UMLS:C0345904 - FACTA Search

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Query: UMLS:C0345904 (liver cancer)
15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor-infiltrating lymphocytes (TIL) were isolated from 22 human primary and metastatic liver tumors, and expanded in vitro in the presence of either interleukin-2 (IL-2, 100 U/ml) plus tumor necrosis factor alpha (TNF alpha, 1000 U/ml), IL-2 (1000 U/ml) plus IL-4 (1000 U/ml) or IL-2 (1000 U/ml) alone. TIL proliferated in culture in 20/22 cases. Among different cytoline combination, TNF alpha and IL-2 were most effective in promoting the outgrowth of CD3+CD8+T lymphocytes (mean +/- SEM: 90% +/- 5) in the cultures of TIL from primary liver tumors. Cytotoxicity against autologous tumor cells was demonstrated in all early cultures of TIL from primary liver cancers in the presence of IL-2 plus TNF alpha. In contrast, cultures of TIL derived from colon cancer metastatic to liver had significantly lower levels of autotumor cytotoxicity and proportions of CD3+CD8+ cells (40% +/- 13) than those of TIL from primary liver tumors. The addition on day 0 of interferons (alpha or gamma) to TIL cultured in the presence of TNF alpha and IL-2, significantly augmented cytotoxicity against autologous tumor. In contrast, incubation of TIL in the presence of IL-4 and IL-2 did not result in increased autotumor responses in the cultures of TIL from primary liver tumors. The expansion (-fold) of TIL (day 30) cultured in the presence of IL-2 alone compared to that in the presence of TNF alpha and IL-2 was significantly greater for hepatocellular carcinoma (median, 280 vs 260) than for autologous peripheral blood lymphocytes (36 vs 27), cholangiocarcinoma (42 vs 51) or TIL from metastatic colon cancer (39 vs 30). Outgrowth of TIL in IL-2 plus TNF alpha offers an opportunity for in vitro enrichment in cells with autotumor cytotoxicity in primary liver tumors. However, this cytokine combination was unable to promote and sustain growth of autotumor effectors from TIL in metastatic liver cancer.
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PMID:Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. 184 44

In order to evaluate the combination therapy for liver and bile tract cancer, the effects of anticancer drugs and hyperthermia were observed using cultured human cancer cell lines. In the case of gall bladder cancer cell line (NOZ), combination of adriamycin and hyperthermia showed more effective inhibition for cell proliferation than MMC + hyperthermia and 5-FU + hyperthermia. Hepatocellular carcinoma cell line (JHH-4) showed remarkable inhibition of cell growth and secretion of albumin by combination treatment of adriamycin and hyperthermia. Morphologically, JHH-4 cells were enlarged and the nucleus was also enlarged with combination adriamycin and hyperthermia by phase contrast microscopy. Cytoskeleton of JHH-4 cells became irregular and intercellular borderline was unclear by plasma polymerization replica method (PPRM). The effects of BRM (OK-432 and TNF) on HCC cell lines was also investigated. OK-432 directly inhibited proliferation of JHH-4 cells. We observed internalization of OK-432 by JHH-4 cells with TEM and 16-mm movie. TNF showed various effects on human HCC cell lines. Proliferation of two cell lines was inhibited, and one tended to be enhanced after the addition of TNF to the medium. Hyperthermia influenced the effects of TNF to HCC cell lines. We think that this paper is a very significant study for improving the therapy for hepato-biliary cancers.
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PMID:[Combination therapy of hyperthermia and other methods in liver and bile tract cancers--evaluation of these methods using cancer cell lines in vitro]. 254 27

Firstly, using HCC cell lines, the effects of r-h TNF were investigated. The authors had already confirmed that these cell lines were derived from human HCC. Each cell line showed a different growth curve on addition of TNF to the culture medium. JHH-4 exhibited enhancement of growth under the optimum concentration of TNF. On the other hand, growth of JHH-5 and JHH-7 was inhibited by TNF. JHH-7 were more sensitive to TNF than JHH-5, however, the direct effect of TNF on JHH-7 was not potent, as 10(4) u/ml TNF could not prevent proliferation of JHH-7. Morphological examinations were also performed. Phase-contrast microscopy showed that the JHH-4 cells were enlarged and tended to pile up after the addition of TNF to the culture medium. JHH-7 cells became detached from the culture dish due to cell death. Electron microscopy showed irregular proliferation of the rough endoplasmic reticulum of JHH-4 cells and increased number of lysosomes in JHH-7 cells. Furthermore, hyperthermia exhibited an interesting reciprocal action. Proliferation of JHH-4 was inhibited by low concentrations of TNF together with 41.4 degrees C hyperthermia in contrast to the effects of TNF alone. JHH-7 became more sensitive to TNF under hyperthermia at 41.4 degrees C. On the other hand, normal human fibroblast 'HAIN-55' were not affected by TNF at 37.0 degrees C, 41.4 degrees C or 42.5 degrees C. In this paper, the authors tried to study the effects of TNF and hyperthermia on human HCC cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of TNF on human hepatocellular carcinoma cell lines and their modification by hyperthermia]. 285

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.
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PMID:Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643. 911 Nov 98

WY-14,643 [4-chloro-6-(2,3-xylidino)pyrimidinylthio-acetic acid] is a well-known non-genotoxic carcinogen and peroxisome proliferator that causes liver cancer in rodents by unknown mechanisms. Its ability to sustain elevated rates of hepatocyte DNA synthesis is most likely pivotal in the ultimate development of tumors. The source of this mitogenic stimulus following treatment of rats with WY-14,643 has been hypothesized to be Kupffer cells, the resident hepatic macrophages, since they are activated by peroxisome proliferators in vivo. Therefore, these studies were designed to determine if Kupffer cells are causally responsible for WY-14 643-induced increases in hepatocyte DNA synthesis in vivo. WY-14,643 (100 mg/kg) increased DNA synthesis 8-fold 24 h after treatment; however, inactivation of Kupffer cells with methyl palmitate, a nonhydrolyzable fatty acid ester and known Kupffer cell inhibitor, completely prevented the mitogenic effect of WY-14,643. On the other hand, the ability of WY-14,643 to induce peroxisomes was not affected by methyl palmitate. These data demonstrate that induction of peroxisomes is not dependent on factors from Kupffer cells and support the idea that stimulation of DNA synthesis and induction of peroxisomes occur via distinct mechanisms. Additionally, WY-14,643 increased liver mRNA transcripts of the hepatocyte mitogen tumor necrosis factor alpha (TNF alpha) more than twofold. This increase was also prevented by inactivating Kupffer cells with methyl palmitate. Therefore, it is concluded that Kupffer cells are causally responsible for WY-14,643-induced increases in hepatocyte DNA synthesis most likely by increasing production of TNF alpha, a hepatic mitogen.
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PMID:Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. 927 15

Induction of liver cancer by peroxisome proliferators such as nafenopin is frequently associated with increased liver growth, increased DNA synthesis and suppression of apoptosis. The cytokine, tumour necrosis factor alpha (TNF alpha), and non-parenchymal liver cells have been implicated in mediating the hepatic response to peroxisome proliferators. Here, we have investigated the dependency of the hepatocyte response to peroxisome proliferators on non-parenchymal cells, a major source of hepatic cytokines. Addition of non-parenchymal cells, or conditioned medium from non-parenchymal cell cultures, increased DNA synthesis (220% and 270% of control, respectively) and suppressed transforming growth factor beta(1)-induced hepatocyte apoptosis (32% and 54% of control, respectively). Removal of non-parenchymal cells from normal hepatocyte cultures prevented both the nafenopin- and TNF alpha-induced increase in DNA synthesis and suppression of hepatocyte apoptosis; this response was restored by returning non-parenchymal cells to the purified hepatocytes. TNF alpha was detected in the medium of non-parenchymal cell (3-15 pg/ml) and normal hepatocyte cultures (25-100 pg/ml) by bioassay using L929 cells. However, the contribution of TNF alpha released from non-parenchymal cells was small compared with that released spontaneously by hepatocytes. Nafenopin significantly increased the release of TNF alpha from non-parenchymal cells to 56 +/- 18 pg/ml, but had little effect on TNF alpha release by hepatocytes. However, the concentration of exogenous TNF alpha required to elicit a response in hepatocytes was 100 pg/ml and above. These data provide evidence that hepatic non-parenchymal cells are permissive for the growth response of hepatocytes in vitro to peroxisome proliferators and this may be mediated, at least in part by TNF alpha. However, the levels of TNF alpha released spontaneously or in response to peroxisome proliferators are insufficient per se to induce a growth response.
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PMID:Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro. 1113 4

The nonviral gene delivery systems are usually not very effective in transferring gene into target cells, and the intensity and duration of the gene expression is very poor. The EBNA1/oriP maintain EBNA1/oriP-based plasmids as episome, contribute to nuclear transport of the plasmid and transcriptional up-regulation of target gene. The EBNA1/oriP based plasmid enhances the transfection rate as well as magnitude and longevity of gene expression. This article reviews recent preclinical gene therapy studies with the EBV plasmid vectors conducted against various diseases. For gene therapy against malignancies, the EBNA1/ oriP based plasmid encoding the HSV1-TK suicide gene was combined with a cationic polymer to transfer into HCC cell line. The expression level of TK gene was 100- to 1000-fold higher than the conventional plasmid. The sensitivity of HCC to ganciclovir (GCV) elevated several hundred-fold. The EBNA1/oriP based plasmid equipped with tumor specific promoter, such as CEA promoter, enabled targeted killing of CEA-positive tumor cell. Transfection of EBNA1/oriP based plasmid carrying IL-12 and IL-18 gene either locally, or systemically, induced therapeufic antitumor immune responses including augmentation of the cytotoxic T lymphocyte and natural killer activities and growth retardation of tumors. For gene therapy of congenital diseases and chronic diseases, the EBNA1/oriP based plasmid encoding the adenosine deaminase gene was transfered into human hematopoietic progenitor cells. The ADA activity was elevated 1.5-to 2-fold. Intracardiomuscrlar transfer of the EBNA1/oriP based plasmid encoding the beta-AR gene may be useful for the treatment of severe heart failure. Human tumor necrosis factoralpha (hTNFalpha) is one of the most important inflammatory cytokines. It has been implicated in many autoimmune and inflammatory diseases. sTNFR can efficiently neutralize the bioactivities of hTNFalpha. In primary study we cloned the chimeric protein sTNFR II-IgG Fc and expect to use it in the gene therapy of the inflammatory disease relative to TNF. In summary, The EBNA1/oriP based plasmid shows advantage in gene therapy of cancer, congenital and inflammatory diseases. Moreover, the EBNA1/oriP element may greatly contribute to the engineering of a human artificial chromosome, the ultimate device for controllable gene therapy.
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PMID:[Progress of EBNA1/oriP-based plasmid applied in gene therapy]. 1610 85

Isolated hepatic perfusion of nonresectable liver cancer using the combination of TNF and melphalan can be associated with a treatment-related hepatotoxicity. We investigated whether, apart from TNF, also melphalan is cytotoxic in primary murine liver cells in vitro and investigated mediators, mode of cell death, and cell types involved. Melphalan induced a caspase-dependent apoptosis in hepatocytes, which was not seen in liver cell preparations depleted of Kupffer cells. Neutralization of TNF prevented melphalan-induced apoptosis and liver cells derived from mice genetically deficient in either TNFR 1 or 2, but not from lpr mice lacking a functional CD95 receptor, were completely resistant. Cell-cell contact between hepatocytes and Kupffer cells was required for apoptosis to occur. Melphalan increased membrane-bound but not secreted TNF in Kupffer cells and inhibited recombinant TNF-alpha converting enzyme in vitro. Melphalan induced also severe hepatotoxicity in the isolated recirculating perfused mouse liver from wild-type mice but not from TNFR 1 or 2 knockout mice. In conclusion, this study shows that melphalan elicits membrane TNF on Kupffer cells due to inhibition of TNF processing and thereby initiates apoptosis of hepatocytes via obligatory activation of both TNFRs. The identification of this novel mechanism allows a causal understanding of melphalan-induced hepatotoxicity.
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PMID:Kupffer cell-expressed membrane-bound TNF mediates melphalan hepatotoxicity via activation of both TNF receptors. 1614 57

Tobacco smoke and its metabolites are carcinogens that increase tissue oxidative stress and induce target tissue inflammation. We hypothesized that genetic variation of inflammatory pathway genes plays a role in tobacco-related carcinogenesis and is modified by tobacco smoking. We evaluated the association of 12 single nucleotide polymorphisms of 8 inflammation-related genes with tobacco-related cancers (lung, oropharynx, larynx, esophagus, stomach, liver, bladder, and kidney) using 3 case-control studies from: Los Angeles (population-based; 611 lung and 553 upper aero-digestive tract cancer cases and 1,040 controls), Taixing, China (population-based; 218 esophagus, 206 stomach, 204 liver cancer cases, and 415 controls), and Memorial Sloan-Kettering Cancer Center (hospital-based; 227 bladder cancer cases and 211 controls). After adjusting for age, education, ethnicity, gender, and tobacco smoking, IL10 rs1800871 was inversely associated with oropharyngeal cancer (CT+TT vs. CC adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.50-0.95), and was positively associated with lung cancer among never smokers (TT vs. CT+CC aOR: 2.5, 95% CI: 1.3-5.1) and inversely with oropharyngeal cancer among ever smokers (CT+TT vs. CC aOR: 0.63, 95% CI: 0.41-0.95). Among all pooled never smokers (588 cases and 816 controls), TNF rs1799964 was inversely associated with smoking-related cancer (CC vs. CT+TT aOR: 0.36, 95% CI: 0.17-0.77). Bayesian correction for multiple comparisons suggests that chance is unlikely to explain our findings (although epigenetic mechanisms may be in effect), which support our hypotheses, suggesting that IL10 rs1800871 is a susceptibility marker for oropharyngeal and lung cancers, and that TNF rs1799964 is associated with smoking-related cancers among never smokers.
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PMID:Single nucleotide polymorphisms of 8 inflammation-related genes and their associations with smoking-related cancers. 2011 37

Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
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PMID:Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. 2063 47

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