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)

The mechanism of intrasinusoidal arrest of circulating cancer cells, which is a critical step in liver metastasis, appears to be facilitated by tumor-derived proinflammatory factors that increase sinusoidal cell adhesion receptors for cancer cells. However, how this prometastatic microenvironment is up-regulated remains unknown. Using intrasplenically injected B16 melanoma (B16M) cells, we show that the expression of vascular cell adhesion molecule-1 (VCAM-1) significantly increased in hepatic sinusoidal endothelium (HSE) cells over physiologic baseline within the first 24 hours of metastatic cancer cell infiltration in the liver. This correlated with increased in vitro adhesion of B16M cells to HSE cells isolated from B16M cell-injected mice. In vivo VCAM-1 blockade with specific antibodies before B16M cell injection decreased sinusoidal retention of luciferase-transfected B16M cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated HSE cells had a prometastatic contribution. Because VCAM-1 expression is oxidative stress-inducible, recombinant catalase was in vivo administered, resulting in a complete abrogation of both VCAM-1 expression and B16M cell adhesion increases in HSE cells isolated from B16M cell-injected mice. Catalase also abrogated the proadhesive response of HSE cells to B16M-conditioned medium (B16M-CM) in vitro, although this did not affect the concomitant release of major proinflammatory cytokines by HSE cells. HSE cells treated with B16M-CM released interleukin (IL)-18 via tumor necrosis factor-alpha (TNF-alpha)-dependent IL-1beta in vitro. In turn, H(2)O(2) production from B16M-CM-treated HSE cells was regulated by IL-18. Thus, liver-infiltrating B16M cells activated their adhesion to HSE through a sequential process involving TNF-alpha-dependent IL-1beta, which induced IL-18 to up-regulate VCAM-1 via H(2)O(2). The pivotal position of H(2)O(2) was further supported by the fact that incubation of HSE cells with nontoxic concentrations of H(2)O(2) directly enhanced VCAM-1-dependent B16M cell adhesion in vitro without proinflammatory cytokine mediation, which emphasizes the key role of oxidative stress in the pathogenesis of liver inflammation and metastasis.
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PMID:Hydrogen peroxide mediates vascular cell adhesion molecule-1 expression from interleukin-18-activated hepatic sinusoidal endothelium: implications for circulating cancer cell arrest in the murine liver. 1148 15

F10 and BL6 cells of B16 mouse melanoma cells are metastatic after intravenous injection, but only BL6 cells can metastasize to lungs after subcutaneous injection. Differences in gene expression between the two cell lines were examined, and a greater expression of the Sik-similar protein (Sik-SP) gene was found in BL6 cells. Structurally, Sik-SP belongs to the nucleolar Nop5/Sik family whose members play central roles in ribosome biogenesis; however, the function of Sik-SP has not been examined. Cytology with green fluorescent protein-fused proteins showed that Sik-SP was localized to the nucleolus. To examine whether Sik-SP is involved in ribosome biogenesis, two parameters were measured: magnitude of ribosomal RNA synthesis per nucleus and magnitude of protein production from the same amount of mRNA of an exogenous luciferase gene. Both values and, in addition, nucleolar size were larger in COS-7 monkey kidney cells overexpressing Sik-SP and BL6 cells than in mock-transfected COS-7 and F10 cells, respectively. Sik-SP seemed to promote ribosome biogenesis in the nucleolus. Furthermore, the expression of Sik-SP seemed to confer a greater cell growth response to serum, because such a response was greater in BL6 cells and F10 cells overexpressing Sik-SP than in untreated and mock-transfected F10 cells. Sik-SP may render melanoma cells more competent to survive through augmenting the activity of nucleolus.
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PMID:Increased expression of a nucleolar Nop5/Sik family member in metastatic melanoma cells: evidence for its role in nucleolar sizing and function. 1158 64

Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.
Clin Exp Metastasis 2000
PMID:Regulation of activator protein-1 activity in the mediastinal lymph node metastasis of lung cancer. 1168 58

Heparanase-1 (HPR1) is an endoglycosidase that specifically degrades the heparan sulfate chains of proteoglycan, a component of blood vessel walls and the extracellular matrix. Recent studies demonstrated that HPR1 expression is increased in a variety of malignancies and may play a critical role in tumor metastases. The HPR1 gene and its genomic structure have been recently cloned and characterized. To understand the mechanisms of HPR1 gene expression and regulation, we first mapped the transcription start site of the HPR1 gene and found that HPR1 mRNA was transcribed from the nucleotide position 101 bp upstream of the ATG codon. A 3.5-kb promoter region of the HPR1 gene was cloned. Sequence analysis revealed that the TATA-less, GC-rich promoter of the HPR1 gene belongs to the family of housekeeping genes. This 3.5-kb promoter region exhibited strong promoter activity in two thyroid tumor cell lines. Truncation analysis of the HPR1 promoter identified a minimal 0.3-kb region that had strong basal promoter activity. Truncation and mutational analysis of the HPR1 promoter revealed three Sp1 sites and four Ets-relevant elements (ERE) significantly contributing to basal HPR1 promoter activity. Binding to the Sp1 sites by Sp1 and to the ERE sites by GA-binding protein (GABP) was confirmed by electrophoretic mobility shift assay and competition and supershift electrophoretic mobility shift assays. Cotransfection of Sp- and GABP-deficient Drosophila SL-2 cells with the HPR1 promoter-driven luciferase construct plus the expression vector encoding the Sp1, Sp3, or GABP gene induced luciferase gene expression. Mutation or truncation of the Sp1 or ERE sites reduced luciferase expression in both SL-2 cells and thyroid tumor cell lines. Coexpression of GABPalpha/beta and Sp1 or Sp3 further increased luciferase reporter gene expression. Our results collectively suggest that Sp1 cooperates with GABP to regulate HPR1 promoter activity.
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PMID:Cloning and characterization of the human heparanase-1 (HPR1) gene promoter: role of GA-binding protein and Sp1 in regulating HPR1 basal promoter activity. 1177 47

The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (-1659/-1622) necessary for the ATF3-mediated repression. This region lacked CREB/AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 in p53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that gamma-irradiation-induced slowed G(2)/M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53.
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PMID:ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter. 1179 11

The development of novel anti-cancer strategies requires more sensitive and less invasive methods to detect and monitor in vivo minimal residual disease in cancer models. Bone marrow metastases are indirectly detected by radiography as osteolytic and/or osteosclerotic lesions. Marrow micrometastases elude radiographic detection and, therefore, more sensitive methods are needed for their direct identification. Injection of cancer cells into the left cardiac ventricle of mice closely mimics micrometastatic spread. When luciferase-transfected cells are used, whole-body bioluminescent reporter imaging can detect microscopic bone marrow metastases of approximately 0.5 mm(3) volume, a size below the limit in which tumors need to induce angiogenesis for further growth. This sensitivity translates into early detection of intramedullary tumor growth, preceding the appearance of a radiologically evident osteolysis by approximately 2 weeks. Bioluminescent reporter imaging also enables continuous monitoring in the same animal of growth kinetics for each metastatic site and guides end-point analyses specifically to the bones affected by metastatic growth. This model will accelerate the understanding of the molecular events in metastasis and the evaluation of novel therapies aiming at repressing initial stages of metastatic growth.
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PMID:Optical imaging of cancer metastasis to bone marrow: a mouse model of minimal residual disease. 1189 Dec 10

Gelatinase A, also denoted matrix metalloproteinase 2, plays multiple critical roles in the neoplastic process, including facilitation of neoangiogenesis and formation of distal metastases. The transcriptional regulation of the gelatinase A gene is under the control of strong, evolutionarily conserved cis-acting enhancer elements, designated the r2 (human) or RE-1 (rat), that harbor contiguous binding motifs for the transcription factors activating protein-2 (AP2), p53, and YB-1. Using recombinant transcription factors, complex patterns of RE-1 binding were observed by electrophoretic mobility shift assay. Increased complex formation was detected with the AP2/YB-1 and AP2/p53 combinations, while YB-1 competed with p53 for binding. The combination of AP2, p53, and YB-1 yielded novel ternary complexes, particularly when binding to single-stranded RE-1 probes. Transient transfection of hepatocellular carcinoma cell lines with a series of gelatinase A luciferase reporter constructs were in accordance with the binding patterns determined by electrophoretic mobility shift assay. Combined AP2 and p53 increased gelatinase A luciferase reporter activity significantly, and the inclusion of YB-1 yielded further increase in both reporter activity and secreted levels of gelatinase A protein. YB-1 and p53 expression are increased following multiple genotoxic stresses, including irradiation, and the synergistic interactions of these induced transcription factors with the widely expressed AP2 protein provide a probable pathophysiologic mechanism for the enhanced tumor cell synthesis of gelatinase A induced by radiation.
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PMID:Combinatorial interactions of p53, activating protein-2, and YB-1 with a single enhancer element regulate gelatinase A expression in neoplastic cells. 1197 33

The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
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PMID:An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. 1203 98

Colorectal cancer can metastasize to the liver, but remain liver confined for years. A critical step in developing treatments for intrahepatic cancer involves assessment in an orthotopic intrahepatic model. The purpose of this study was to develop a noninvasive intrahepatic tumor model to study the efficacy of 5-flucytosine/yeast cytosine deaminase (5FC/yCD)-based gene therapy for liver tumors. Luciferase expressing human colorectal carcinoma (HT-29luc) cells were generated by retroviral infection and implanted in the left liver lobe of nude mice. The bioluminescence was measured every week for a period of 1 month, then animals were killed and tumors were measured by calipers. After we found a correlation between photon counts and tumor size, animals were implanted with tumors composed of either 0%, 10%, or 100% yCD/HT-29luc cells, and treated with 5FC. Tumor bioluminescence was measured during treatment and tumor histology examined at the time of death. We found that 5FC caused significant regression of yCD expressing tumors. Furthermore, visible tumors at the time of death, which emitted little bioluminescence, contained little or no viable tumor. We then developed an adenoviral vector for yCD. Intraperitoneal administration of adenovirus containing yCD led to the production of yCD enzyme within intrahepatic tumors. These results suggest that (1) intrahepatic cancer responds to 5FC when cells express yCD; (2) the luciferin-luciferase system permits non-invasive real time imaging of viable intrahepatic cancer; and (3) this system can be used to carry out gene therapy experiments using yCD adenovirus.
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PMID:The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model. 1208 Mar 78

The pleura covers the lung parenchyma, chest wall, and diaphragm with a single layer of flat cells that are easy to genetically modify with adenovirus (Ad) vectors. Although intrapleural gene therapy has been used to treat intrapleural disorders, we hypothesized that it may also be used to deliver extracellular gene products to the lung parenchyma. In this context, this study is based on the concept that administration of adenovirus gene transfer vectors into the pleural cavity will mediate expression of gene products in mesothelial cells, and that the extracellular products produced by these genetically modified cells will reach the lung parenchyma. To assess this concept, Ad(beta)gal (expressing beta-galactosidase [beta-Gal]) or AdLuc (expressing luciferase) was administered into the right pleural cavity of BALB/c mice, as compared with intravenous injection via the jugular vein or the intratracheal route. Histologic assessment of lungs and pleural surface after intrapleural administration of Ad(beta)gal demonstrated beta-Gal expression limited to the pleural mesothelium and cells adjacent to the pleural surface. Right intrapleural administration of AdLuc showed higher level of luciferase in both the right and left lung (right vs. left, p > 0.8), compared with the intratracheal (p < 0.05) or intravenous routes (p < 0.02), that is, unilateral intrapleural administration is sufficient to transfer genes bilaterally to the pleura. To assess the ability of intrapleural gene transfer to modify lung parenchymal processes, CT26.CL25 tumor cells (3 x 10(5)) were injected via the jugular vein to generate tumor metastases in the lung parenchyma followed 24 hr later by administration to the right pleura of 5 x 10(8) PFU of Adsflt (an Ad "antiangiogenesis" vector expressing a soluble, secreted, extracellular portion of the Flt-1 receptor for vascular endothelial growth factor). Compared with phosphate-buffered saline, or the control vector AdNull (no transgene), mice receiving Adsflt by the intrapleural route had a marked suppression of tumor growth in the parenchyma of both lungs as assessed 12 days after tumor administration (p < 0.005). Treatment of preestablished lung metastases with Adsflt administered by the intrapleural route significantly improved long-term survival as compared with control animals (p < 0.0001). Thus, although intrapleural administration of an Ad vector encoding an intracellular protein mediates gene expression only in mesothelial cells and the local tissues, intrapleural delivery of a vector expressing a secreted protein can be used to modify processes throughout the lung parenchyma. In the context that intravascular gene transfer is an ineffective strategy to deliver gene products to the lung parenchyma, and that intratracheal administration is associated with alveolar inflammation secondary to host defenses against Ad vectors, these findings demonstrate that intrapleural administration represents a strategy that can be used to effectively deliver extracellular gene products to the lung parenchyma via a site that is readily accessible, and where inflammation against the vector will not have significant pathophysiologic consequences.
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PMID:Gene transfer to the pleural mesothelium as a strategy to deliver proteins to the lung parenchyma. 1221 68


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