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

We have established monoclonal antibodies (MAbs) against human vascular endothelial growth factor/vascular permeability factor121 (VEGF/VPF121). Two (MV101 and MV303) of the 28 MAbs neutralized the mitogenic activity of VEGF/VPF121 on human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner. Both of the MAbs reacted to VEGF/VPF121 and also VEGF/VPF165 with somewhat different binding properties in a sandwich-type enzyme-linked immunosorbent assay (ELSIA). The binding of MV101 and MV303 to VEGF/VPF121 was competitive, but MV415, another anti-VEGF/VPF121 MAb without neutralizing activity, did not complete with either of the antibodies. MV101 and MV303 specifically recognized the native form of VEGF/VPF121 and VEGF/VPF165 in Western blotting. They did not react with VEGF/VPF when the antigens were fractionated under reducing conditions. These observations suggested that MV101 and MV303 might recognize the epitopes closely located on the configuration of VEGF/VPF121 molecule and the epitopes recognized by MV101 and MV303 may play an important role in the VEGF/VPF-receptor signal transduction. These MAbs significantly suppressed the growth of a human hepatoma, PLC/PRF/5, in vivo.
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PMID:Isolation and characterization of neutralizing monoclonal antibodies to human vascular endothelial growth factor/vascular permeability factor121 (VEGF/VPF121). 857 96

Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine and the resulting conjugates could interact with DNA in a noncovalent bond to form a complex. Using pSV2-beta-galactosidase as a reporter gene, it has been demonstrated that exogenous gene was transferred into bovine aortic arch-derived endothelial cells (ABAE) and human malignant melanoma cell lines (A375) in vitro. In vivo experiments, exogenous gene was transferred into tumor vascular endothelial cells and tumor cells of subcutaneously transplanted human colon cancer LOVO, human malignant melanoma A375 and human hepatoma graft in nude mice. This system could also target gene to intrahepatically transplanted human hepatoma injected via portal vein in nude mice. These results are correlated with the relevant receptors (flt-1, flk-1/KDR) expression on the targeted cells and tissues.
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PMID:A novel gene delivery system targeting cells expressing VEGF receptors. 1032 85

We previously reported that in vitro hypoxic condition enhanced VEGF level and its receptor expression in hepatic cancer cell line, HepG2. Transcatheter hepatic arterial embolization (TAE) therapy is one of the vasculo-occlusive and hypoxic challenges to hepatocellular carcinoma (HCC). Therefore, we examined the level of VEGF in sera of patients with HCC who underwent TAE during the course of the treatment. Thirty-eight patients with HCC and hepatitis C virus-positive cirrhosis were studied. Peripheral blood samples were taken before and 1, 3 and 7 days after TAE with informed consent. The serum levels of VEGF as well as hepatocyte growth factor (HGF), another hepatic remodeling factor, were measured. The molar ratio (BTR) of serum branched chain amino acid (BCAA) to tyrosine (Tyr), the serum levels of AST, ALT and LDH were also examined. Although the level of AST, ALT and LDH reached the peak value within 1 day after TAE, VEGF level increased significantly 7 days later. On the other hand, there were no significant alterations in the levels of HGF and BTR during the course of TAE. Although the level of HGF was significantly correlated with the level of VEGF before TAE, this correlation was no more observed after TAE. These data collectively suggest that VEGF may be secreted in response to clinical hypoxic intervention, TAE, independent of HGF or altered amino acid metabolism. VEGF may play a role as a sensitive marker for tumor ischemia.
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PMID:Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma. 1033 62

Mechanisms regulating angiogenesis in human hepatomas were analyzed. Huh7 hepatoma cells transplanted into athymic mice formed highly vascularized reddish tumors with abundant microvessels, while angiogenesis by PLC/PRF/5 hepatoma cells was less remarkable. However, the production of angiogenesis stimulators such as VEGF and IL6 by Huh7 cells was much less than by PLC/PRF/5 cells. In addition, the production of angiogenesis inhibitor TSP-1 by Huh7 cells was greater than by PLC/PRF/5 cells. Therefore, the difference in angiogenesis between these two hepatomas was not explained by the production of these known angiogenesis regulators. On the other hand, PLC/PRF/5 cells but not Huh7 cells secreted an inhibitor of the proliferation of vascular endothelial cells, which was enhanced by p53-gene transfer. These results suggest that the production of this p53-inducible angiogenesis inhibitor is responsible, at least partly, for the regulation of angiogenesis in human hepatomas.
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PMID:Regulation of angiogenesis in human hepatomas: possible involvement of p53-inducible inhibitor of vascular endothelial cell proliferation. 1045 46

The vascular endothelial growth factor-A (VEGF-A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF-A are mediated through flt-1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than those of VEGF-A nAb. The autophosphorylation of KDR/ Flk-1 in the peritoneal wall was almost completely abolished by KDR/ Flk-1 nAb, whereas a certain level of activation was still shown by VEGF-A nAb treatment. Another VEGF-family, VEGF-C, which also binds KDR/Flk-1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk-1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF-A, VEGF-C may also be involved in the malignant ascites formation via KDR/ Flk-1 activation.
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PMID:The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. 1128 48

Ras-VEGF-concerned angiogenesis is correlated with oncogene maintenance, tumorigenesis, metastasis and resistance to anti-cancer therapies; however, this association is not clearly elucidated by serum VEGF, due to VEGF signalling in blood cells themselves. The present study aimed to elucidate tumorigenic VEGF signalling in eight human HCC cell types and reveal the kinetics of tumorigenic VEGF signalling in three time intervals, thereby discovering the relationships of VEGF-concerned angiogenesis signalling with the extent of the human HCC cell growth, metastasis and resistance to anti-cancer drugs, by using the poorly metastatic SMMC7721, 7402/D+ (doxorubicin-resistance) and 7402/D- (doxorubicin-withdrawal), the highly metastatic MHCC1 non-transfected human HCC cell lines, and the highly metastatic A3-1, F8, F11 and E3 human HCC cell lines transfected with expressing green fluorescence protein into the phenotype of MHCC1 cells, and quantitative 'sandwich' ELISA analyses. The unique results indicated attributes and objective laws as follows. Human HCC cell growth requires time-dependent tumorigenic VEGF signalling; levels of VEGF signalling are positively correlated with each cell phenotype itself; and levels of VEGF signalling are inversely correlated with the possibility of metastasis and drug resistance. The contrast data first reveal important clues for exploring dual metastatic mechanisms via tumor cell-generated non-endothelium vasculogenesis and VEGF-endothelium-attached angiogenesis that may be essential for developing novel strategies aimed at VEGF-concerned signal networks in ischemic/metastatic diseases and transgenic models.
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PMID:Kinetics of tumorigenic vascular endothelial growth factor signalling and its significance in human hepatocellular carcinoma cells. 1129 13

In this study we have explored the feasibility of generating angiostatin by incorporating an endoproteolytic furin cleavage site into plasminogen to allow conversion of the precursor molecule into an angiostatic active K1-3 fragment. We show that secretable angiostatin can be successfully generated from cells infected with adenovirus carrying the furin-mutated plasminogen (AdmuthPlgK3). Supernatant from cells transduced with AdmuthPlagK3 inhibits tube formation and proliferation and migration of human umbilical vein endothelial cells with an efficiency similar to that of supernatant from cells infected with adenovirus expressing kringle 1-3 of plasminogen (AdK1-3). Administration of AdmuthPlgK3 and AdK1-3 in mice results in significantly decreased endothelial cell infiltration in VEGF-embedded Matrigel plugs. Treatment with AdmuthPlgK3 and AdK1-3 exerts strong antitumoral effect in models of hepatocellular carcinoma and Lewis lung cancer. This antitumor effect was associated with decreased microvessel density in the tumors. Taken together, our data demonstrate that angiostatin endowed with strong antiangiogenic and antitumor effects can be released from a furin-mutated plasminogen acting as a precursor. This strategy may have potential to develop angiostatic anti-cancer therapies.
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PMID:A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen. 1242 12

Ninety individuals (76 males and 14 females) were classified into four groups. G1 (Control) included 20 healthy individuals. G2 (Chronic hepatitis) included 20 patients, G3 (Liver cirrhosis group) included 30 patients, and G4 (HCC) included 20 patients with HCC. All groups were subjected to clinical examination, abdominal ultrasonography, complete blood picture, HCV antibodies, HBs Ag, and function tests (total and direct bilirubin, total plasma proteins and albumin, prothrombin time and concentration, and liver enzymes AST, ALT and ALP). Patients of G3 & 4 were classified according to Child-Pugh classification into A. B and C. Upper endoscopic examination was done for 36/50 patients with chronic hepatitis or HCC. Circulating VEGF levels were determined by ELISA. There was a statistically high significant levels of circulating VEGF in G1, 2 & 3 than in the controls. A statistically significant higher level of circulating VEGF in G4 than in G3 & G4, and a statistically negative significant between VEGF levels and platelet count in G2. No significant correlation between VEGF and the grade of esophageal varices in G3 & G4. and no significant correlation between VEGF and upper GIT bleeding or spider naevi (vascular skin changes) in G2. A statistically significant was in correlation between VEGF and degree of hepatic dysfunction.
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PMID:Vascular endothelial growth factor level in chronic liver diseases. 1251 23

To investigate the relationship of the expression of vascular endothelial factor (VEGF) and matrix metalloproteinase-2 (MMP-2) with the recurrence and metastasis of hepatocellular carcinoma (HCC), the expression of VEGF and MMP-2 in HCC tissue(n = 50) and in normal liver tissue(n = 30) were examined by immunochemistry. The results showed that the positive rates of VEGF and MMP-2 in HCC tissue were 86% and 60% respectively, and in normal liver tissue were 53.3% and 30% respectively. The positive rates of VEGF and MMP-2 in HCC were significantly higher than those in normal liver tissue. The positive rates of VEGF and MMP-2 in HCC with intra- or extra-hepatic metastasis were higher than those of HCC without metastasis. VEGF and MMP-2 play important roles in the invasion and metastasis of HCC.
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PMID:Expression of vascular endothelial growth factor and matrix metalloproteinase-2 correlates with the invasion and metastasis of hepatocellular carcinoma. 1285 90

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade's studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experimental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC.
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PMID:A decade's studies on metastasis of hepatocellular carcinoma. 1468 50


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