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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoclonal antibodies (MoAbs) were raised against epidermal growth factor (EGF) receptors on a human epidermoid carcinoma cell line, A431. Administration of anti-EGF receptor MoAbs inhibited tumor formation in athymic mice by A431 cells and by another epidermal carcinoma cell line, T222. When one of the same MoAbs was used in therapy against Li-7 (a human hepatoma) and HeLa cells (a cervical carcinoma), tumor growth was not affected. The number of EGF receptors on A431 cells was about 100-fold higher than on T222, Li-7, and HeLa cells, suggesting that the number of EGF receptors may not be an important determinant in suppressing tumor growth. Three anti-EGF receptor MoAbs were used in the present studies. MoAbs 528 (immunoglobulin G2a) and 225 (immunoglobulin G1) are capable of competing with EGF for receptor binding and inhibit proliferation of A431 cells in culture. The other MoAb, 455 (immunoglobulin G1), is incapable of blocking the binding of EGF to its receptors and has no effect on the proliferation of cultured A431 cells. All three MoAbs inhibited A431 tumor growth in athymic mice, indicating that the antibody isotype and the site of binding on the EGF receptor are not the determinants of antiproliferative activity in vivo. The observation that MoAb against the receptor for EGF is cytostatic rather than cytocidal in vitro against A431 cells, yet completely prevents tumor growth in vivo, suggests that some host animal responses also may be involved in the antitumor effect. MoAbs against growth factor receptors could provide useful immunotherapeutic agents.
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PMID:Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. 631 79

A test of the mitogenic activity of greater than 40 purified and crude sources of hormones and growth factors revealed that epidermal growth factor, high density lipoprotein, an extract of bovine pituitary, hypothalamus, or whole brain, and the medium conditioned by differentiated human hepatoma cells were mitogenic for cultured endothelial cells derived from human umbilical vein. The four active agents combined with an improved nutrient medium and a collagen- or fibronectin-coated culture surface supported the growth of the endothelial cell population at a rate of 0.70-0.80 generations per day at both low and high cell densities in serum-free medium. The brain-derived activity exhibited properties reported by Maciag et al. [Maciag, T., Hoover, A. & Weinstein, R. (1982) J. Biol. Chem. 257, 5333-5336] and Gordon et al. [Gordon, P. B., Sussman, I. I. & Hatcher, V. B. (1983) In Vitro 19, 661-671]. The liver cell-derived activity was a specific product of differentiated hepatoma cells. The medium from HeLa cells, relatively undifferentiated rat liver cell lines, and human fibroblasts was inactive. Purified plasma proteins of liver origin could not substitute for the hepatoma cell-conditioned medium. The hepatoma cell-derived activity was non-dialyzable, heat-labile, stable between pH 4 to 11, inactivated by trypsin and mercaptoethanol treatment, and stable after treatment with 6 M urea and phenylmethylsulfonyl fluoride. The results provide a simplified model for elucidation of the endocrinology of human endothelial cell growth, function, and aging. We suggest an endocrine role of both the nervous system and liver in the regeneration of endothelial cells.
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PMID:Brain- and liver cell-derived factors are required for growth of human endothelial cells in serum-free culture. 633 82

Hepatic stimulator substance (HSS), a partially purified extract of weanling or regenerating adult rat liver, is an organ-specific stimulator of liver growth in vivo and in vitro. The HTC hepatoma cell line is particularly responsive to HSS. The present experiments show that HSS will stimulate HTC cells in the complete absence of serum, although graded doses of fetal cal serum (FCS), from 0.1 to 5.0%, will increase the degree of stimulation in a dose-dependent manner. In contrast, when HSS is absent, increasing doses of FCS above 0.5% inhibit DNA synthesis. Much of this inhibition is removed by prior dialysis of the FCS and maximum enhancement of the HSS-induced stimulation occurs with only 0.1-0.5% of the dialysed FCS. Sera from older animals have less or even negative effect. Evidence is presented to show that the enhanced stimulation by HSS in the presence of serum is not due to insulin, glucagon, epidermal growth factor (EGF), or platelet derived growth factor (PDGF) and that HSS does not act via a shared receptor for one of these hormones. These experiments provide further evidence that HSS is a unique stimulator of liver growth and lend support to a model of organ-specific growth control.
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PMID:Stimulation of HTC hepatoma cell growth in vitro by hepatic stimulator substance (HSS). Interactions with serum, insulin, glucagon, epidermal growth factor and platelet derived growth factor. 636 7

Insulin stimulates the growth and proliferation of a variety of somatic cells in culture, and evidence suggests that insulin is also an important regulator of growth in vivo. In cell culture, insulin interacts synergistically with other hormones and growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), tumor-promoting phorbol esters, and thrombin, to stimulate progression through the cell cycle of cells that have been arrested in G1 by deprivation for serum. In addition, insulin is required by most cells for optimal long term growth in hormone-supplemented serum-free media. In some cells, such as human skin fibroblasts, the growth-promoting effects of insulin appear to be mediated primarily by its low affinity interaction with receptors for insulin-like growth factor I (IGF-I). In other cells, such as hepatocytes, hepatoma cells, adrenocortical tumor cells, mammary carcinoma cells, and F9 embryonal carcinoma cells, insulin appears to stimulate growth by binding to high affinity insulin receptors. The insulin and IGF-I receptor proteins, like the receptor proteins for other growth-promoting hormones such as EGF and PDGF, are closely associated with tyrosine-specific protein kinase activities. The mechanism by which the binding of insulin to its receptor and activation of the receptor-associated tyrosine protein kinase activity control intracellular protein phosphorylation and dephosphorylation reactions, such as the phosphorylation of ribosomal protein S6, is a subject of considerable current interest. The phosphorylation of ribosomal protein S6 may be related mechanistically to the activation by insulin of protein synthesis, and hence the passage of cells through the G1 phase of the cell cycle. Malignant transformation does not generally result in a total loss of the growth requirement of cells for insulin or insulin-like growth factors, although transformation is accompanied in some cases by a qualitative reduction in the insulin/IGF requirement. Abnormalities in insulin production or sensitivity in vivo are accompanied by abnormalities in growth; thus, insulin appears to be an important regulator of growth in vivo. Some of the growth-promoting effects of insulin in vivo may be attributable to direct action of insulin, while other effects may be caused by the regulatory effect of insulin on somatomedin production, and possibly on somatomedin action.
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PMID:Growth-stimulatory actions of insulin in vitro and in vivo. 637 81

Although a long held tenet of biology has been that endogenous inhibitors can modulate cell proliferation, little progress was made in purifying any such inhibitor. This was largely due to the rarity of non-malignant cell cultures in which regulation of cell division was still operative, and to problems in separating cytotoxic and cytostatic effects in the complex biological extracts which were being studied. During the last decade, hepatic proliferation inhibitors of varying degrees of purity have been isolated using regenerating rat liver or hepatoma cell cultures as test systems. In these early studies, a number of inhibitors with differing molecular weights, physicochemical properties and biological responses were purified from liver cytosol and/or serum. Some of them could inhibit DNA synthesis or mitosis and thus were considered to be G1 or G2 inhibitors. However, experiments which could give precise answers about mechanisms of action could not be done until an inhibitor purified to homogeneity was available. Using well-characterized rat liver diploid epithelial cell cultures, which maintain a number of liver properties and which do not possess any transformation markers or malignant properties, we recently purified an hepatic proliferation inhibitor to a homogenous protein. It has a molecular weight of 26 000 daltons and an isoelectric point of 4.65. It specifically inhibits cell division and DNA synthesis in a number of non-malignant rat liver epithelial cell types, and has no effect on transformed liver cells, or hepatoma cells, in culture. Its effect is not mediated through destruction or sequestration of essential nutrients or calcium ions. Nor have preliminary experiments shown the hepatic proliferation inhibitor to interfere with the binding of epidermal growth factor to its receptors. The majority of the cells treated with the inhibitor are blocked in the G1 phase. Further experiments to study its mechanism of action and the inter-relationship, if any, between the cell cycle block induced by serum or nutrient deprivation, and the inhibitor-induced cycle block are in progress.
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PMID:Hepatic proliferation inhibitor. 642 63

Rat hepatoma cells were cultured in a medium with suboptimal concentration of fetal calf serum. In this low serum culture, retinoic acid inhibited the cell proliferation and enhanced the number of receptors for epidermal growth factor (EGF). On the contrary, teleocidin, a possible naturally occurring tumor promoter from Streptomyces, was a weak mitogen and inhibited EGF binding. A concurrent treatment of AH66 cells with these two compounds showed that they acted antagonistically. Retinoic acid inhibited the mitogenic action of teleocidin, while teleocidin suppressed the retinoic-acid enhancement of the number of EGF receptors. Retinoic acid could not prevent the alterations of the cell surface properties induced by a prolonged treatment with teleocidin. Furthermore, these two compounds appeared to be involved in the regulation of glycoprotein synthesis and the stimulation of cellular glycoprotein synthesis by retinoic acid was abolished by teleocidin. The present data suggest that retinoic acid selectively antagonizes the mitogenic action of teleocidin, and also indicate that the hepatoma cell cultures appear to prove a useful system for exploring the mechanisms of action of both retinoic acid and teleocidin.
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PMID:Antagonistic action of retinoic acid and teleocidin on the proliferation and epidermal growth factor binding of rat hepatoma cells. 679 26

To target gene expression to malignant hepatic cells, we have constructed recombinant retroviral vectors containing a reporter gene encoding nuclear beta-galactosidase (nls-LacZ) under transcriptional control of regulatory sequences from the rat alpha-fetoprotein (AFP) or human insulinlike growth factor II (IGFII) genes. The AFP and IGFII P3 promoters activate transcription during fetal development and are often reactivated in hepatocellular carcinoma (HCC). Infection of several cultured cell types with the retroviral vector containing the IGFII P3 sequence resulted in expression of the reporter gene in all cell lines tested, including those that do not produce IGFII. In contrast, selective expression was achieved by vectors containing the AFP transcriptional regulatory sequence. Nuclear beta-galactosidase activity was detectable in cells from lines that produce AFP, and not in cells that do not express the AFP gene. In most infected cell lines, retroviral RNA synthesis from the 5' LTR was inhibited, and deletion of the retroviral LTR enhancer did not change expression from either the IGFII P3-nls-LacZ or the AFP-nls-LacZ cassettes. After treatment of cells with 12-O-tetradecanoylphorbol-13-acetate and epidermal growth factor (EGF), the decrease in concentrations of endogenous AFP messenger RNA (mRNA) and nls-LacZ mRNA transcribed from the transferred AFP regulatory sequence were similar. In the context of an integrated provirus, the AFP transcriptional regulatory sequence is therefore subject to similar regulatory control as that of the endogenous gene. These data show that the AFP sequence, and not the IGFII P3 promoter we used, is suitable for targeting gene expression to malignant hepatic cells.
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PMID:Hepatoma cell-specific expression of a retrovirally transferred gene is achieved by alpha-fetoprotein but not insulinlike growth factor II regulatory sequences. 748 90

Using an automated cell analyzer system, the effect of hepatocyte growth factor/scatter factor (HGF/SF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), endothelial acidic fibroblast growth factor (a-FGF), platelet derived growth factor (PDGF), and recombinant human insulinlike growth factor (IGF) on the motility and morphology of Madin-Darby canine kidney (MDCK), rat hepatomas, C2, and H5-6 and murine mammary carcinoma (EMT-6) cells was investigated. Treatment of MDCK cells with HGF/SF, bFGF, EGF, and a-FGF resulted in an increase in average cell velocity and in the fraction of moving cells. Cells treated with the PDGF and IGF did not show significant alterations in velocity. MDCK cells treated with each growth factor were classified into groups of "fast" and "slow" moving cells based on their average velocities, and the average morphologic features of the two groups were quantitated. Fast-moving cells had larger average area, circularity, and flatness as compared to slow-moving cells. Factors that stimulated cell movement also induced alterations in cell morphologic parameters including spreading, flatness, area, and circularity. HGF/SF also scattered and stimulated motility of C2 and H5-6 hepatoma cells. In contrast to MDCK cells, there was no significant difference between the morphology of the fast moving and slow moving C2 and H5-6 cells. These studies suggest that growth factor cytokines have specific effects on motility of normal and tumor cells.
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PMID:Effect of hepatocyte growth factor/scatter factor and other growth factors on motility and morphology of non-tumorigenic and tumor cells. 751 97

Ethanol inhibits insulin (IN) and epidermal growth factor (EGF)-induced hepatocyte DNA synthesis. Growth factor receptor kinases, such as IN and EGF, phosphorylate insulin receptor substrate (IRS-1) and p36 protein kinase substrate, respectively, on tyrosine residues. IRS-1 and p36 are thought to be important intracellular signal transduction molecules involved in the regulation of cell growth. These investigations explored the effect of ethanol additions on the expression and tyrosyl phosphorylation (TP) of p36 and IRS-1 in a human hepatocellular carcinoma cell line (FOCUS) in relationship to cell proliferation induced by IN and serum growth factor stimulation. It was found that p36 was constitutively and highly expressed in serum-starved cells and protein, and mRNA levels did not change with cell proliferation induced by growth factors. However, exposure of FOCUS cells to ethanol additions substantially inhibited TP of p36. The early TP of IRS-1 induced by IN stimulation was also reduced by ethanol additions. Finally, there was a parallel decrease of FOCUS cell proliferation in ethanol-exposed cultures. These studies suggest that one possible mechanism of ethanol inhibitory effect on cell proliferation is through reduced TP of putative intracellular signal transduction molecules, such as p36 and IRS-1.
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PMID:Effect of ethanol on p36 protein kinase substrate and insulin receptor substrate 1 expression and tyrosyl phosphorylation in human hepatocellular carcinoma cells. 754 50

Intracellular pH (pHi) plays an important role in the metabolic activation of quiescent cells after a proliferative stimulus, and Na+/H+ exchange activity is required for growth in some extrahepatic tumors. To investigate intracellular acid/base homeostasis in hepatoma cells and the effects of putative liver growth factors on Na+/h+ exchange activity, we have studied intracellular pH (pHi) regulation in Hep G2 cells, a well-differentiated hepatoma cell line, both in resting conditions and after administration of epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), and insulinlike growth factor-II (IGF-II). The effects of fetal calf serum, TGF alpha, and amiloride on 3H-Thymidine incorporation were also studied. Amiloride (1 mmol/L) and external Na+ removal decreased baseline pHi in both HEPES and KRB. In HEPES, cells recovered from an acid load (20 mmol/L NH4Cl) by an amiloride inhibitable Na+/H+ exchange. In KRB, an additional, DIDS-inhibitable, Na(+)- and HCO3- dependent, but Cl(-)-independent acid extruder (Na:HCO3 cotransport) was activated. No evidence was found for a Cl/HCO3 exchange acting as acid loader. Administration of EGF and TGF alpha, but not of IGF-II, induced a dose-dependent, amiloride-inhibitable increase in baseline pHi, together with an increase in Na+/H+ exchange activity, shifting to the right the JH/pHi curve. Finally, 3H-thymidine incorporation in Hep G2 cells, in the presence of FCS or TGF alpha, was strongly inhibited by amiloride. In conclusion, in Hep G2 cells, pHi is mainly regulated by Na+/H+ exchange, which activity can be stimulated by EGF and TGF alpha, but not by IGF-II. Administration of TGF alpha stimulates DNA synthesis, an effect that is blocked by amiloride, an inhibitor of Na+/H+ exchanger. These data suggest that Na+/H+ exchange activation may play a critical role in the growth of some hepatic tumors.
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PMID:Intracellular pH regulation in Hep G2 cells: effects of epidermal growth factor, transforming growth factor-alpha, and insulinlike growth factor-II on Na+/H+ exchange activity. 763 29


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