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Biomedical subjects

Iain H McKillop

Publications and source records attributed to Iain H McKillop.

10 recordsLinked to original sources
PubMed2006

Decreased aquaporin expression leads to increased resistance to apoptosis in hepatocellular carcinoma.

Cells undergoing apoptosis are characterized by decreased cell size due to changes in intracellular ion concentration and rapid, aquaporin (AQP)-dependent water movement out of the cell, events required for the activation of pro-apoptotic enzymes. The current study demonstrates AQP 8 and 9 expression is significantly decreased in hepatocellular carcinoma (HCC) versus normal liver. Isolation of hepatic tumor cells (H4IIE) and hepatocytes confirmed a lack of water movement across the H4IIE cell membrane via AQPs and identified an inherent resistance of H4IIE cells to apoptotic stimuli. In contrast, hepatocytes rapidly responded to osmotic challenge through AQP-dependent water movement and underwent cell death following apoptotic stimulation.

Animals↗
PubMed2006

Molecular pathogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common life-threatening malignancies in the world. This cancer generally arises within the boundaries of well-defined causal factors, of which viral hepatitis infection, aflatoxin exposure, chronic alcohol abuse, and nonalcoholic steatohepatitis are the major risk factors. Despite the identification of these etiological agents, hepatocarcinogenesis remains poorly understood. The molecular mechanisms leading to the development of HCC appear extremely complex and only recently have begun to be elucidated. Currently, surgical resection or liver transplantation offer the best chance of cure for the patient with HCC; however, these therapies are hindered by inability of many of these patients to undergo liver resection, by tumor recurrence and by donor shortages. A lack of suitable therapeutic strategies has led to a greater focus on prevention of HCC using antiviral agents and vaccination. Overall, the current outlook for patients with HCC is bleak; however, a better understanding of the molecular and genetic basis of this cancer should lead to the development of more efficacious therapies.

Animals↗
PubMed2006

Bosentan inhibits tumor vascularization and bone metastasis in an immunocompetent skin-fold chamber model of breast carcinoma cell metastasis.

Angiogenic factors including endothelin-1 (ET-1) play a key role in the progression of breast metastases to bone. We investigated the impact of ET-1 on the development of bone metastases in an immunocompetent murine skin-fold chamber model. Murine mammary carcinoma 4T1 was injected in a skin-fold chamber implanted on CB6 mice along with bone explants. Furthermore, mice were treated with or without a dual selective antagonist of both ET-1 receptors. The progression of the vascularization within the chamber was monitored over time by intravital microscopy (IVM). The tumor growth and the development of bone metastases were assessed by cytokeratin-19 gene expression and histological studies. Results indicate that this new model associated with IVM allows for the continuous monitoring of the change in vascularization associated with the development of bone metastases. Additionally, treatment with an antagonist of both ET-1 receptors was associated with the presence of significantly less vessels near the tumor mass compared to control mice. These changes were correlated with smaller tumor masses and reduced bone invasion (P < 0.05). Thus, in an immunocompetent murine model of breast carcinoma metastases to bone, our data support the hypothesis that vascularization plays a role in tumor development and progression and that ET-1 specifically modulates the angiogenesis associated with breast metastases to the bone.

Angiogenesis Inhibitors↗
PubMed2006

Role of cyclic-AMP responsive element binding (CREB) proteins in cell proliferation in a rat model of hepatocellular carcinoma.

The role of cyclic adenosine monophosphate (cAMP) is poorly understood in the regulation of normal and abnormal hepatic cell growth. In this study, we examined the regulation of intracellular cAMP levels and its effect on nuclear cAMP responsive elements (CREs) in a rat model of hepatocellular carcinoma (HCC). Tumorigenic liver cells were cultured from an in vivo model of HCC and the role of cAMP in cell mitogenesis determined. These data demonstrated agents that elevate intracellular cAMP ([cAMP]i) levels caused significant dose-dependent inhibition of serum-stimulated mitogenesis in HCC cells. Cells were next analyzed for transcription factor expression and activity following increased [cAMP]i. These data demonstrated time- and dose-dependent increases in CRE binding protein (pCREB) activity, a maximal response occurring after 10-20 min before returning to basal levels within 60 min. In contrast, increased [cAMP]i levels led to sustained inducible cAMP early repressor (ICER) II/IIgamma mRNA and protein induction. To understand these data in relation to the in vivo setting, HCC tumors were analyzed and compared to pair-matched normal liver (NL) samples. These studies demonstrated significantly elevated Gsalpha-protein expression in HCC versus NL in the absence of significant changes in basal cAMP levels. Analysis of total and active CREB demonstrated significantly increased total CREB/pCREB in HCC versus NL. Further analysis of CRE expression demonstrated significantly increased expression of ICER mRNA and protein in HCC versus sham operated (Sh). These data demonstrate cAMP, while capable of stimulating promitogenic CREB activation inhibits cell mitogenesis in HCC possibly via ICER induction.

Animals↗
PubMed2005

Alcohol and liver cancer.

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.

Alcoholism↗
PubMed2005

Interleukin-6 inhibits cell proliferation in a rat model of hepatocellular carcinoma.

BACKGROUND: Interleukin-6 (IL-6) plays a critical role in normal hepatic growth and liver regeneration. The aims of the present study are to determine the expression of components of IL-6 signaling in an in vivo model of hepatocellular carcinoma (HCC) and address the role of IL-6 signaling in the progression of HCC. METHODS: An in vivo rat HCC model was established and IL-6 receptor (IL-6R) and downstream signaling pathway expression and activity were determined in HCC and normal liver specimens. Tumorigenic HCC cells from resected HCC samples and normal hepatocytes were then isolated and cultured in the presence and absence of recombinant human IL-6 (rhIL-6). RESULTS: HCC specimens demonstrated decreased IL-6Ralpha/gp130 expression as compared with the normal liver. In contrast, HCC samples had significantly increased IL-6 messenger RNA expression and signal transducers and activators of transcription (STAT)3 activity. Using in vitro cell cultures, we demonstrated that IL-6 stimulated STAT3 and extracellular regulated kinase (ERK) activity in both HCC cells and isolated hepatocytes. However, while STAT3 activation profiles were similar, IL-6 stimulated ERK activity in a biphasic manner in HCC cells and a monophasic, sustained ERK activation in hepatocytes. In HCC cells, a significant induction of cyclin-dependent kinase (CDK) inhibitors, p21(waf1/cip1) and p27(Kip1) occurred, an effect that was not observed in normal hepatocytes. Finally, we established that IL-6 acted to inhibit serum-stimulated DNA synthesis and cell mitogenesis in HCC cells in vitro. CONCLUSIONS: These data demonstrate altered expression of components of IL-6 signaling in HCC in vivo. IL-6 treatment of HCC cells inhibits serum-stimulated mitogenesis, possibly via differences in activation profiles of intracellular signaling pathways and their effect on CDK inhibitor expression/activity.

Animals↗
PubMed2003

Massive liver growth in mice induced by systemic interleukin 6 administration.

The multifunctional cytokine interleukin 6 (IL-6) is expressed in a wide variety of disease states and pathologic processes. Mice deficient in IL-6 display abnormal and delayed liver regeneration and repair. Currently, IL-6 is thought to influence liver growth indirectly by priming hepatocytes to respond to growth factors such as hepatocyte growth factor (HGF) by inducing expression of HGF and by inhibiting hepatocyte apoptosis, as distinct from the direct mitotic effects of IL-6 on myeloid and other cell types. Here, we show that systemic administration of IL-6 using CHO cell tumors in nude mice results in dramatic hepatomegaly and hepatocyte hyperplasia in the absence of liver injury. Liver mass and liver to body mass ratios increased to 2 to 3 times normal because of proliferation of hepatocytes. Liver growth was associated with high levels of serum IL-6 and with activation of the IL-6-signaling pathway, including increased expression of IL-6 receptor-alpha/gp80, activation of the signal transducer and activator of transcription-3 (STAT-3), and mitogen-activated protein kinase (MAPK/ERK)-signaling pathways and induction of downstream target genes, including c-myc. HGF receptor and transforming growth factor alpha (TGF-alpha)/epidermal growth factor (EGF) receptor activation were decreased in hypertrophied livers, suggesting that IL-6-induced liver growth was independent of these known hepatocyte mitotic pathways. In conclusion, we suggest that IL-6 may function as a direct hepatic mitogen in vivo and, furthermore, that IL-6 warrants closer examination as a potent liver growth factor with potential clinical utility for increasing liver mass following injury.

Animals↗
PubMed2002

Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma.

Hepatocyte growth factor-scatter factor (HGF-SF) is a potent hepatic mitogen yet inhibits hepatocellular carcinoma (HCC) cell growth in vitro. Insulin-like growth factor I (IGF-I) is a pleiotropic growth factor shown to be important in cell growth and differentiation in other tumors. We hypothesized that IGF-I may play a role in regulating HGF-SF activity and HCC progression. Using an in vivo model of HCC, we showed elevated IGF-I messenger RNA (mRNA) expression in normal liver from tumor-burdened animals in the absence of changes in circulating IGF-I levels. Analysis of IGF-I receptor (IGF-IR) and HGF-SF (c-met) receptor expression showed significantly higher expression of both receptors in normal liver compared with an HCC specimen. Using cultured HCC cells from this model, we next showed that treatment with IGF-I led to significant increases in mitogen-activated protein kinase (MAPK) activity. Furthermore, we observed significant time-dependent increases in the expression of the c-fos and c-jun proto-oncogenes after addition of IGF-I (n = 5 per group, P <.05). Despite activation of a MAPK pathway and increased proto-oncogene expression, IGF-I failed to significantly affect cell mitogenesis. In contrast, HGF significantly inhibited cell mitogenesis in HCC lines (68.4% +/- 9.4% vs. control, n = 4, P <.05). Pretreatment of HCC cells with IGF-I (60 minutes) led to significant HGF-SF stimulation of total cell mitogenesis dependent on both IGF-I and HGF-SF dose (194% +/- 8% increase vs. control, n = 4, P <.05). In conclusion, tumor burden is important in altering intrahepatic growth factor synthesis. Signal cooperation between multiple cytokine pathways is an important factor in the progression of HCC.

Animals↗