Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1864663 (HCC)
 2,985 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

BACKGROUND: Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN) conditioned medium alone, and supplemented with serine proteinase inhibitor alpha-1 antitrypsin (AAT) or its C-terminal fragment (C-36 peptide), on cultured lung cancer cells. METHODS: Lung cancer HCC cells were grown in a regular medium or in a PMN-conditioned medium in the presence or absence of AAT (0.5 mg/ml) or its C-36 peptide (0.06 mg/ml) for 24 h. Cell proliferation, invasiveness and release of IL-8 and VEGF were analyzed by [3H]-thymidine incorporation, Matrigel invasion and ELISA methods, respectively. RESULTS: Cells exposed to PMN-conditioned medium show decreased proliferation and IL-8 release by 3.9-fold, p < 0.001 and 1.3-fold, p < 0.05, respectively, and increased invasiveness by 2-fold (p < 0.001) compared to non-treated controls. In the presence of AAT, PMN-conditioned medium loses its effects on cell proliferation, invasiveness and IL-8 release, whereas VEGF is up-regulated by 3.7-fold (p < 0.001) compared to controls. Similarly, C-36 peptide abolishes the effects of PMN-conditioned medium on cell invasiveness, but does not alter its effects on cell proliferation, IL-8 and VEGF release. Direct HCC cell exposure to AAT enhances VEGF, but inhibits IL-8 release by 1.7-fold (p < 0.001) and 1.4-fold (p < 0.01) respectively, and reduces proliferation 2.5-fold (p < 0.01). In contrast, C-36 peptide alone did not affect these parameters, but inhibited cell invasiveness by 51.4% (p < 0.001), when compared with non-treated controls. CONCLUSIONS: Our data provide evidence that neutrophil derived factors decrease lung cancer HCC cell proliferation and IL-8 release, but increase cell invasiveness. These effects were found to be modulated by exogenously present serine proteinase inhibitor, AAT, and its C-terminal fragment, which points to a complexity of the relationships between tumor cell biological activities and local microenvironment.
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PMID:alpha1-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro. 1555 67

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in PR positive ZR-75 and MCF-7, or in PR negative MDA-MB-231 cells. This indicated that factors beside PR are involved in progesterone-dependent VEGF regulation. We, therefore, tested additional tumor cell lines reported to contain PR for progestin-dependent VEGF induction. Out of nine PR-positive breast tumor cell lines, progestins induced VEGF in three cell lines that lack wild-type p53 (T47-D, BT-474, and HCC-1428) but not in cell lines that contained the wild-type p53 protein. The T47-D and BT-474 cells express mutant p53, while the p53 protein is absent HCC-1428 cells. The anti-progestin RU-486 blocked progestin-dependent induction of VEGF in T47-D and BT-474 cells but not in HCC-1428 cells. However, RU-486 partially blocked medroxyprogesterone acetate-dependent induction of VEGF in HCC-1428 cells. Estrogen receptor (ER) and PR agonists and antagonists also induce VEGF in HCC-1428 cells and this effect was partially blocked by anti-estrogen ICI-182, 780. Progestin-dependent VEGF induction was completely inhibited by PRIMA-1-activated p53 in all cell-types, but progestin-dependent transcription of a progesterone-regulated minimal promoter was only partially inhibited. PRIMA-1 induced activation of p53 in tumor cell lines was confirmed with a p53-responsive p21 reporter plasmid and by detecting increased levels of p21 proteins in cell lysates. PRIMA-1 induced p53 protein in the HCC-1428 cells while levels of mutant p53 protein in T47-D and BT-474 remained unaltered. Progestin-dependent induction of VEGF was also inhibited by stable transfection of wild-type p53 in T47-D cells. These results are consistent with the hypothesis that wild-type p53 blocks progestin-dependent induction of VEGF in breast cancer cells and this may be a novel anti-angiogenic mechanism for controlling the growth of progestin-dependent tumors.
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PMID:p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells. 1586 Feb 60

The pre-therapeutic serum levels of VEGF and MMP-9 were studied in patients with HCC, cirrhotic patients and in healthy subjects by an ELISA assay to elucidate the relationship between serum VEGF, MMP-9 levels and clinicopathological characteristics of HCC. The serum VEGF and MMP-9 were significantly elevated in HCC patients with macroscopic portal vein invasion and with metastasis as compared to HCC patients with neither invasion nor metastasis. Serum VEGF showed a significant difference between HCC patients with tumor size >5cm and <5 cm, however serum MMP-9 did not vary with tumor size. It was concluded that the portal vein invasion and metastasis in HCC is a complex process involving multiple factors including VEGF-mediated angiogenesis and MMP-9 induced degradation of extracellular matrix. The pre-therapeutic serum VEGF & MMP-9 in HCC might be candidate biomarkers reflecting the disease potential for vascular invasion and metastasis, serum VEGF being a superior biomarker as it correlated also with tumor size.
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PMID:Assessment of the clinical significance of serum vascular endothelial growth factor and matrix metalloproteinase-9 in patients with hepatocellular carcinoma. 1633 96

We investigated the effect of AEE788, a novel dual receptor tyrosine kinase inhibitor of the EGF and the VEGF receptor, for treatment of human HCC cell lines and in a subcutaneous xenograft model. Cell viability and apoptosis of HepG2 and Hep3B cells incubated with 0.1-100 microM AEE788 were quantified. In vivo, HepG2 cells were xenografted to NMRI mice and animals were treated orally with 50 mg/kg AEE788 3x/week. Immunohistochemistry and quantitative Western blotting was performed for pathway analysis in vitro and in vivo. AEE788 reduced growth and induced apoptosis of HCC cells by disrupting mitochondrial transmembrane potentials and inhibiting MAPK phosphorylation. In the xenografts, AEE788 lead to a reduced tumor growth by reducing proliferation and vascularisation. Except for a reversible skin reaction and weight loss, no signs of toxicity were observed. AEE788 is a promising new option for the treatment of HCC.
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PMID:The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice. 1881 86

The study aimed to clarify whether vascular endothelial growth factor mRNA (VEGF mRNA) and TNFa mRNA in the HCC tissues on top of HCV with and without cirrhosis obtained from specimens after curative hepatic resection has a prognostic value and recurrence predictive value compared to other tumor criteria. A total of 160 patients were studied. The preoperative laboratory, radiological and staging to patients was done. Using in situ hybridization technique, VEGF mRNA and TNFa mRNA were determined in liver tissues of, 10 controls, 50 with HCC, 50 with HCV without cirrhosis and 50 HCV with cirrhosis. The results showed that in HCC cases there was positive correlation between increasing age, loss of weight, INR and AFP but not in other cases of CHC with or without cirrhosis. AFP, vascular invasion, encapsulation, tumor size and grade and platelet count were related to patients outcome and recurrence of tumor after follow up of most cases for 3 years. The expression of VEGF in liver tissues was proportional to progress of viral hepatitis to cirrhosis with more expression in cases progressed to malignant changes. More expression of VEGF in HCC was more evident with intense expression in cases with Vascular and capsular invasion and higher level of AFP. Expression of TNF alpha mRNA and VEGF mRNA shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positive with cases developed HCC.
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PMID:Prognostic value of TNF a mRNA and VEGF mRNA expression in patients with chronic hepatitis C genotype-4, with and without cirrhosis and hepatocellular carcinoma to predict disease outcome. 2124 58

Control of VEGF signaling is an intense objective of pre-clinical and clinical studies in HCC disease with steadily increasing clinical application. Despite its emerging role, several aspects of anti-VEGF based treatments are poorly investigated, like the impact on tumor cells themselves, such as the effect on intracellular signaling and apoptosis induction in hepatoma cells. Effects of siRNA-VEGF on VEGF, VEGF-receptor expression and VEGF-A signaling such as AKT and JNK phosphorylation were determined under normoxic or hypoxic conditions in murine hepatoma cells. Apoptosis induction was analyzed by SubG1-fraction, JC1-staining and caspase-8 activation. VEGF receptor expression was analysed by semiquantitative real time PCR. Independent of oxygen status, siRNA-VEGF reduced VEGF levels resulting in decreased AKT and increased JNK phosphorylation in Hepa129 cells. The VEGF-receptors neuropilin-1 (Nrp1) and neuropilin-2 (Nrp2) were downregulated following siRNA-VEGF treatment or hypoxia induction respectively. Functionally, hypoxia significantly increased the apoptosis rate (as analyzed by SubG1-fraction, JC1-staining and JNKphosphorylation) which was further stimulated by siRNA-VEGF treatment. Our data indicate that antitumoral efficacy of an anti-VEGF based treatment with siRNA is partly based on negative autocrine feedback mechanisms which are even enhanced under hypoxic conditions. This observation helps to understand why antitumoral efficacy can be maintained despite of counteracting stimulation of tumoral VEGF secretion due to hypoxia. The direct impact on tumor cells further underscores the attractiveness of an anti-VEGF based siRNA treatment.
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PMID:Combination of hypoxia and RNA-interference targeting VEGF induces apoptosis in hepatoma cells via autocrine mechanisms. 2160 70

Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.
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PMID:Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: a randomized control trial. 2187 60

Whereas surgical resection is the only curative treatment for liver tumors, effective treatment for isolated unresectable lesions when there is tumor progression in spite of several lines of chemotherapy remains to be found. We report herein two cases of patients treated by a 1-hour Hyperthermic Isolated Liver Perfusion (HILP) with a combination of melphalan and bevacizumab leading to complete response. The first patient had liver metastases secondary to previously resected malignant glucagonoma and the second, recurrent hepatocellular carcinoma. We used bevacizumab in association with melphalan for HILP because of the additional effect of an anti-VEGF antibody in these highly vascularized tumors and its locally restricted delivery to the isolated hepatic vascular compartment despite of its classic contraindication in association with surgery. The protocol was approved by the Ethics Committee. Enhanced CT scans during follow-up showed complete tumor necrosis as early as the second postoperative day. Patients had 27 and 7 months disease-free survival and 48 and 41 months overall survival after HILP, for neuroendocrine liver metastases and HILP plus liver transplantation for HCC respectively. Under very specific conditions, bevacizumab in HILP can provide excellent tumor response in hopeless clinical cases of liver tumors.
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PMID:Hyperthermic isolated liver perfusion with melphalan and bevacizumab. 2318 50


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