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 reported previously that tumor cells isolated from metastases of the in vitro transformed squamous cell carcinoma line Pam 212 exhibit an elevation in constitutive production of proinflmmatory cytokines interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and KC (the murine homologue of chemokine Gro-alpha). The basis for constitutive expression of these cytokines after tumor progression in vivo is unknown. Regulation of the expression of these proinflammatory cytokines involves transcription factor nuclear factor kappaB (NF-kappaB), which can be activated by cytokines such as tumor necrosis factor (TNF)-alpha. In this study, we compared the constitutive and TNF-alpha-induced expression of proinflammatory cytokines in parental Pam 212 and metastatic LY-2 and LY-8 cell lines and determined the relationship of cytokine expression to activation of NF-kappaB. We found that the metastatic cell lines exhibited an increase in constitutive and TNF-alpha-inducible expression of proinflammatory cytokines when compared with parental Pam 212 cells. The increased cytokine expression was associated with an increase in constitutive and TNF-alpha-inducible activation of NF-kappaB as demonstrated by electrophoretic mobility shift assay and luciferase-reporter gene assay. Constitutive nuclear localization of NF-kappaB p65 was observed in LY-2 and LY-8 cells in culture and in tumor specimens but rarely in Pam 212 cells, consistent with the constitutive activation of NF-kappaB in tumor cels after selection in vivo. Induction of NF-kappaB by TNF-alpha was inhibited by the addition of protease inhibitors calpain inhibitor I and N-tosyl-phechloromethyl ketone and antioxidant 1-pyrrolidinecarbodithioic acid, whereas constitutive activation of NF-kappaB and cytokine KC mRNA expression was inhibited by N-tosyl-phechloromethyl ketone alone. Overexpression of a human Ikappa(B)alpha dominant suppresser in Pam 212 cells inhibited TNF-alpha-induced NF-kappaB binding activity and KC expression. These data indicate that activation of NF-kappaB contributes to increased expression of proinflammatory cytokines during metastatic tumor progression of squamous cell carcinoma, and that distinct mechanisms may be involved in the regulation of constitutive and TNF-alpha-induced activation of NF-kappaB in squamous cell carcinoma.
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PMID:The host environment promotes the constitutive activation of nuclear factor-kappaB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. 1041 16

The 92-kDa type IV collagenase (MMP-9) plays a critical role in tissue remodeling. We undertook a study to determine whether the KiSS-1 gene, previously shown to suppress cancer spread (metastases), negatively regulates MMP-9 expression. Six cell lines positive for MMP-9 mRNA were deficient in KiSS-1 mRNA. One of these cell lines, HT-1080, stably transfected with a KiSS-1 expression construct, demonstrated substantially lower MMP-9 enzyme activity/protein and in vitro invasiveness. The lower MMP-9 enzyme activity reflected reduced steady-state mRNA levels which, in turn, was due to attenuated transcription. Activation of ERKs and JNKs by phorbol 12-myristate 13-acetate and tumor necrosis factor alpha, respectively, leading to increased MMP-9 amounts was not antagonized by KiSS-1 expression, suggesting that MAPK pathways modulating MMP-9 synthesis are not the target of KiSS-1. Although MMP-9 expression is regulated by AP-1, Sp1, and Ets transcription factors, KiSS-1 did not alter the binding of these factors to the MMP-9 promoter. However, NF-kappaB binding to the MMP-9 promoter required for expression of this collagenase was reduced by KiSS-1 expression. Diminished NF-kappaB binding reflected less p50/p65 in the nucleus secondary to increased IkappaBalpha levels in the cytosols of the KiSS-1 transfectants. Thus, KiSS-1 diminishes MMP-9 expression by effecting reduced NF-kappaB binding to the promoter.
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PMID:KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation. 1106 Mar 11

The purpose of this study was to determine if increased NF-kappaB activity of highly invasive PC-3 cells contributed to their invasive behavior. Increased NF-kappaB activity has been observed in several malignant tumors and it may have an important role in tumorigenesis, progression and chemotherapy resistance. By serial selection, we obtained invasion variant PC-3 cell sublines. The PC-3 High Invasive cells invade readily through a Matrigel reconstituted basement membrane while PC-3 Low Invasive cells have low baseline invasion activity. In these studies, we discovered that NF-kappaB DNA binding activity was increased in PC-3 High Invasive cells when compared to PC-3 Low Invasive cells by electrophoretic mobility shift assay (EMSA). Gel supershift assays showed a 4-fold increase in p65 containing complexes and a 2.2-fold increase in the p50 containing complexes in the PC-3 High Invasive cells. Luciferase reporter assays showed that NF-kappaB dependent transcription activity was increased 10.2 +/- 2.5-fold in the highly invasive cells (P < 0.002). The PC-3 High Invasive cells showed a constitutive increase in phospho-IkappaB alpha and introduction of the super-repressor IkappaB alpha S32/36A inhibited NF-kappaB activity to 19.2 +/- 2.5 percent of control transfected cells (P < or = 0.001). The IkappaBa super-repressor reduced the basement membrane invasion of PC-3 High Invasive cells from 6.2 +/- 1.1 to 3.8 +/- 0.4 percent (P < 0.002) with no decrease in cell viability or proliferation. These results demonstrate that increased NF-kappaB activity contributed directly to the invasive behavior of PC-3 High Invasive prostate cancer cells.
Clin Exp Metastasis 2000
PMID:The role of constitutive NF-kappaB activity in PC-3 human prostate cancer cell invasive behavior. 1159 4

Although an aggressive phenotype of renal cell carcinoma (RCC) is known to frequently be associated with inflammatory paraneoplastic syndrome including serum C-reactive protein (CRP) elevation, the molecular mechanism underlying this clinical phenomenon as well as what yields the malignant phenotype leading to the progression of RCC has yet to be elucidated. Based on the increased level of inflammatory cytokines such as interleukin-6 in advanced cases of RCC, a cytokine-inducible transcription factor, namely, nuclear factor-kappa B (NF-kappa B), may thus play a role in the progression of RCC. An electrophoretic mobility shift assay (EMSA) was carried out to determine the activity of NF-kappa B. Out of 45 cases of RCC, 15 cases (33%) showed a >200% increase in the NF-kappa B activity in comparison with that seen in normal renal tissue. In locally advanced cases (> or =pT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (< or =pT2). All three cases with metastases showed an increased NF-kappa B activity. The NF-kappa B activity determined by EMSA was further confirmed by an immunohistochemical analysis using an antibody recognizing the nuclear localization signal (NLS) in p65 subunit of NF-kappa B. The serum CRP elevation correlated with the increased NF-kappa B activation, and therefore NF-kappa B may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-kappa B activity was associated with an increased expression of both the p65 and p50 subunits of NF-kappa B and a concomitant decreased expression of I kappa B alpha. No functional mutations of the I kappa B alpha gene were detected. The NF-kappa B activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.
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PMID:Increased nuclear factor-kappa B activation is related to the tumor development of renal cell carcinoma. 1266 95

Metastasis of cancer cells is a complex process involving multiple steps including invasion, angiogenesis, and trafficking of cancer cells through blood vessels, extravasations, organ-specific homing, and growth. While matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines play a major role in invasion and angiogenesis, chemokines such as stromal derived factor-1alpha (SDF-1alpha) and their receptors such as CXCR4 are thought to play a critical role in motility, homing, and proliferation of cancer cells at specific metastatic sites. We and others have previously reported that the extracellular signal-activated transcription factor NF-kappaB up-regulates the expression of matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines in highly metastatic breast cancer cell lines. In this report, we demonstrate that NF-kappaB regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of kappaB (IkappaB) in breast cancer cells with constitutive NF-kappaB activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1alpha-mediated migration in vitro. Introduction of CXCR4 cDNA into IkappaB-expressing cells restored SDF-1alpha-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-kappaB subunits p65 and p50 bind directly to sequences within the -66 to +7 region of the CXCR4 promoter and activate transcription. We also show that the cell surface expression of CXCR4 and the SDF-1alpha-mediated migration are enhanced in breast cancer cells isolated from mammary fat pad xenografts compared with parental cells grown in culture. A further increase in CXCR4 cell surface expression and SDF-1alpha-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-kappaB in the migration and the organ-specific homing of metastatic breast cancer cells.
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PMID:NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. 1269 99

Using PCR technique we have analyzed p65 and c-erbB2 genes expression in 47 frozen tissue slides taken from patients diagnosed as ductal and lobular breast cancer, classified as G3, and in a limited panel of proliferative breast disease cases. Expression of p65 was generally connected with small tumor size and with absence of metastases in regional lymph nodes. We have found interdependence between p65 gene expression and negative states of lymph nodes. On the contrary, c-erbB2 expression was observed in patients with large tumors and with metastases to the regional lymph nodes. Between both genes (p65 and c-erbB2) opposite interdependence was found. No statistical dependence between estrogen/progesterone receptor levels and p65 or c-erbB2 expression were noticed. The presence of p65 expression appeared in the group of proliferating breast disease cases which were connected with higher risk of breast cancer. Lack of p65 expression accompanied cases which were classified as fibroadenoma.
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PMID:p65 and c-erbB2 genes expression in breast tumors: comparison with some histological typing, grading and clinical staging. 1286 75

MAb-mediated immunotherapy offers a potential tool for destroying metastasizing colorectal tumor cells. Promising results have been obtained by using xenograft models. However, overexpression of membrane-bound complement regulatory proteins (mCRP) impedes complement-mediated destruction of tumor cells in vitro. mCRP operate in a species selective manner. Therefore a syngeneic animal model is needed to investigate the contribution of mCRP in mAb-mediated immunotherapy. Here we present a syngeneic rat colorectal carcinoma model, which fulfills the conditions necessary to investigate the effect of mCRP expression on mAb-mediated immunotherapy of metastases of solid tumors.CC531 rat colorectal cancer cells were injected subcapsularly into the liver of syngeneic WAG/Rij rats. Four mAb (MG1(IgG2a), MG2(IgG2a), MG3(IgG3) and MG4(2a)(IgG2a)) directed against CC531 cells, were tested for their complement activating abilities in vitro and tumor homing capacities in vivo. Only MG4(2a) was found to activate complement in vitro and home to the tumor cells in vivo. This mAb induced C3-deposition and C-mediated lysis of CC531 cells in vitro when the effects of the C-inhibitors Crry/p65 and CD59 were neutralized. This implies an important role for these mCRP in restricting the effector functions of tumor-associated mAb on these cells. Although C activation could be induced by MG4(2a) in situ on tumor tissue sections, no deposition of C3 could be found on the tumor cells positive for MG4(2a) in vivo. This suggests that complement activation in vivo was inhibited by mCRP. The results indicate the suitability of this syngeneic animal model for studying the effects of mAb immunotherapy. However, the effect of mCRP on tumor cells need to be overcome, e.g. by the use of mAb against tumor antigens and mCRP.
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PMID:Membrane-bound complement regulatory proteins inhibit complement activation by an immunotherapeutic mAb in a syngeneic rat colorectal cancer model. 1290 27

Expression of p16INK4A, the product of the melanoma susceptibility gene CDKN2A, has been shown to decrease in correlation with tumor progression. P16INK4A is a key regulator of cell-cycle function, and likely interacts with a variety of targets alongside cyclin-dependent kinases (CDKs). One such target is nuclear factor KB (NF-kappaB), a pleiotropic transcription factor that plays a crucial role in apoptosis, oncogenesis and cell cycle control. NF-kappaB p65 has been shown to be activated in melanoma cell lines but few studies decribe its expression in the tissue. In the present study we focused on synchronous expression of p16INK4A and NF-kappaB p65 and their functional activation in melanoma cell lines and biopsy tissue. Activation of NF-kappaB p65, as observed by electrophoretic mobility shift assay in cell lines, was correlated with expression and cellular localization of the active and inactive forms of its inhibitor, IkappaB-alpha. In melanocytic lesions, p16INK4A and NF-kappaB p65 expression were inversely correlated with levels of the nuclear component of NF-kappaB p65 increasing from nevi to primary melanomas and metastases.
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PMID:Inverse correlation between p16INK4A expression and NF-kappaB activation in melanoma progression. 1529 71

Recent studies have reported elevated levels of S100A6 in pancreatic ductal adenocarcinoma cells. Here, we describe a detailed analysis of S100A6 expression in benign (n = 32), malignant (n = 60), and premalignant pancreatic ductal cells [96 pancreatic intraepithelial neoplasias (PanIN) from 46 patients]. S100A6 staining was more intense in malignant cells than in benign cells (P = 0.0001). In malignant cells, staining was higher in the nucleus than in the cytoplasm (P = 0.003). Univariate analysis revealed a significant decrease in survival time for patients with high levels of nuclear (P = 0.01) but not cytoplasmic (P = 0.20) S100A6. No evidence was found for an association between nuclear S100A6 expression and other variables, including gender, age at surgery, tumor size or grade, nodal metastases, resection margin, vascular invasion, perineural invasion, p53 or Smad4 levels (both linked to survival in previous studies), or the p65 subunit of nuclear factor-kappaB (a potential regulator of S100A6). Although nodal metastases and resection margin involvement were also associated with poor survival (P = 0.06 in both cases), multivariate analysis suggests that nuclear S100A6 is a significant independent indicator of survival (P = 0.003). Whereas PanIN 1a lesions showed a general absence of S100A6 staining, there was a progressive increase in the proportion of positively stained PanINs with increasing PanIN grade. In particular, we observed an increase in the frequency and intensity of nuclear staining. Our results suggest that up-regulation of S100A6 is an early event in pancreatic cancer development and that elevated levels of nuclear S100A6 may affect clinical outcome.
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PMID:High nuclear S100A6 (Calcyclin) is significantly associated with poor survival in pancreatic cancer patients. 1583 53

We reported earlier that IL-1beta, an NF-kappaB-regulated cytokine, was made by intestinal epithelial cells during detachment-induced apoptosis (anoikis) and that IL-1 was antiapoptotic for detached cells. Since surviving anoikis is a prerequisite for cancer progression and metastases, we are further exploring the link between anoikis and cytokines. Here we determined that multiple genes are expressed following detachment including a number of NF-kappaB-regulated products and therefore aimed to determine whether NF-kappaB signalling plays any role in regulating apoptosis. Using Western blotting, we detected that IkappaBalpha becomes phosphorylated immediately following detachment and that levels of phospho-IkappaBalpha peaked within 20 min. Phosphorylation of IkappaBalpha was followed by Rel A (p65) nuclear translocation. Increased NF-kappaB activity following detachment was confirmed using the detection of NF-kappaB-promoted luciferase gene expression delivered by adenovirus infection. Infection of cells with adenovirus expressing a super-repressor IkappaBalpha protein and pharmacological inhibitors of NF-kappaB resulted in the failure to phosphorylate IkappaBalpha, a more rapid activation of caspases and earlier apoptosis. We also detected that IkappaB kinase alpha (IKKalpha) and not IKKbeta became phosphorylated following detachment. Since IKKalpha is activated by NF-kappaB-inducing kinase (NIK), we overexpressed native NIK using an adenovirus vector that resulted in enhanced phospho-IkappaBalpha and nuclear p65 in detached cells compared to control detached cells but did not result in a significantly greater number of cells surviving to 24 h. We conclude that detachment directly activates NF-kappaB, which, in addition to launching an inflammatory cytokine wave, contributes to a delay in apoptosis in intestinal epithelial cells.
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PMID:Activation of NF-kappaB following detachment delays apoptosis in intestinal epithelial cells. 1600 76


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