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)

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2',4,6,6'-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2',4,6,6'-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH(2)-terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH(2)-terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl-induced MMP-3 expression and accelerated transendothelial migration of tumor cells.
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PMID:Interplay between epidermal growth factor receptor and Janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells. 1677 83

Metastasis, the aggressive spread of a malignant tumor to distant organs, is a major cause of death in cancer patients. Despite this critical role in cancer outcomes, the molecular mechanisms that control this process are just beginning to be understood. Metastasis is largely dependent upon the ability of tumor cells to invade the barrier formed by the basement membrane and to migrate through neighboring tissues. This review will summarize the evidence that tumor cell invasion is the result of oncogene-mediated signal transduction pathways that control the expression of a specific set of genes that together mediate tumor cell invasion. We focus on the role of the transcription factor AP-1 to both induce the expression of genes that function as invasion effectors and repress other genes that function as invasion suppressors. This identifies AP-1 as a critical regulator of a complex program of gene expression that defines the invasive phenotype.
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PMID:Transcription factors control invasion: AP-1 the first among equals. 1679 38

Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-alpha modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-alpha in CD44 expression of cancer cells. Recent clinical work using TNF-alpha inhibitors for the treatment of ovarian cancer makes the study of TNF-alpha interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-alpha on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-alpha differentially modulates the expression of CD44 in TNF-alpha-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-alpha up-regulation of CD44 expression was dependent on the activation of c-Jun NH(2)-terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-alpha failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.
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PMID:Tumor necrosis factor-alpha differentially modulates CD44 expression in ovarian cancer cells. 1690 92

Basal cell carcinoma (BCC) is one of the most common skin neoplasms in humans and is usually characterized by local aggressiveness with little metastatic potential, although deep invasion, recurrence, and regional and distant metastases may occur. Here, we studied the mechanism of BCC invasion. We found that human BCC tissues and a BCC cell line had significant expression of CXCR4, which was higher in invasive than non-invasive BCC types. Further, of 19 recurrent tumors among 390 BCCs diagnosed during the past 12 years, 17/19 (89.5%) had high CXCR4 expression. We found that the CXCR4 ligand, stromal-cell-derived factor 1alpha (SDF-1alpha), directed BCC invasion and that this was mediated by time-dependent upregulation of mRNA expression and gelatinase activity of matrix metalloproteinase-13 (MMP-13). The transcriptional regulation of MMP-13 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the AP-1 component c-Jun. Finally, CXCR4-transfected BCC cells injected into nude mice induced aggressive BCCs that co-expressed CXCR4 and MMP-13. The identification of SDF-1alpha/CXCR4 as an important factor in BCC invasiveness may contribute insight into mechanisms involved in the aggressive potential of human BCC and may improve therapy for invasive BCCs.
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PMID:Involvement of matrix metalloproteinase-13 in stromal-cell-derived factor 1 alpha-directed invasion of human basal cell carcinoma cells. 1709 30

Tumor metastasis to sentinel lymph nodes represents the first step of tumor dissemination in most human cancers and serves as a major prognostic indicator for disease progression. Recent studies have revealed that tumors can actively induce the formation of lymphatic vessels, and that tumor lymphangiogenesis is correlated with lymph node metastasis in experimental cancer models and in several types of human cancers. Metastatic tumor cells may continue to promote lymphatic vessel growth even after their metastasis to sentinel lymph nodes, likely promoting further cancer spread. Vascular endothelial growth factor-C (VEGF-C) and VEGF-D were the first specific lymphangiogenesis factors identified, acting predominantly via VEGF receptor-3 (VEGFR-3) that is expressed by lymphatic endothelial cells, and a large number of clinical studies have shown a correlation between tumor expression of VEGF-C or VEGF-D and lymph node metastasis. VEGFR-3 activation promotes lymphatic endothelial cell proliferation, migration, and survival via the extracellular signal-regulated kinase 1/2, the phosphatidylinositol 3-kinase/AKT, and the c-Jun NH(2)-terminal kinase 1/2 pathways. Additional tumor lymphangiogenesis factors have been recently identified, including VEGF-A. Importantly, blockade of the VEGFR-3 pathway by specific antibodies, by soluble receptor constructs, and by small molecule kinase inhibitors efficiently inhibits experimental tumor lymphangiogenesis and metastasis and might also represent a novel therapeutic avenue for the treatment of human cancers.
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PMID:Pathways targeting tumor lymphangiogenesis. 1714 2

The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are a family of dual-specificity protein phosphatases that dephosphorylate both phospho-threonine and phospho-tyrosine residues in MAP kinases, including the c-Jun N-terminal protein kinase (JNK)/stress-activated protein kinase (SAPK), the p38 MAPK, and the extracellular signal-related kinase (ERK). Since phosphorylation is required for the activation of MAP kinases, dephosphorylation by MKPs inhibits MAPK activity, thereby negatively regulating MAPK signaling. It is known that deregulation of MAPK signaling is the most common alteration in human cancers. Recent studies have suggested that MKPs play an important role not only in the development of cancers, but also in the response of cancer cells to chemotherapy. Thus, understanding the roles of MKPs in the development of cancer and their impact on chemotherapy can be exploited for therapeutic benefits for the treatment of human cancer.
Cancer Metastasis Rev 2007 Dec
PMID:Role of mitogen-activated protein kinase phosphatases (MKPs) in cancer. 1771 36

Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed "anoikis." Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers. PPC-1 anoikis-resistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH(2)-kinase and p38, these kinases were not functionally important for the effect of anisomycin on anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy.
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PMID:A chemical screen identifies anisomycin as an anoikis sensitizer that functions by decreasing FLIP protein synthesis. 1780 46

Mitogen-activated protein kinase kinase 4/c-Jun NH(2)-terminal kinase kinase 1 (MKK4/JNKK1; hereafter referred to as MKK4) is a dual-specificity kinase with a critical role in regulating the activity of c-Jun NH(2)-terminal kinase and p38 kinases. We identified a novel biological function for MKK4 in the regulation of growth of ovarian and prostate cancer metastases. Clinical correlative studies showed that MKK4 protein levels were reduced in high-grade prostate cancer and prostate and ovarian cancer metastases compared with normal tissue, which prompted investigation into the mechanism(s) responsible for down-regulation of MKK4 in a panel of cancer cell lines. Initial studies found that low levels of MKK4 protein did not correlate with either exon deletion or decreased levels of MKK4 mRNA, suggesting that MKK4 protein levels were regulated posttranscriptionally by either reduced translation or reduced protein stability. Endogenous MKK4 was highly stable and not subject to altered proteolysis. Instead, MKK4 biosynthesis seemed to be regulated by altered translation. In support of this assertion, we found that cytosolic MKK4 mRNA was shifted toward active polysomes in cells with higher levels of MKK4 protein, suggesting that MKK4 mRNA was translated more efficiently in these cells. This study supports a novel mechanism for the regulation of MKK4 protein levels. Further, these findings have potential therapeutic implications for modulating the expression of a signaling kinase involved in the regulation of metastatic growth.
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PMID:Mitogen-activated protein kinase kinase 4/c-Jun NH2-terminal kinase kinase 1 protein expression is subject to translational regulation in prostate cancer cell lines. 1833 56

In many patients without clinical metastases, cancer cells have already escaped from the primary tumor and entered a distant organ. A long-standing question in metastasis research is why some disseminated cancer cells fail to complete steps of metastatic colonization for extended periods of time. Our laboratory identified c-Jun NH(2)-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4 (JNKK1/MKK4) as a metastasis suppressor protein in a mouse xenograft model of experimental i.p. ovarian cancer metastasis. In this model, expression of JNKK1/MKK4 via activation of p38 delays formation of >or=1-mm implants and prolongs animal survival. Here, we elucidate the time course of this delay as well as the biological mechanisms underpinning it. Using the Gompertz function to model the net accumulation of experimental omental metastases, we show that MKK4-expressing implants arise, on average, 30 days later than controls. Quantitative real-time PCR shows that MKK4 expression does not have a substantial effect on the number of cancer cells initially adhering to the omentum, and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling analysis shows that there is no increase in apoptosis in these cells. Instead, immunohistochemical quantitation of cell cycle proteins reveals that MKK4-expressing cells fail to proliferate once they reach the omentum and up-regulate p21, a cell cycle inhibitor. Consistent with the time course data, in vitro kinase assays and in vivo passaging of cell lines derived from macroscopic metastases show that the eventual outgrowth of MKK4-expressing cells is not due to a discrete selection event. Rather, the population of MKK4-expressing cells eventually uniformly adapts to the consequences of up-regulated MKK4 signaling.
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PMID:c-Jun NH2-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4-mediated inhibition of SKOV3ip.1 ovarian cancer metastasis involves growth arrest and p21 up-regulation. 1838 22

Chondrosarcoma is a low-grade sarcoma characterized by developing metastases and high local recurrence rate. Bone morphogenetic protein-2 (BMP-2) plays an essential role in tumor progression and metastasis. Here we found that BMP-2 induced the migration of human chondrosarcoma cells (JJ012 cells). BMP-2 also increased the secretion of metalloproteinase-13 (MMP-13) in JJ012 cells, as shown by reverse transcriptase-polymerase chain reaction, western blot and zymographic analysis. The MMP-13 small interfering RNA inhibited the BMP-2-induced MMP-13 expression and thereby significantly inhibited the BMP-2-induced cell migration. Furthermore, phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor suppressed BMP-2-induced MMP-13 mRNA expression. Transient transfection with dominant negative p85 and Akt mutant also showed that the PI3K/Akt signaling pathway was involved in BMP-2-induced MMP-13 expression. In addition, AP-1 decoy oligodeoxynucleotide also suppressed the MMP-13 promoter activity enhanced by BMP-2. Moreover, BMP-2 increased the binding of c-Fos and c-Jun to the AP-1 element on the MMP-13 promoter. Taken together, our results indicated that BMP-2 enhanced the invasiveness of chondrosarcoma cells by increasing MMP-13 expression through the PI3K, Akt, c-Fos/c-Jun and AP-1 signal transduction pathway.
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PMID:Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. 1903 72


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