Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncolytic vesicular stomatitis virus (VSV) is being developed as a novel therapeutic agent for cancer treatment, although it is toxic in animals when administered systemically at high doses. Its safety can be substantively improved by an M Delta 51 deletion in the viral genome, and yet VSV(M Delta 51) induces a much greater, robust cellular inflammatory response in the host than wild-type VSV, which severely attenuates its oncolytic potency. We have reported that the oncolytic potency of wild-type VSV can be enhanced by vector-mediated expression of a heterologous viral gene that suppresses cellular inflammatory responses in the lesions. To develop an effective and safe VSV vector for cancer treatment, we tested the hypothesis that the oncolytic potency of VSV(M Delta 51) can be substantively elevated by vector-mediated expression of M3, a broad-spectrum and high-affinity chemokine-binding protein from murine gammaherpesvirus-68. The recombinant vector rVSV(M Delta 51)-M3 was used to treat rats bearing multifocal lesions (1-10 mm in diameter) of hepatocellular carcinoma (HCC) in their liver by hepatic artery infusion. Treatment led to a significant reduction of neutrophil and natural killer cell accumulation in the lesions, a 2-log elevation of intratumoral viral titer, substantively enhanced tumor necrosis, and prolonged animal survival with a 50% cure rate. Importantly, there were no apparent systemic and organ toxicities in the treated animals. These results indicate that the robust cellular inflammatory responses induced by VSV(M Delta 51) in HCC lesions can be overcome by vector-mediated intratumoral M3 expression, and that rVSV(M Delta 51)-M3 can be developed as an effective and safe oncolytic agent to treat advanced HCC patients in the future.
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PMID:rVSV(M Delta 51)-M3 is an effective and safe oncolytic virus for cancer therapy. 1853 93

Most hepatocellular carcinomas (HCCs) express oncofetal alpha-fetoprotein (AFP). We and others have demonstrated efficient tumor control mediated by cellular immune responses in mice bearing subcutaneous tumors derived from the AFP-expressing murine HCC cell line Hepa 1-6 by DNA vaccination against AFP. In the present study, we examined AFP DNA vaccination in the AFP-expressing primary murine HCC model BW7756. In this model AFP DNA vaccination resulted in only minimal lymphocytic infiltration and failed to control tumor growth. To augment the AFP-specific cellular immune response, intratumoral expression of chemokine IP-10 (interferon-inducible protein-10) and the proinflammatory cytokine interleukin (IL)-12 by adenoviral vectors (AdmIL-12 and AdmIP-10) was analyzed. Intratumoral injection of AdmIL-12 and AdmIP-10 resulted in transient tumor regressions, without prolongation of animal survival. By contrast, AFP DNA vaccination followed by intratumoral injection of AdmIL-12 and AdmIP-10 resulted in tumor regression in all animals and in prolongation of animal survival; in 25% of animals the tumors became undetectable. This study demonstrates for the first time that activation of effector cells against a tumor antigen induced by the combination of DNA vaccination and intratumoral chemokine and cytokine expression is superior to the respective treatment strategies alone. This effect may be mediated by attraction of activated effector cells to the tumor tissue.
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PMID:Immunotherapy of murine hepatocellular carcinoma by alpha-fetoprotein DNA vaccination combined with adenovirus-mediated chemokine and cytokine expression. 1854 8

The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.
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PMID:Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1- and 5-dependent manner in mice. 2942 58

Chemokines are involved in human hepatocellular carcinoma (HCC) carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 +/- 1.13, 2.34 +/- 1.16 and 1.63 +/- 1.26, respectively and that the CXCR4 protein levels were 1.38 +/- 0.13, 1.96 +/- 0.32 and 1.86 +/- 0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 +/- 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes (CI) of 3.9 +/- 1.1 and 4.1 +/- 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 +/- 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.
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PMID:Roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells. 1895 61

The aim of this study is to assess whether fucoidan modulates the expression of chemokine ligand 12 (CXCL12)/chemokine receptor 4 (CXCR4) and exerts antitumor activity toward Huh7 hepatoma cells. According to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, fucoidan inhibited the growth of Huh7 cells and HepG2 cells in a dose-dependent manner, with a 50% inhibition of cell growth (IC50) of 2.0 and 4.0 mg/ml, respectively. alpha-fetoprotein levels in medium collected from fucoidan-treated cells were significantly decreased in Huh7 cells but not in HepG2 cells. Western blotting revealed that the amount of alpha-fetoprotein was decreased by 1.0 mg/ml of fucoidan in Huh7 cells, whereas it was unchanged in HepG2 cells. In Huh7 cells, CXCL12 mRNA expression was significantly downregulated by 1.0 mg/ml of fucoidan, whereas CXCR4 mRNA expression was unchanged by fucoidan. CXCL12 and CXCR4 mRNA were barely expressed in HepG2 cells. In addition, 1.0 mg/ml of fucoidan mildly arrested the cell cycle and induced apoptosis in Huh7 cells. The findings suggest that fucoidan exhibits antitumor activity toward Huh7 cells through the downregulation of CXCL12 expression.
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PMID:Inhibitory effect of fucoidan on Huh7 hepatoma cells through downregulation of CXCL12. 1937 7

Recent studies have demonstrated that the chemokine receptor CXCR4 plays a crucial role in organ-specific metastasis formation. Although a variety of studies showed the expression of chemokine receptors, in particular, CXCR4, by gastrointestinal tumors, the precise mechanisms of chemokine receptor-mediated homing of cancer cells to specific sites of metastasis remained elusive. Here, we used liver metastatic human HEP-G2 hepatoma and HT-29LMM colon cancer cells expressing functional CXCR4 to dissect the metastatic cascade by intravital fluorescence microscopy. Immunohistochemistry revealed that the CXCR4 ligand CXCL12 is expressed by endothelial cells and likely Kupffer cells lining the liver sinusoids. Tumor cell adhesion and extravasation in vivo was quantitatively analyzed using intravital fluorescence microscopy. Treatment of cells with an anti-CXCR4 antibody did not affect cell adhesion but significantly impaired tumor cell extravasation (HEP-G2; isotype control: 22.3% +/- 4.3% vs anti-CXCR4: 6.0% +/- 5.0%, P < .001). In addition, pretreatment of tumor cells with the ligand CXCL12 enhanced the activation of the small GTPases Rho, Rac, and cdc42 as well as tumor cell extravasation without affecting tumor cell adhesion within liver sinusoids. Taken together, the findings of the present study provide first in vivo insights into the early events of chemokine ligand/receptor-mediated liver metastasis formation of tumor cells and define tumor cell extravasation rather than tumor cell arrest as the rate-limiting event.
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PMID:CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. 1956 10

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by beta-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.
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PMID:Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. 1964 41

Vascular endothelial growth factor-correlated chemokine 1 (VCC-1), a novel chemokine, is hypothesized to be associated with carcinogenesis. VCC-1 is expressed in hepatocellular carcinoma (HCC) cells, but its function remains unknown. To investigate the molecular effects of VCC-1 on HCC cells, the HCC cell line SMMC7721 was stably transfected with the recombinant plasmid pcDNA3.1/VCC-1. Our data demonstrated that overexpression of VCC-1 in SMMC7721 cells significantly enhanced the cellular proliferation, invasive ability, and tumor growth, when compared with both empty vector control cells and parental cells. These results strongly suggest that VCC-1 plays an important role in SMMC7721 invasion and tumor growth, and indicate that VCC-1 may serve as a potential biomarker for anti-HCC therapies.
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PMID:Overexpression of VCC-1 gene in human hepatocellular carcinoma cells promotes cell proliferation and invasion. 1965 64

We have recently reported that the CXC-chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 induces proliferation, migration, and invasion of the Huh7 human hepatoma cells through its G-protein-coupled receptor CXCR4 and that glycosaminoglycans (GAGs) are involved in these events. Here, we demonstrate by surface plasmon resonance that the chemokine binds to GAG mimetics obtained by grafting carboxylate, sulfate or acetate groups onto a dextran backbone. We also demonstrate that chemically modified dextrans inhibit SDF-1/CXCL12-mediated in vitro chemotaxis and anchorage-independent cell growth in a dose-dependent manner. The binding of GAG mimetics to the chemokine and their effects in modulating the SDF-1/CXCL12 biological activities are mainly related to the presence of sulfate groups. Furthermore, the mRNA expression of enzymes involved in heparan sulfate biosynthesis, such as exostosin-1 and -2 or N-deacetylase N-sulfotransferases remained unchanged, but heparanase mRNA and protein expressions in Huh7 cells were decreased upon GAG mimetic treatment. Moreover, decreasing heparanase-1 mRNA levels by RNA interference significantly reduced SDF-1/CXCL12-induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation. Therefore, we suggest that GAG mimetic effects on SDF-1/CXCL12-mediated hepatoma cell chemotaxis may rely on decreased heparanase expression, which impairs SDF-1/CXCL12's signaling. Altogether, these data suggest that GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and may affect heparanase expression, leading to reduced SDF-1/CXCL12 mediated in vitro chemotaxis and growth of hepatoma cells.
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PMID:Glycosaminoglycan mimetics inhibit SDF-1/CXCL12-mediated migration and invasion of human hepatoma cells. 1971 93


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