly metastatic colon carcinoma 26. Oleic acid (OA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) demonstrated significant inhibition. In the case of DHA, this inhibitory potential was markedly reduced by co-administration of linoleic acid (LA) or EPA. Furthermore, while tumor cells treated with DHA showed a very low potential for lung colony formation when injected i.v., this again being partially reversed by co-administration of EPA. UFAs were found to be well absorbed into tumor tissues after oral administration, causing marked changes in relative levels, the arachidonic acid (AA) content, in particular, being markedly decreased by treatment with DHA or EPA, but not with DHA plus EPA or with DHA plus LA. Investigation of the gelatinolytic activity of the 57-kDa and 92-kDa isoforms of type-IV collagenase (MMP-2 and MMP-9, respectively) showed a clear reduction in the former by treatment with OA, while DHA, but not DHA plus LA or EPA, caused a decrease in the 92-kDa isoform, which was well correlated with AA content in tumor tissues (r = 0.900, p < 0.001). These results suggest that inhibition of metastasis due to treatment with OA and DHA might be due to depressed type-IV collagenase activity.
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PMID:Inhibitory effects of oleic and docosahexaenoic acids on lung metastasis by colon-carcinoma-26 cells are associated with reduced matrix metalloproteinase-2 and -9 activities. 938 79

The interaction between tumor cells and platelets facilitates the formation of metastasis in a way depending on the platelet aggregating ability of the tumor cell, but the mechanism remains to be elucidated. We have shown, by zymography and Western blot, that platelets greatly increased the secretion to the culture medium of MMP-9 by human mammary tumor cells MDA-MB231. This increase, which was dependent on protein synthesis, was caused by the platelet aggregates interacting with the tumor cells and not by the soluble factors released during platelet activation. Platelet subcellular fractionation allowed the localization of the inducing factor to the membrane fraction of the platelet granules, thus requiring platelet aggregation in order to become accessible on the platelet surface.
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PMID:Upregulation of MMP-9 expression in MDA-MB231 tumor cells by platelet granular membrane. 941 86

Bombesin is a potent inducer of signal trasduction pathways involved in the proliferation and invasion of androgen-insensitive prostatic tumor cells. This study examines the bombesin-mediated modulation of pericellular proteolysis, monitoring cell capability to migrate and invade basement membranes, using a chemo-invasion assay and analyzing protease production. The results suggest that bombesin could modulate the invasive potential of prostatic cell lines regulating secretion and cell-surface uptake of uPA and MMP-9 activation. In fact, in PC3 and DU145 cells but not in LNCaP cells, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) are induced by bombesin treatment. Bombesin also stimulates cell proliferation and this effect can be inhibited blocking uPA by antibodies and/or uPA inhibitor p-aminobenzamidine. Moreover, HMW-uPA induces cell proliferation in LNCaP cells, which do not produce uPA in the basal conditions, while PC3 and DU145 cell growth is supported by autocrine production of uPA. The increment of uPA activity on the external plasma membrane causes an increased pericellular plasmin activation. This effect is inhibited by antibodies against uPA and by p-aminobenzamidine. Similarly to EGF, bombesin stimulates secretion and activation of MMP-9 and TIMP-1 production. MMP-9 activation can be also obtained by HMW-uPA treatment, suggesting that plasma-membrane-bound uPA can start a proteolytic cascade involving MMP-9. Therefore, in in vitro assays, bombesin is able to modulate pericellular proteolysis and cell proliferation, differently distributing and activating proteolytic activities. This effect can be related to the "non-random" degradation of the extracellular matrix in which membrane uPA-uPAreceptor complexes could start bombesin-induced directional protein degradation during metastatic spread.
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PMID:In vitro regulation of pericellular proteolysis in prostatic tumor cells treated with bombesin. 945 4

Recent data suggest that patients with more hypoxic solid tumors are more likely to develop metastases and die. We speculated that upregulation of the metastasis-associated type IV collagenase MMP-9 (gelatinase B) by hypoxia might be correlated with the increased risk of distant failure in patients with hypoxic tumors. The promoter for MMP-9 contains consensus binding sites for the transcription factors NFkappaB and AP-1 which are upregulated under hypoxic conditions in HeLa cells and these transcription factors are critical to transcriptional activation of the MMP-9 gene. A variety of tumor cell lines were examined for induction of MMP-9 and the related protease MMP-2 under hypoxic conditions. Although hypoxia did upregulate MMP-9 in one alveolar rhabdomyosarcoma cell line, we were unable to demonstrate a consistent hypoxia-mediated increase in MMP-9 protein, RNA, or transcriptional activity measured with reporter constructs. These results suggest that MMP-9 expression is not directly affected by exposure to hypoxia in vitro.
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PMID:Studies of type IV collagenase regulation by hypoxia. 950 Feb 1

The 92-kDa type IV collagenase (MMP-9) is a metalloproteinase frequently localized in both tumor stroma and in tumor cells, particularly at the tumor invasion front. To explore the factors regulating transcriptional activation of MMP-9 in stromal cells, we used a model system in which fibroblast MMP-9 expression can be upregulated by cell-cell contact with metastatic transformed rat embryo cells. Using transient transfection of reporter gene constructs containing 5'-deleted or mutated MMP-9 promoter fragments, as well as electrophoretic mobility shift assays, the upstream NFkappaB, SP-1, and Ets sites and the downstream AP-1 site and retinoblastoma binding element were shown to be necessary for basal transcriptional activity of fibroblast MMP-9. In contrast only Ets or SP-1 appeared to be involved in contact-mediated induction of MMP-9. Mutation of the upstream AP-1 site increased both basal and contact-stimulated promoter activation. Deletion of the alternating purine-pyrimidine repeat in the downstream promoter decreased transcriptional activity. Together these findings suggest that Ets and SP-1 are the central transcriptional activators of MMP-9 gene expression in fibroblasts specifically responding to tumor cell contact, and that promoter conformation may regulate MMP-9 expression.
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PMID:Tumor cell contact mediated transcriptional activation of the fibroblast matrix metalloproteinase-9 gene: involvement of multiple transcription factors including Ets and an alternating purine-pyrimidine repeat. 951 98

During invasion and metastasis, cancer cells interact closely with the extracellular matrix molecules by attachment, degradation, and migration. We demonstrated previously the local degradation of fluorescently labeled gelatin matrix by cancer cells at invasive membrane protrusions, called invadopodia. Using the newly developed quantitative fluorescence-activated cell sorting-phagocytosis assay and image analysis of localized degradation of fluorescently labeled matrix, we document here that degradation and site-specific removal of cross-linked gelatin matrix is correlated with the extent of phagocytosis in human breast cancer cells. A higher phagocytic capacity is generally associated with increasing invasiveness, documented in other invasion and motility assays as well. Gelatin phagocytosis is time and cell density dependent, and it is mediated by the actin cytoskeleton. Most of the intracellular gelatin is routed to actively acidified vesicles, as demonstrated by the fluorescent colocalization of gelatin with acidic vesicles, indicating the intracellular degradation of the phagocytosed matrix in lysosomes. We show here that normal intracellular routing is blocked after treatment with acidification inhibitors. In addition, the need for partial proteolytic degradation of the matrix prior to phagocytosis is demonstrated by the inhibition of gelatin phagocytosis with different serine and metalloproteinase inhibitors and its stimulation by conditioned medium containing the matrix metalloproteinases MMP-2 and MMP-9. Our results demonstrate that phagocytosis of extracellular matrix is an inherent feature of breast tumor cells that correlates with and may even directly contribute to their invasive capacity. This assay is useful for screening and evaluating potential anti-invasive agents because it is fast, reproducible, and versatile.
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PMID:Phagocytosis of cross-linked gelatin matrix by human breast carcinoma cells correlates with their invasive capacity. 951 43

Intratumoral proteases are known to be involved in not only tumor cell invasion but also a variety of stromal reactions including neovascularization. In this study, we have examined the expression of matrix metalloproteinases (MMPs) by gelatin gel zymography and compared its expression with angiogenesis activities including the expression of several endothelial growth regulators and intratumoral microvessel density (MVD) in human breast cancer tissues. There was a significant correlation between activated MMP-2 expression and vascular endothelial growth factor (VEGF) expression (p=0.045). In addition, the expression of activated MMP-9 expression was significantly correlated with thymidine phosphorylase (TP) expression (p=0.0044). Pro MMP-9 expression tended to correlated with the increment of MVD (p=0.063). MMP-2 and MMP-9 expressions were frequently co-upregulated with endothelial growth regulators in human breast cancer tissues, which underlines the cooperative function of MMPs in neovascularization.
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PMID:Relationship between matrix metalloproteinase expression and tumor angiogenesis in human breast carcinoma. 953 74

Thyroid cancer can degrade basement membranes and invade tissues. This depends on a cascade of matrix metalloproteinases involving membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9. We analyzed the expression and role of these MMPs and their specific inhibitors TIMP-2 and TIMP-3 in human highly purified thyroid epithelial, C 643, HTh 74, SW 1736, and 8505 C thyroid carcinoma and thyroid-derived fibroblast cell cultures. The effect of phorbol-myristate acetate (PMA), and of the inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on MMP and TIMP mRNA levels were monitored by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) including an internal homologous competitor fragment. The highest MT1-MMP mRNA levels were found in thyroid-derived fibroblasts. The MT1-MMP mRNA expression was increased up to 10-fold by PMA, while all other growth factors tested had only negligible effects. The thyroid carcinoma cells themselves did not seem to play a crucial role in the production of MT1-MMP in thyroid tumors. Higher MMP-2 mRNA levels were found in all cell types investigated. The highest MMP-2 mRNA levels were determined in thyroid-derived fibroblasts and HTh 74 cells. We found a lack of MMP-2 response to IL-1, TNF-alpha, and phorbol esters. In unstimulated cells, MMP-9 mRNA was found near the detection limit or at low levels. In nearly all cell types, treatment with PMA, IL-1, and TNF-alpha caused an increase of the MMP-9 mRNA levels. The results of basal and stimulated MMP-2 and MMP-9 mRNA expression were confirmed at the protein level by gelatin zymography. TIMP-2 and TIMP-3 mRNAs were expressed at high levels. In contrast to the basal TIMP-3 mRNA levels, which varied over a great range, there were no striking differences the cell types from analyzing TIMP-2 mRNA. There were no or only slight stimulatory effects on TIMP-2 and TIMP-3 mRNA expression by IL-1, TNF-alpha, and PMA. Taken together, most enzymes of the MT-MMP/MMP class of proteases facilitating invasion of thyroid tumor cells seem to have been produced by fibroblasts, not by the tumor cells themselves. However, some dedifferentiated thyroid tumor cell lines may be capable of secreting some of these enzymes, as in the case of HTh 74 cells.
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PMID:mRNA levels of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 and of their inhibitors TIMP-2 and TIMP-3 in normal thyrocytes and thyroid carcinoma cell lines. 954 6

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
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PMID:Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket. 954 12

The matrix metalloproteinases (MMP) have been implicated in tumor invasion and metastasis both by immunohistochemical studies and from the observation that specific metalloproteinase inhibitors block tumor invasion and metastasis. Oligonucleotide primers for thirteen MMPs (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16) were optimized for use in RT-PCR. A semi-quantitative RT-PCR assay was used to determine the pattern of MMP mRNA expression in 84 normal and transformed or carcinogen transformed human cell lines and strains derived from different tissues. The results demonstrate one or more cell lines which express thirteen members of the MMP family. In addition, various oncogene transfected human fibroblast cell strains were analyzed for MMP expression. We confirm that over-expression of the H-ras oncoprotein correlates with up-regulation of MMP-9 and demonstrate that over-expression of v-sis also up-regulates MMP-9. A cell line immortalized following myc expression was found to up-regulate MMP-7, MMP-11 and MMP-13. Inappropriate expression of several MMP mRNAs was detected in breast, prostate, bone, colon and oral tumor derived cell lines. Identification of at least one cell line expressing each of thirteen MMPs and the observation of oncogene induced expression of several MMPs should facilitate analysis of the transcriptional mechanisms controlling each MMP.
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PMID:Overview of matrix metalloproteinase expression in cultured human cells. 955 Feb 65


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