Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATF/CREB family of eukaryotic transcription factors contain the bZIP structural motif and mediate their transcriptional activities via heterodimerization with ATF and AP-1 family members. Quenching of CREB-associated proteins by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreases radiation resistance of human melanoma cells. The purpose of this study was to determine the role of CREB in tumor growth and metastasis of human melanoma using KCREB. Highly metastatic MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analysed for changes in their tumorigenic and metastatic potential. Expression of KCREB in MeWo human cells decreased their tumorigenic and metastatic potential in nude mice compared with parental and control transfected cells. The KCREB-transfected cells displayed downregulation of 72 kDa collagenase type IV (MMP-2) mRNA expression and activity and decreased invasiveness through Matrigel-coated filters. Moreover, transcriptional activities mediated by the CAT gene driven by the MMP-2 promoter were decreased by 14-45-fold in KCREB-transfected cells. In addition, the cell-surface adhesion molecule MCAM/MUC18 that is involved in metastasis of human melanoma was downregulated in the KCREB-transfected cells. These data indicate that, through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of the metastatic phenotype of human melanoma cells.
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PMID:Dominant-negative CREB inhibits tumor growth and metastasis of human melanoma cells. 936 24

The matrix metalloproteinase (MMP) inhibitor TIMP-2 has a high specificity for gelatinase A/MMP-2. An imbalance between gelatinase A and TIMP-2 in favor of enzymatic activity is linked to the degradation of the extracellular matrix (ECM) associated with several physiologic and pathologic events, including angiogenesis, invasion and metastasis. Since TIMPs are secreted molecules, they have the potential to be used for gene therapy of certain tumors. We transfected B16F10 murine melanoma cells, a highly invasive and metastatic cell line, with an expression vector harboring a cDNA encoding for human TIMP-2. The clones obtained were isolated and examined for TIMP-2 over-expression and changes in tumor cell phenotype. The amount of recombinant TIMP-2 produced correlated with a reduction in invasion. In an in vivo angiogenesis assay, TIMP-2-transfected clones showed reduced levels of blood vessel formation, and in vitro conditioned media from TIMP-2 transfectants showed diminished induction of endothelial cell migration and invasion. TIMP-2 over-expression limited tumor growth in vivo and neoangiogenesis when cells were injected subcutaneously in mice in the presence of Matrigel. However, TIMP-2 overexpressing clones were found to be more resistant to apoptosis than parental and control melanoma cells, while necrosis was increased. Our data confirm the role of TIMP-2 in the down-regulation of metastasis and angiogenesis but indicate a possible involvement in tumor cell survival.
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PMID:TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis. 946 15

Angiogenesis depends on both cell adhesion and proteolytic mechanisms. In fact, matrix metalloproteinase 2 (MMP-2) and integrin alphavbeta3 are functionally associated on the surface of angiogenic blood vessels. A fragment of MMP-2, which comprises the C-terminal hemopexin-like domain, termed PEX, prevents this enzyme binding to alphavbeta3 and blocks cell surface collagenolytic activity. PEX blocks MMP-2 activity on the chick chorioallantoic membrane where it disrupts angiogenesis and tumor growth. Importantly, a naturally occurring form of PEX can be detected in vivo in conjunction with alphavbeta3 expression in tumors and during developmental retinal neovascularization. Levels of PEX in these vascularized tissues suggest that it interacts with endothelial cell alphavbeta3 where it serves as a natural inhibitor of MMP-2 activity, thereby regulating the invasive behavior of new blood vessels.
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PMID:Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. 947 98

Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.
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PMID:Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives. 948 12

We have examined the effects of the synthetic matrix metalloproteinase inhibitor, batimastat (BB-94) and the angiotensin-converting enzyme inhibitor, captopril, on metalloproteinase activity of murine Lewis-lung-carcinoma cells (3LL) in vitro, and on local growth and lung metastasis of the same tumor implanted intramuscularly in syngeneic C57BL/6 mice. The effect of BB-94 and captopril on the survival of the 3LL-tumor-bearing mice was also examined. Here we report that captopril treatment resulted in decreased transcription and protein levels of gelatinase A by 3LL cells. Both BB-94 and captopril also prevented substrate degradation by gelatinase A and B released in conditioned medium by cultured cells. Treatment of tumor-bearing animals with BB-94 (i.p.) or captopril (in drinking water) resulted in significant inhibition of the mean tumor volume (25 and 33% respectively) and of the mean lung metastasis number (26 and 29% respectively). When both agents were given, they acted in synergy, resulting in 51 and 80% inhibition of tumor growth and metastasis. The survival time of the mice treated with both BB-94 and captopril was also significantly longer compared with the groups treated with each agent alone or with the vehicle. Our data support the hypothesis of an essential role of metalloproteinase(s) in the metastatic process. Moreover, blockade of invasion, angiogenesis and other processes mediated by metalloproteinases may underlie the anti-tumor and anti-metastatic effect of BB-94 and captopril and their combination. It is conceivable that this combination could be tested in selected clinical conditions as an adjuvant modality to cytotoxic therapy.
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PMID:Inhibition of gelatinase A (MMP-2) by batimastat and captopril reduces tumor growth and lung metastases in mice bearing Lewis lung carcinoma. 1032 30

Several lines of evidence suggest that tumor growth, angiogenesis, and metastasis are dependent on matrix metalloproteinase (MMP) activity. However, the lack of inhibitors specific for the type IV collagenase/gelatinase family of MMPs has thus far prevented the selective targeting of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) for therapeutic intervention in cancer. Here, we describe the isolation of specific gelatinase inhibitors from phage display peptide libraries. We show that cyclic peptides containing the sequence HWGF are potent and selective inhibitors of MMP-2 and MMP-9 but not of several other MMP family members. Our prototype synthetic peptide, CTTHWGFTLC, inhibits the migration of human endothelial cells and tumor cells. Moreover, it prevents tumor growth and invasion in animal models and improves survival of mice bearing human tumors. Finally, we show that CTTHWGFTLC-displaying phage specifically target angiogenic blood vessels in vivo. Selective gelatinase inhibitors may prove useful in tumor targeting and anticancer therapies.
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PMID:Tumor targeting with a selective gelatinase inhibitor. 1042 41

Matrix metalloproteinase 2 (MMP-2) facilitates tumor growth and metastasis in colon cancer. Although tumor cells may produce MMP-2, stromal cells, such as macrophages and fibroblasts, contribute significantly to MMP-2 synthesis in human tumors. We characterized four human colon cancer cell lines with differing biological behavior for MMP-2 expression. While the parent tumors from which the cell lines were derived all expressed MMP-2 mRNA, MMP-2 transcripts were detected in only one cell line, TF-17C, which is nontumorigenic in a nude mouse tumor model. TF-43C, which is tumorigenic and metastatic in the same tumor model, did not produce MMP-2, yet the tumors which arose from it after injection into nude mice did contain MMP-2 mRNA, suggesting a contribution from stromal cells. Co-culturing TF-43C with fibroblasts resulted in an increase in MMP-2 protein, whereas co-culturing with the nontumorigenic cell line TF-13Cm did not alter constitutive fibroblast MMP-2 secretion. Conditioned medium from TF-43C cells also stimulated fibroblast MMP-2 production. These data suggest that a soluble factor from TF-43C cells can stimulate fibroblast MMP-2 production and support the hypothesis that colon cancer cell interactions with stromal fibroblasts may be important determinants of tumor behavior in vivo.
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PMID:Evidence for tumor-host cooperation in regulating MMP-2 expression in human colon cancer. 1043 5

Expression of membrane type-1 matrix metalloproteinase (MT1-MMP) is closely correlated with tumor invasiveness. We investigated the effect of hyperthermia on the production of MT1-MMP in human fibrosarcoma HT-1080 cells. Heat shock at 42 degrees C suppressed the production and gene expression of MT1-MMP in HT-1080 cells. Heat shock-induced suppression of MT1-MMP production resulted in the inhibition of progelatinase A (proMMP-2) activation and the increased release of tissue inhibitor of metalloproteinases 2 from cell surface. In addition, in vitro tumor invasion assay in a Matrigel model indicated that heat shock inhibited the invasive activity of HT-1080 cells. These results suggest that heat shock preferentially suppresses the production of MT1-MMP and thereby inhibits proMMP-2 activation, events which subsequently inhibit tumor invasion. Therefore, heat shock shows an anti-invasive effect along with the known mechanism of inhibiting tumor growth.
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PMID:Heat shock suppresses membrane type 1-matrix metalloproteinase production and progelatinase A activation in human fibrosarcoma HT-1080 cells and thereby inhibits cellular invasion. 1054 12

Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.
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PMID:Suppression of angiogenesis by lentiviral delivery of PEX, a noncatalytic fragment of matrix metalloproteinase 2. 1103 4

The purpose of this study was to determine the role of CREB and its associated proteins in melanoma progression. We used MeWo human melanoma cells transfected with a dominant negative construct of CREB, KCREB. KCREB has a mutation in its DNA-binding domain and can not bind the CRE element. Expression of KCREB yields proper heterodimerization with CREB and its associated proteins, but the proteins associated with KCREB do not confer the same degree of transcriptional activity as they would in the case of wild-type CREB. Here, we demonstrate that expression of KCREB in MeWo melanoma cells leads to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain at least partially this effect of KCREB. The first, is one in which CREB and its associated proteins play an essential role in invasion. We showed that the invasive properties of KCREB-transfected MeWo cells were reduced due to the downregulation of the CRE-dependent expression of the type IV collagenase MMP-2 and the adhesion molecule MCAM/MUC18. In the second mechanism, CREB and its associated proteins act as survival factors for human melanoma cells. Here we demonstrated that expression of KCREB in MeWo cells rendered them susceptible to apoptosis induced by thapsigargin, which in turn increased the intracellular level of Ca2+. Thapsigargin induced CREB and ATF-1 phosphorylation and activated CRE-dependent transcription in MeWo cells. Collectively, our data demonstrate that CREB and its associated proteins play an important role in tumor growth and metastasis of human melanoma.
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PMID:Regulation of tumor growth and metastasis of human melanoma by the CREB transcription factor family. 1110 32


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