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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) induces the expression of human stromelysin-1, a matrix metalloproteinase involved in tumor invasion and metastasis. Here it is shown that stromelysin-1 gene induction by PDGF depends on Ras and involves three previously identified promoter elements (the stromelysin-1 PDGF-responsive element (SPRE) site, the two head-to-head polyomavirus enhancer A-binding protein-3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During mitogenic induction, these responsive elements appear to be organized in two independent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result from specific element cross-talking. Interestingly, expression of a dominant negative mutant of Raf-1 significantly interfered with the induction through PEA3-AP-1 but not with that operating through SPRE-AP-1. Conversely, only the induction operating through SPRE-AP-1 was affected significantly by the expression of a dominant negative mutant of the atypical lambda/iota protein kinase C (lambda/iotaPKC). These data strongly suggest that the signal triggered by PDGF flows through Ras and bifurcates toward two distinct pathways, one operating through Raf and involving PEA3-AP-1 and the other one Raf-independent, operating through lambda/iotaPKC and SPRE-AP-1. Furthermore, we present evidence suggesting that the novel SPRE-binding transcription factor SPBP cross-couples with c-Jun to transactivate the SPRE site.
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PMID:Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene. 866 78

We examined the effects of the synthetic matrix metalloproteinase inhibitor batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival.
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PMID:Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). 866 19

The prognostic factors for esophageal cancer from the viewpoint of molecular biology are reviewed. Among several oncogenes and suppressor genes erbB, int2/hst1/Cyclin D1 and MDM2 gene amplifications are significant prognostic factors for esophageal cancer. The value of p53 mutation, and expression of matrix metalloproteinase (MMPs) in the prediction of patients' survival are controversial, so further research is needed. High expression of tumor proliferation-related factors (Ki67, PCNA, and AgNOR), abnormalities of adhesion molecule (E-Cadherin, alpha-Catenin), activation of autocrine mechanism of growth factor (EGFR-TGF alpha, EGF), and DNA ploidy pattern, which is thought to be the result of an accumulation of genomic abnormalities are also prognostic factors for esophageal cancer.
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PMID:[Prognostic factors for esophageal cancer--from the viewpoint of molecular biology]. 868 32

It has been reported that several genes may be good indicators for determining biological behavior, including the prognosis, of colorectal cancers. We have summarized these reported genes, such as tumor suppressor gene, oncogenes, metastasis suppressor gene, adhesion molecules, growth factors, proteinases, and others, including microsatellite instability. Some of the genes such as p53, DCC, c-met, or matrix metalloproteinase are considered to be reliable for determining biological aggressiveness. We introduced several interesting genes which we are focusing using cDNA subtraction library analysis. We hope that these genes are well combined for best analysis of the biological behavior of colorectal cancers and use for practical clinical analysis. In addition, we hope that novel important genes indicative for prognosis will be found.
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PMID:[Prognostic factors of colon cancer from a molecular biology standpoint]. 868 33

During progression towards malignancy, many tumor cells display changes in their repertoire of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The recent finding that many members of the MMPs are regulated by protooncogenes may explain the frequent observation of changes in MMP gene expression during progression of many tumor types. While studies involving enzymatic assays of MMPs are usually confined to one or a few MMPs, reverse transcription-PCR (RT-PCR) permitted the analysis of seven members of the MMP family and two members of the TIMP family in several normal and transformed cell lines. RT-PCR permitted us to confirm the observation that MMP-9 is activated following transformation and also to observe the previously unreported activation of MMP-7 in SV40-transformed cells. It has previously been found that MMP-1, -2, -3, -8, and -9 are upregulated by phorbol esters; we have found that MMP-10 is also upregulated by phorbol esters. The phorbol ester upregulation of MMP-1, -3, and -10 was found to be abolished in cells transformed by SV40 virus. Several studies have shown that MMP-1 is upregulated by an integrin-mediated signal transduction pathway. This study demonstrates that MMP-3 and MMP-10 are also regulated by integrin-mediated signal transduction and that upregulation by this pathway is abolished following SV40 transformation. In summary, the more global view of MMP expression afforded by RT-PCR indicates that MMP-1, -3, and -10 are regulated by both integrin-mediated signal transduction and phorbol esters. While fibroblasts and transformed bone cells express several members of the MMP gene family, several other cell types do not express MMPs.
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PMID:Regulation of matrix metalloproteinases following cellular transformation. 869 36

Matrilysin (MAT) is a member of the matrix metalloproteinase (MMP) family which is believed to degrade components of the extracellular matrix (ECM) during processes of tissue remodeling. Although MAT is similar to the stromelysins in its substrate specificity, and to interstitial collagenase in the crystal structure of its catalytic domain, this enzyme is unique in that it lacks the carboxy-terminal segments encoded by other MMP genes. Characterization of the human MAT gene has revealed that the promoter region contains typical MMP promoter elements such as AP-1 and PEA3, which mediate responsiveness to growth factors, oncogenes, and phorbol esters. Activated recombinant forms of human MAT cleave ECM and basement membrane proteins such as fibronectin, collagen type IV, laminin, and particularly elastin, entactin, and cartilage proteoglycan aggregates. Furthermore, MAT appears to mediate the proteolytic processing of other molecules (e.g. tumor necrosis factor alpha precursor, urokinase plasminogen activator). MAT is expressed in a variety of tumors ranging from adenomas to carcinomas and adenocarcinomas of the breast, colon, prostate, stomach, upper aerodigestive tract, lung, and skin, where it may be involved in tumor formation as well as the tissue degradation which accompanies tumor cell extravasation. Localization of MAT mRNA and protein to the tumor cells is unusual in that the majority of MMPs are produced in the stroma. This distinctive tissue-restricted pattern of MAT expression is a recapitulation of the expression pattern in normal human tissue, where MAT protein localizes to secretory and ductal epithelium in the endometrium and in various exocrine glands. In the mouse, high constitutive levels of MAT mRNA are found in epithelial cells in the uterus, small intestine, and extra-testicular ducts. Taken together, these findings suggest that MAT may have a specific role in normal gland and organ function, a possibility which can be explored further by the genetic manipulation of MAT levels in vivo.
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PMID:Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. 872

Microvessel density has been proposed as a prognostic factor in breast carcinoma. In paired samples of human breast carcinoma and the adjacent non-neoplastic tissue, proliferating microvessels were associated with in situ ductal and lobular carcinomas. In invasive carcinomas, the microvessels were located within the tumor stroma. Recombinant tissue inhibitor of metalloproteinases-1 (rTIMP-1) was produced in a baculovirus system to examine its effect on angiogenesis. When present as a molecule of 29 kDa, rTIMP-1 inhibited matrix metalloproteinase (MMP) activity. However, a 66 kDa aggregate of TIMP-1 did not block MMP activity, although it inhibited in vitro angiogenesis as the 29 kDa form did. Studies have been initiated to characterize the effects of overexpression of TIMP-1 on breast carcinoma cells. Preliminary findings show TIMP-1 mediated changes in morphology and downregulation of MMP activity. These findings suggest that the angiogenesis inhibitory activity of TIMP-1 is unrelated to its antimetalloproteinase activity and that TIMP-1 may affect cellular function in different ways.
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PMID:Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis. 874 92

The 92 kDa matrix metalloproteinase (gelatinase B, MMP-9) plays a major role in the facilitation of tumor metastasis and in inflammatory disorders characterized by excessive matrix protein destruction. MMP-9 is transcriptionally induced in multiple cell types by exposure to the inflammatory mediators bacterial endotoxin, interleukin-1 (IL-1) or tumor necrosis factor-alpha (TNF-alpha). CT-2519, (1-(5-isothiocyanatohexyl)-3,7-dimethylxanthine), a synthetic small molecule from an anti-inflammatory compound library, was evaluated for its effect on endotoxin and cytokine-induced MMP-9 synthesis by a monocytic leukemic cell line, THP-1, and a monocyte/macrophage line, RAW 264.7. CT-2519 dose-dependently inhibited endotoxin and cytokine-induced synthesis of MMP-9 by these cells. Furthermore, both MMP-9 secretion and matrix invasion by cells of a human fibrosarcoma cell line, HT-1080, were inhibited by CT-2519 in a dose-dependent manner. Northern blot analyses and studies utilizing MMP-9 promoter constructs indicated that the inhibitory action of CT-2519 occurs at the level of transcriptional suppression. Given the observation that cellular activation by endotoxin, IL-1 and TNF-alpha may be mediated, at least in part, through induction of certain species of phosphatidic acid (PA), the effect of CT-2519 on lipid levels was analyzed. CT-2519 effectively reduced endotoxin-mediated increases in particular cellular lipid levels. Pharmacologic modulation of cytokine-dependent gene products, such as MMP-9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory disorders.
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PMID:Pharmacological inhibition of gelatinase B induction and tumor cell invasion. 875 12

Tumor progression to the stage of metastasis may result in part from the selection of certain primary tumor cell clones which are phenotypically competent for survival, invasion, and growth at secondary sites. Selection for traits such as loss of growth inhibitory responses, acquisition of increased adhesiveness, increased local immunosuppression, and enhanced motility and collagenase activities likely contribute to cancer progression and may be regulated through the action of growth factors. The transforming growth factors (TGF-beta) family of growth factors has often been associated with these traits and tumor progression; therefore, elimination or subversion of TGF-beta-responsive pathways should be considered as a mechanistic framework for metastatic events. In this report, we have compared growth and extracellular matrix responses to TGF-beta in six metastatic and six primary tumor-derived cell lines in a mouse model of prostate cancer. We have found that tumor cell lines derived from focal pulmonary metastasis secreted relatively greater quantities of total TGF-betas, lost most or all TGF-beta1 growth inhibition, but responded to TGF-beta1 through induction of the type IV collagenase matrix metalloproteinase-9, whereas cell lines derived from tumors which proliferated at the primary site retained the growth inhibition but lacked collagenase activity. Synthesis of another extracellular matrix protein, plasminogen activator inhibitor 1, was stimulated by TGF-beta1 in both primary as well as metastatic tumors. These results suggest that acquisition of differential responses to the TGF-beta family could result in phenotypic traits which facilitate tumor metastasis from certain primary site clones.
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PMID:Transforming growth factor beta1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. 876 34

We examined production and tissue localization of matrix metalloproteinase (MMP)-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B), tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in human breast carcinomas. In more than half of the cases, MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 was on the carcinoma cell membranes as well, whereas MMP-3 was positively stained in less than 15% of the cases. MMP-1 staining in carcinoma cells was significantly higher in scirrhous carcinoma than in other types of carcinoma. MMP-9 expression was remarkably higher in the carcinoma cases with lymphnode metastasis than in the non-metastatic cases. MMP-3 was mainly expressed in T-lymphocytes infiltrated in the tumor stroma. Stromal fibroblasts were positive for all these MMPs except for MMP-3. The TIMP-1 levels released into the culture media by carcinoma tissues were significantly lower than those by fibroadenoma tissues, although there were no significant differences in the levels of MMP-1, MMP-2, MMP-9 and TIMP-2. Gelatin zymographical analyses showed that the activation rate of the zymogen of MMP-2 (proMMP-2) is significantly higher in the more advanced carcinoma group with lymphnode metastasis than in the metastasis-negative and fibroadenoma groups. These data indicate that MMP-1, MMP-2 and MMP-9 are highly expressed in human breast carcinoma tissue and suggest that activation of proMMP-2 may be an indicator of lymphnode metastasis of the breast carcinoma.
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PMID:Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. 876 24


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