Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted >1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Dunn). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers.
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PMID:Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice. 1452 22

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

KITENIN promotes invasion of mouse colon adenocarcinoma (CT-26) cells in vivo. Here, we studied the effects of in vivo KITENIN ablation on established tumors by using pSUPER vectors (pSUPER-KITENIN) producing short interfering RNA (siRNA). When pSUPER-KITENIN was given weekly or semiweekly for 1 month into tail vein of syngeneic mice that have established colon tumors, tumor size regressed markedly and metastases were inhibited. In mice injected with pSUPER-KITENIN, serum interleukin-2 (IL-2) and IFN-gamma increased and CD4+ and CD8+ T cells infiltrated in the regressed tumor tissues. These effects, observed beginning 2 days after i.v. injection, imply that immune response is involved in the antitumor action of pSUPER-KITENIN. Using a yeast two-hybrid assay, we identified two KITENIN-interacting proteins for the possible mediators of these actions: 90K protein, a known immune modulatory glycoprotein, and protein kinase C inhibitor (PKCI). 90K was increased in the culture medium from CT-26/antisense KITENIN/90K cells. Double culture of accessory cells with CT-26/antisense KITENIN/90K cells revealed increased secretion of IL-1 and IL-6. Overexpression of 90K in CT-26/antisense KITENIN cells further delayed tumor growth compared with that of CT-26/antisense KITENIN cells. Actin arrangement was distorted in CT-26/antisense KITENIN and CT-26/antisense PKCI cells, whereas overexpression of PKCI resulted in increased invasiveness to fibronectin. Thus, antitumor effects of KITENIN siRNA derives from both the generation of a tumor-specific immune response in vivo through increased 90K secretion from tumor cells and the suppression of tumor invasion in which PKCI is related to increased invasiveness. Moreover, siRNA targeting of KITENIN can function as a chemotherapeutic strategy against colon cancer.
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PMID:Suppression of progression and metastasis of established colon tumors in mice by intravenous delivery of short interfering RNA targeting KITENIN, a metastasis-enhancing protein. 1620 73

Cytokines such as IL-1 and TNF are primarily pro-inflammatory. The inflammation induced by these cytokines is reflected in the type of genes they induce. In the pathogenesis of carcinogenesis as well as tumor growth and spread, cytokines such as IL-1 and TNF induce chemokines that attract neutrophils. Neutrophils are key players in the production of reactive oxygen species and carcinogenesis. Another aspect of pro-inflammatory cytokines is the induction of adhesion molecules and metalloproteinases, both of which provide mechanisms for tumor invasion. Blocking cytokines, however, will reduce tumor growth and spread if administered at sufficient concentrations and will require parenteral therapy. However, blocking cytokines will not kill tumor cells nor prevent carcinogenesis. Blocking cytokines is best as an adjunct therapy together with tumorocidal drugs.
Cancer Metastasis Rev 2006 Sep
PMID:The paradox of pro-inflammatory cytokines in cancer. 1702 30

Cancer cells often acquire a constitutively active nuclear factor-kappaB (NF-kappaB) program to promote survival, proliferation and metastatic potential by mechanisms that remain largely unknown. Extending observations from an immunologic setting, we demonstrate that microRNA-146a and microRNA-146b (miR-146a/b) when expressed in the highly metastatic human breast cancer cell line MDA-MB-231 function to negatively regulate NF-kappaB activity. Lentiviral-mediated expression of miR-146a/b significantly downregulated interleukin (IL)-1 receptor-associated kinase and TNF receptor-associated factor 6, two key adaptor/scaffold proteins in the IL-1 and Toll-like receptor signaling pathway, known to positively regulate NF-kappaB activity. Impaired NF-kappaB activity was evident from reduced phosphorylation of the NF-kappaB inhibitor IkappaBalpha, reduced NF-kappaB DNA-binding activity and suppressed expression of the NF-kappaB target genes IL-8, IL-6 and matrix metalloproteinase-9. Functionally, miR-146a/b-expressing MDA-MB-231 cells showed markedly impaired invasion and migration capacity relative to control cells. These findings implicate miR-146a/b as a negative regulator of constitutive NF-kappaB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.
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PMID:Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. 1850 31

Over the past five decades, those interested in markers of radiation effect have focused primarily on tumor response. More recently, however, the view has broadened to include irradiated normal tissues-markers that predict unusual risk of side-effects, prognosticate during the prodromal and therapeutic phases, diagnose a particular toxicity as radiation-related, and, in the case of bioterror, allow for tissue-specific biodosimetry. Currently, there are few clinically useful radiation-related biomarkers. Notably, levels of some hormones such as thyroid-stimulating hormone (TSH) have been used successfully as markers of dysfunction, indicative of the need for replacement therapy, and for prevention of cancers. The most promising macromolecular markers are cytokines: TGFbeta, IL-1, IL-6, and TNFalpha being lead molecules in this class as both markers and targets for therapy. Genomics and proteomics are still in nascent stages and are actively being studied and developed.
Cancer Metastasis Rev 2008 Sep
PMID:Molecular markers of radiation-related normal tissue toxicity. 1850 99

Cachexia is a devastating process especially in pancreatic cancer patients and contributes to their poor survival. We attempted to clarify the pathological and molecular changes that occur in the liver during the development of cachexia. Using immunohistochemistry we investigated the infiltration of inflammatory mononuclear cells in liver biopsies of pancreatic cancer patients with or without cachexia, and the potential relevance of the cells for the nutritional and inflammatory status. Additionally, these findings were compared with the patients' clinical parameters. We found a significantly higher amount of CD68 immunoreactive macrophages in liver cross sections of patients with pancreatic cancer and cachexia. The number of CD68-positive macrophages was significantly inversely correlated with the nutritional status. Additionally, in these CD68-positive areas a significant increase in IL-6 and IL-1 immunoreactive cells was localized. Moreover, we found significantly increased areas of CD68-positive macrophages in liver biopsies of patients with a more dedifferentiated (aggressive) grading of the tumor. In conclusion, these results suggest that a crucial interaction between the tumor, PBMCs, and the liver may play a central role in the development and regulation of cachexia. Furthermore, pancreatic cancer may be able to alter systemic organ function even without obvious metastatic disease.
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PMID:Liver macrophages contribute to pancreatic cancer-related cachexia. 1914 9

SP is an undecapeptide that belongs to the family of related neurokinins termed tachykinins. SP is one of the mediators responsible for the neural-immune/hematopoietic cross-talk. It is released from the nerve fibers of the autonomic and enteric nervous systems in lymphoid organs and is also produced by the resident, stromal or hematopoietic cells. SP stimulates the production of hematopoietic cytokines (e.g. IL-1, IL-3, IL-6, SCF, GM-CSF) by bone marrow stromal cells. It enhances the proliferation of bone marrow progenitors, both directly by binding to progenitor's receptors and indirectly by interacting with marrow stromal cells. SP can also modulate immune and hematopoietic functions like phagocytosis, immunoglobulin production, lymphocyte proliferation and platelet aggregation. SP fragments derived from endopeptidase activity could also exert immune and hematopoietic regulation. The biological effects of SP are mediated through interactions with certain G protein-coupled receptors: the neurokinin (NK) receptors. Different studies have shown that NK receptors are localized on immuno-competent cells, including monocytes/macrophages, neutrophils, mast cells, dendritic cells and T or B lymphocytes, bone marrow stromal cells and hematopoietic progenitors. The disturbance of the neural-hematopoietic-immune axis may be implicated in hematological malignancies. SP seems to be important in the neoplastic transformation of bone marrow, leading to the development of acute leukaemia in children; myelofibrosis and also metastases to bone marrow of solid tumors in early stages of these diseases.
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PMID:[Substance P as a regulatory peptide of hematopoiesis and blood cell functions]. 1925 69

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-gamma (IFN-gamma)-producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X(7) purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1beta (IL-1beta). The priming of IFN-gamma-producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3(-/-)) or caspase-1-deficient (Casp-1(-/-)) mice unless exogenous IL-1beta is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7(-/-) or Nlrp3(-/-) or Casp1(-/-) hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
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PMID:Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. 2239 93

Inflammation underlies most age-related diseases, including cancer, but the etiology is poorly understood. One proposed factor is the presence of senescent cells, which increase with age. The senescence response arrests the proliferation of potentially oncogenic cells, and most senescent cells secrete high levels of proinflammatory cytokines and other proteins. The complex senescence-associated secretory phenotype is likely regulated at multiple levels, most of which are unknown. We show that cell surface-bound IL-1alpha is essential for signaling the senescence-associated secretion of IL-6 and IL-8, 2 proinflammatory cytokines that also reinforce the senescence growth arrest. Senescent human fibroblasts expressed high levels of IL-1alpha mRNA, intracellular protein, and cell surface-associated protein, but secreted very little protein. An IL-1 receptor (IL1R) antagonist, neutralizing IL-1alpha antibodies, and IL-1alpha depletion by RNA interference all markedly reduced senescence-associated IL-6/IL-8 secretion. Depletion of the key IL-1R signaling component IRAK1 also suppressed this secretion, and IL-1alpha neutralizing antibodies prevented IRAK1 degradation, indicating engagement of the IL-1R signaling pathway. Furthermore, IL-1alpha depletion reduced the DNA binding activity of NF-kappaB and C/EBPbeta, which stimulate IL-6/IL-8 transcription. IL-1alpha was a general regulator of senescence-associated IL-6/IL-8 secretion because IL-1alpha blockade reduced IL-6/IL-8 secretion whether cells senesced owing to DNA damage, replicative exhaustion, oncogenic RAS, or chromatin relaxation. Furthermore, conditioned medium from IL-1alpha-depleted senescent cells markedly reduced the IL-6/IL-8-dependent invasiveness of metastatic cancer cells, indicating that IL-1alpha regulates the biological effects of these cytokines. Thus, cell surface IL-1alpha is an essential cell-autonomous regulator of the senescence-associated IL-6/IL-8 cytokine network.
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PMID:Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. 1980 69


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