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)

Nuclear factor (NF)-kappaB is frequently over-expressed in non-small cell lung cancer (NSCLC), but the exact role of this observation remains unclear. In this regard, activation of the transcription factor may govern distinct steps of NSCLC progression, such as carcinogenesis, angiogenesis, and metastasis. In these studies we attempted to dissect the effects of two proteins of the NF-kappaB pathway (p65/RelA and IkappaBetaalpha) on experimental metastasis of murine NSCLC, using a novel approach of bioluminescent detection of NF-kappaB activation in tumor cells. Stable integration of a NF-kappaBeta reporter confirmed high basal activation of the transcription factor in mouse NSCLC cells in vitro and during experimental metastasis to the lungs, like human NSCLC. In the mouse model of NSCLC metastasis, NF-kappaBeta-dependent luciferase expression served as a reliable indicator of tumor cell delivery to the lungs, establishment of metastatic tumors, and lung tumor burden. In vitro transient p65/RelA and IkappaBetaalpha gene transfer to mouse NSCLC cells resulted, respectively, in significant NF-kappaB activation and inhibition, without affecting cell growth. However, p65/RelA overexpression in NSCLC cells drastically reduced in vivo metastasis to the lungs, while overexpression of IkappaBetaalpha had no effect. In conclusion, using bioluminescent detection of NF-kappaB activation in mouse lug adenocarcinoma cells, we found a negative impact of p65/RelA on NSCLC metastasis.
Clin Exp Metastasis 2008
PMID:Use of bioluminescent imaging to investigate the role of nuclear factor-kappaBeta in experimental non-small cell lung cancer metastasis. 1800 76

Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micro-metastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.
Clin Exp Metastasis 2008
PMID:Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. 1807 13

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis.
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PMID:LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. 1841 96

In the present report, the possible role of a recently described functional polymorphism of the osteopontin (OPN) promoter at position -443 (-443T/C) for OPN expression in melanoma cells was addressed. As shown by real-time PCR analysis, melanoma metastases that were homozygous for the -443C allele expressed significantly higher levels of OPN mRNA compared with those that were either heterozygous (-443T/C) or homozygous for the -443T allele. In line with this, immunoblotting showed significantly enhanced baseline and bFGF-induced OPN protein expression in melanoma cell lines which were homozygous for the -443C allele, compared with cell lines with other allelic variants. Similar results were obtained in in vitro luciferase assays. Chromatin immunoprecipitation (ChIP) demonstrated binding of c-Myb to the -443 OPN promoter region, and binding could significantly be enhanced after bFGF stimulation. Moreover, as shown by electrophoretic mobility shift assays (EMSA), recombinant DNA-binding domain of c-Myb bound in a sequence-specific manner to this region. Finally, the role of c-Myb for OPN gene regulation via binding to the -443 promoter region could be further substantiated by ectopic overexpression of c-Myb in melanoma cells, using different reporter gene constructs. Taken together, it is demonstrated that the -443 promoter region exerts influence on OPN gene expression in melanoma cells, and differential binding of c-Myb transcription factor appears to play a major role in this process. These findings might be a feasible explanation for different OPN expression levels in metastatic tumors and may also have prognostic and therapeutic relevance.
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PMID:The functional -443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor. 1845 27

Cervical cancer is the second most common type of malignant tumor among women worldwide. When the disease is confined locally, it can be controlled with surgical resection and radiotherapy. However, patients with recurrent or metastatic disease often have a poor prognosis. Measurement of serum levels of squamous cell carcinoma (SCC) antigens has been widely used as serological markers for SCC of uterine cervix. Recently, it has been demonstrated that cervical cancer patients with elevated squamous cell carcinoma antigen-2 (SCCA2) expression in tumor cells carry a poor prognosis. Here, by using a luciferase reporter assay, we show that SCCA2 promoter was active in SCCA2-producing human cervical cancer cell lines, including Cx, Cxwj, SiHa and HeLa cells, but relatively quiescent in normal cervical epithelial cells. We then developed a conditionally replicating adenovirus, designated Ad-KFH, under the transcriptional control of the SCCA2 promoter. This E1B-55 kDa-deleted oncolytic adenovirus replicated specifically in and lysed SCCA2-producing cervical cancer cells. Furthermore, in a peritoneal metastatic tumor model, Ad-KFH retarded Cxwj tumor growth in NOD/severe combined immunodeficient mice and prolonged survival of tumor-bearing mice, especially when combined with cisplatin. These results suggest that Ad-KFH may provide a new strategy of gene therapy for advanced or recurrent uterine cervical cancer.
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PMID:Conditionally replicating E1B-deleted adenovirus driven by the squamous cell carcinoma antigen 2 promoter for uterine cervical cancer therapy. 1849 52

Nab-paclitaxel is an albumin-bound 130-nm particle form of paclitaxel that has shown an improved efficacy in experimental tumor models and clinical studies compared with solvent-based paclitaxel. Anti-vascular endothelial growth factor A (VEGF-A) antibody bevacizumab is known to enhance antitumor activity of cytotoxic drugs. This study evaluated the effects of combined nab-paclitaxel and bevacizumab therapy on growth and metastatic spread of orthotopic breast tumors. Cytotoxic and clonogenic assays measured VEGF-A-dependent modulation of nabpaclitaxel toxicity on cultured tumor cells. Antitumor effects were assessed in mice with luciferase-tagged, well-established MDA-MB-231 tumors (250-310 mm3) treated with one, two, or three cycles of nab-paclitaxel (10 mg/kg, daily for five consecutive days), bevacizumab (2-8 mg/kg, twice a week), or with combination of both drugs. VEGF-A protected MDA-MB-231 cells against nab-paclitaxel cytotoxicity, whereas bevacizumab sensitized cells to the effect of the drug. Combined bevacizumab and nab-paclitaxel treatment synergistically inhibited tumor growth and metastasis resulting in up to 40% of complete regressions of well-established tumors. This therapy also decreased the incidence of lymphatic and pulmonary metastases by 60% and 100%, respectively. The significant increase in the cure of tumor-bearing mice in the nab-paclitaxel/bevacizumab combined group compared with mice treated with single drugs strongly advocates for implementing such strategy in clinics.
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PMID:Nab-paclitaxel efficacy in the orthotopic model of human breast cancer is significantly enhanced by concurrent anti-vascular endothelial growth factor A therapy. 1851 98

Tumor cell-associated chemokine receptors play distinct roles in cancer biology, including enhancement of lymph node (LN) metastasis. To determine if CCR7 influences tumor formation in skin, we inoculated B16 cells transduced with CCR7 and luciferase (CCR7-luc-B16) or with retroviral vector and luciferase (pLNCX2-luc-B16) into ear skin and footpads of wild-type (WT) mice. In contrast to pLNCX2-luc-B16 cells, 97% of CCR7-luc-B16 cell-inoculated mice formed skin tumors as well as cervical LN metastases by Day 21 following ear inoculation. CCR7-expressing and control B16 cells, however, formed tumors of similar size and with high-efficiency in SCID-beige mice. Cells from both lines accumulated in the skin of WT mice in similar numbers until Day 7. By Day 11, however, control cells decreased tenfold, whereas CCR7-luc-B16 cells formed small tumor nodules. Tumor cells were infrequently detected in draining cervical LNs up to 11 days after injection of both cell lines, but stable nodal metastases were only observed after CCR7-luc-B16 ear tumors had been established (Day 21). ELISPOT assays revealed that IFN--producing cells in draining LNs from CCR7-luc-B16-injected ears were reduced through Day 7. After footpad injection, tumor formation by CCR7-expressing B16 cells was enhanced only with small, initial tumor cell inocula. With larger inocula, tumor formation was equivalent, but the numbers of tumor-infiltrating leukocytes were reduced by approximately sixfold in CCR7-B16 tumors compared with pLNCX2-B16 tumors of equal size. IFN- and CXCL10 were reduced 35- and sixfold, respectively, in CCR7-B16 cell tumors (vs. control tumors). Thus, CCR7 expression enhances tumorigenesis in addition to facilitating LN metastasis.
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PMID:CCR7 regulates B16 murine melanoma cell tumorigenesis in skin. 1851 42

Using alternative splicing reporters we have previously observed mesenchymal epithelial transitions in Dunning AT3 rat prostate tumors. We demonstrate here that the Dunning DT and AT3 cells, which express epithelial and mesenchymal markers, respectively, represent an excellent model to study epithelial transitions since these cells recapitulate gene expression profiles observed during human prostate cancer progression. In this manuscript we also present the development of two new tools to study the epithelial transitions by imaging alternative splicing decisions: a bichromatic fluorescence reporter to evaluate epithelial transitions in culture and in vivo, and a luciferase reporter to visualize the distribution of mesenchymal epithelial transitions in vivo.
Clin Exp Metastasis 2008
PMID:Dunning rat prostate adenocarcinomas and alternative splicing reporters: powerful tools to study epithelial plasticity in prostate tumors in vivo. 1852 50

Liver metastasis is one of the most important prognostic factors in lung cancer patients. However, current therapies are not sufficient. RNA interference provides us a powerful and promising approach for treating human diseases including cancers. Herein, we investigated the in vitro effects of PLK-1 small interfering RNA (siRNA) on human lung cancer cell lines and the in vivo usage of PLK-1 siRNA with atelocollagen as a drug delivery system in a murine liver metastasis model of lung cancer. PLK-1 was overexpressed in cell lines and in cancerous tissues from lung cancer patients. PLK-1 siRNA treatment inhibited growth and induced apoptosis in a concentration-dependent manner. To verify in vivo efficacy, we confirmed that atelocollagen was a useful drug delivery system in our model of implanted luciferase-labeled A549LUC cells by detecting reduced bioluminescence after an i.v. injection of luciferase GL3 siRNA/atelocollagen. PLK-1 siRNA/atelocollagen was also successfully transfected into cells and inhibited the progression of metastases. This study shows the efficacy of i.v. administration of PLK-1 siRNA/atelocollagen for liver metastases of lung cancer. We believe siRNA therapy will be a powerful and promising strategy against advanced lung cancer.
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PMID:Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth of liver metastases of lung cancer. 1879 Jul 71

Phor21-betaCG(ala), a 36-amino acid peptide comprised of a lytic peptide (Phor21) conjugated to a modified 15-amino acid segment of the beta-chain of chorionic gonadotropin (betaCG(ala)), selectively kills cancer cells that over-express luteinizing hormone/chorionic gonadotropin (LH/CG) receptors by disrupting cellular membrane structure. These studies were designed to further characterize its in-vitro inhibition and in-vivo destruction of prostate cancer cells, biostability and pharmacokinetics to determine its pharmacokinetic and pharmacodynamic profile. Inhibitory effects of Phor21-betaCG(ala) were tested in PC-3 and Caco-2 cells as well as in nude mice bearing PC-3 cells transfected with the luciferase gene (PC-3.luc). Plasma stability, protease hydrolysis and pharmacokinetics of Phor21-betaCG(ala) were measured by using liquid chromatography mass spectrometry (LC/MS/MS). Phor21-betaCG(ala) selectively inhibited proliferation in-vitro and in-vivo metastases of PC-3 cells. Phor21-betaCG(ala) was relatively stable in mouse, rat, dog and human plasma. Its degradation was partially due to protease hydrolysis and thermodynamic catalysis. Intravenous administration of Phor21-betaCG(ala) showed its blood C(max) and AUC(0-->infinity) around the in-vitro effective levels. In the tested rodents, Phor21-betaCG(ala) displayed a moderate volume of distribution at steady state (Vd(ss)) and slow clearance (Cl) in the rodents. In conclusion, Phor21-betaCG(ala) displayed promising in-vitro and in-vivo anti-cancer activity with favourable pharmacokinetics, and may offer a novel approach to metastatic cancer chemotherapy.
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PMID:Pharmacokinetics and pharmacodynamics of Phor21-betaCG(ala), a lytic peptide conjugate. 1895 64


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