endothelin-1 and Liver-Neoplasms

Social anxiety (SA) and depression are prevalent, often comorbid disorders, associated with poor psychosocial functioning. Experimental psychopathology approaches can clarify the transdiagnostic mechanisms underlying these disorders, but most laboratory tasks are limited. We developed and validated the Audio-Dialogue Inductions of Social Stress (A-DISS) experimental task to model real-time rejection sensitivity in a realistic and developmentally relevant context. Participants are asked to imagine overhearing peers at a party talking badly about them (Rejection) or a teacher at their school (Neutral).. The Rejection condition elicited higher negative affect/lower positive affect while the Neutral condition sustained stable affect. Findings were consistent across gender and race/ethnicity. Moderation analyses were statistically significant; participants with elevated SA or depression reported feeling more rejected, insecure, and anxious after Rejection than those with below average symptoms.. Findings provide preliminary validation of a novel peer rejection task for research on understanding the affective experience of real-time rejection overall, especially for those with elevated SA and depression. SA and depression symptoms each uniquely moderating the effects of Rejection exposure on similar affective states, suggests individuals with SA or depression may benefit from interventions targeting specific reactions to rejection/stress and transdiagnostic risk factors.. Our results suggest that T lymphocyte immune dysfunction does exist in adult ITP patients and plays an important role in the pathogenesis of ITP.. ClinicalTrials.gov, identifier NCT03575988.. Brown/beige adipocyte-specific h

Topics: A549 Cells; Acute Lung Injury; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Adult; Aged; Animals; Anthropometry; Anti-Inflammatory Agents; Antiviral Agents; Arachidonic Acid; Archaeoglobus fulgidus; Australia; Blood Glucose; Blotting, Western; Carcinoma, Hepatocellular; Cathartics; Cell Differentiation; Chemokine CCL2; Child; China; Colonoscopy; Crosses, Genetic; Cyclin B1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Finland; Follow-Up Studies; Genes, Dominant; Glycated Hemoglobin; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Homeodomain Proteins; Humans; Hypothalamus; Incidence; Inflammatory Bowel Diseases; Interleukin-1beta; Interleukin-6; Italy; Lipopolysaccharides; Liver Cirrhosis; Liver Neoplasms; Lung; Male; Mice; MicroRNAs; Middle Aged; Motivational Interviewing; NAD; Neuroendocrine Tumors; NF-kappa B; Nitric Oxide; Nitriles; Outpatients; Oxidoreductases; Phenotype; Pilot Projects; Polyethylene Glycols; Polymorphism, Genetic; Prospective Studies; Protein Interaction Maps; Quality of Life; Reproducibility of Results; Shewanella; Signal Transduction; Spain; Sulfides; Sulfones; Thermogenesis; Transcription Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; United Kingdom

EndoTAG-1 (ET), a novel formulation of cationic liposomes carrying embedded paclitaxel (Taxol), shows antitumoral activity, targeting tumor endothelial cells in solid tumors. Patients with advanced metastatic cancer were evaluated investigating effects on pharmacokinetics and tumor vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and contrast-enhanced ultrasound (CEUS).. The pharmacokinetic (PK) profile of ET (22 mg/m(2) i.v.) was evaluated after single and repeated doses. DCE-MRI and CEUS explored hepatic metastases before, during and after the 4-week treatment cycle. Angiogenic biomarkers were assessed. Tumor response was evaluated by modified RECIST.. The PK profile demonstrated slight accumulation of paclitaxel after repeated doses. DCE-MRI parameters K(trans) and/or iAUC(60) showed a trend to decrease. Changes of blood flow-dependent parameters of DCE-MRI and CEUS were well correlated. Angiogenic biomarkers revealed no clear trend. ET was generally well tolerated; common toxic effects were fatigue and hypersensitivity reactions. Nine (9 of 18) patients had stable disease after the first treatment cycle. Four patients without disease progression continued treatment.. This study including multiple pretreated patients with different metastatic cancer revealed individually distinctive hemodynamic alterations by DCE-MRI. The PK profiles of ET were similar as observed previously.

Topics: Adult; Aged; Angiogenesis Inhibitors; Angiotensin II; Area Under Curve; Breast Neoplasms; Colorectal Neoplasms; Contrast Media; Endothelin-1; Female; Humans; Interleukins; Liposomes; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Ultrasonography; Vascular Endothelial Growth Factor A

The intermittent Pringle manoeuvre during hepatectomy results in a better clinical outcome when the accumulated ischaemia time is less than 120 min. The aim of this study was to investigate hepatic gene expression related to microcirculatory modulation and ultrastructural changes in patients having the intermittent Pringle manoeuvre.. Forty patients who underwent hepatectomy for liver tumours were randomly assigned to liver transection with intermittent Pringle manoeuvre (Pringle group, n = 20) or without the manoeuvre (control group, n = 20). The clinical data and hepatic expression of endothelin (ET) 1 and endothelial nitric oxide synthase (eNOS) combined with liver ultrastructure were compared.. The Pringle manoeuvre resulted in less blood loss (8.9 versus 12.4 ml/cm(2); P = 0.034), a shorter transection time (2.7 versus 4.1 min/cm(2); P = 0.015) and a lower serum bilirubin level on postoperative day 2 (26 versus 35 microm/l; P = 0.04). The hepatic messenger RNA content of ET-1 decreased by 38 per cent of the basal level in the Pringle group, whereas it increased by 28 per cent in the control group (P = 0.026). More patients in the control group showed swelling of mitochondria in hepatocytes and disruption of sinusoidal lining cells (12 of 20 patients versus three of 20 in the Pringle group; P = 0.008).. The intermittent Pringle manoeuvre results in less disturbance of the hepatic microcirculation and better preservation of liver sinusoids after hepatectomy.

Topics: Adult; Aged; Endothelin-1; Female; Gene Expression; Hepatectomy; Humans; Immunohistochemistry; Ligation; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III

Multikinase inhibitors, such as sorafenib, are used for the treatment of advanced carcinomas but the response shows limited efficacy or varies a lot with patients. Here we adopted the systems approach combined with high-throughput data analysis to discover key mechanism embedded in the drug response. When analyzing the transcriptomic data from the Cancer Cell Line Encyclopedia (CCLE) database, endothelin 1 (EDN1) was enriched in cancer cells with low responsiveness to sorafenib. We found that the level of EDN1 is higher in the tissue and blood of hepatocellular carcinoma (HCC) patients showing poor response to sorafenib. In vitro experiment showed that EDN1 not only induces activation of angiogenic-promoting pathways in HCC cells but also stimulates proliferation and migration. Moreover, EDN1 is related with poor responsiveness to sorafenib by mitigating unfolded protein response (UPR), which was validated in both transcriptomic data analysis and in silico simulation. Finally, we found that endothelin receptor B (EDNRB) antagonists can enhance the efficacy of sorafenib in both HCC cells and xenograft mouse models. Our findings provide that EDN1 is a novel diagnostic marker for sorafenib responsiveness in HCC and a basis for testing macitentan, which is currently used for pulmonary artery hypertension, in combination with sorafenib in advanced HCC patients.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Endothelin-1; Humans; Liver Neoplasms; Mice; Sorafenib; Systems Analysis; Xenograft Model Antitumor Assays

Endothelin-1 (ET-1), a member of endothelins family, binds to ETA receptor (ETAR) and ETB receptor to exert its role in multiple cellular processes. Although ET-1 and its receptors has been reported to be overexpressed in many cancers, and overexpression of ET-1 is able to trigger hepatocarcinogenesis in zebrafish, the functions of ET-1 and its receptors in hepatocellular carcinoma (HCC) cell migration and invasion remain unclear. In the present study, we found that ETAR was greatly expressed in HCC cells and HCC tissues. ETAR expression as well as ET-1 expression was associated with vascular invasion and tumor stage in HCC. Activation of ETAR by ET-1 dose-dependently promoted cell migration and invasion of HCC cells, while silencing of ETAR by siRNA or blocking of ETAR by specific inhibitor resulted in significant reduction in ET-1-mediated migration and invasion. Furthermore, ET-1 induced activation of ERK1/2 and AKT and increased MMP-3 production via ETAR. In addition, using inhibitors of ERK1/2 and AKT, we found that ERK1/2 and AKT pathways were both involved in ETAR-mediated migration, invasion, and MMP-3 production. Taken together, our findings suggest that activation of ETAR by ET-1 promotes HCC cell migration and invasion via activating ERK1/2 and AKT signaling pathways and upregulating MMP-3 expression. Thus, ETAR may play an important role in the progress of HCC.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Endothelin-1; Female; Gene Expression; Humans; Liver Neoplasms; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 3; Middle Aged; Neoplasm Grading; Neoplasm Staging; Protein Isoforms; Proto-Oncogene Proteins c-akt; Receptors, Endothelin; Signal Transduction; Tumor Burden

The endothelin (ET)-1/endothelin A receptor (ETAR) axis is reportedly involved in tumor cell invasion, survival, and metastasis. However, the role of ETAR in colon cancer metastasis and the underlying mechanisms have not been defined. In the present study, we assessed the role of ETAR in colon cancer metastasis in vitro and in vivo. Overexpression and knockdown of ETAR were respectively performed in SW480 and SW620 human colon cancer cells. Overexpression of ETAR in SW480 cells significantly increased cell survival against cisplatin, cell invasion, and matrix metalloproteinase (MMP)-2 expression, which was strengthened by exogenous ET-1 and abolished by selective ETAR antagonist BQ123 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Knockdown of ETAR in SW620 cells markedly decreased cell survival against cisplatin, cell invasion, and MMP-2 expression, which was strengthened by BQ123 and LY294002, and partially rescued by exogenous ET-1. In a colon cancer liver metastasis mouse model, while ETAR overexpression promoted colon cancer liver metastases, ETAR knockdown markedly decreased liver metastases. In conclusion, our in vitro data demonstrate that ETAR mediates the promoting effects of ET-1 on colon cancer cell survival, invasion and MMP-2 expression by a PI3K-mediated mechanism. Our in vivo data indicate that ETAR markedly promotes colon cancer liver metastasis. This study provides direct evidence for a critical role of ETAR in colon cancer metastasis, which suggests that ETAR antagonism could benefit patients with metastatic colon cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cisplatin; Colonic Neoplasms; Endothelin A Receptor Antagonists; Endothelin-1; Flow Cytometry; Humans; In Vitro Techniques; Liver Neoplasms; Matrix Metalloproteinase 2; Mice; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptor, Endothelin A; Tumor Cells, Cultured

Hepatocarcinogenesis commonly involves the gradual progression from hepatitis to fibrosis and cirrhosis, and ultimately to hepatocellular carcinoma (HCC). Endothelin 1 (Edn1) has been identified as a gene that is significantly up-regulated in HBx-induced HCC in mice. In this study, we further investigated the role of edn1 in hepatocarcinogenesis using a transgenic zebrafish model and a cell culture system. Liver-specific edn1 expression caused steatosis, fibrosis, glycogen accumulation, bile duct dilation, hyperplasia, and HCC in zebrafish. Overexpression of EDN1 in 293T cells enhanced cell proliferation and cell migration in in vitro and xenotransplantation assays and was accompanied with up-regulation of several cell cycle/proliferation- and migration-specific genes. Furthermore, expression of the unfolded protein response (UPR) pathway-related mediators, such as spliced XBP1, ATF6, IRE1, and PERK, was also up-regulated at both the RNA and protein levels. In the presence of an EDN1 inhibitor or an AKT inhibitor, these increases were diminished and the EDN1-induced migration ability also was disappeared, suggesting that the EDN1 effects act through activation of the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes. Additionally, p-AKT is enhanced in the edn1 transgenic fish compared to the GFP-mCherry control. The micro RNA miR-1 was found to inhibit the expression of EDN1. We also observed an inverse correlation between EDN1 and miR-1 expression in HCC patients. In conclusion, our data suggest that EDN1 plays an important role in HCC progression by activating the PI3K/AKT pathway and is regulated by miR-1.

Topics: Animals; Carcinoma, Hepatocellular; Cell Cycle; Cell Movement; Cell Proliferation; Endothelin-1; Fatty Liver; Gene Expression; HEK293 Cells; Humans; Liver Cirrhosis; Liver Neoplasms; MicroRNAs; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Unfolded Protein Response; Zebrafish; Zebrafish Proteins

Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.

Topics: Animals; Cell Line; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Endothelin-1; Gene Expression; Gene Expression Regulation; Hematopoietic Stem Cells; Hepatic Stellate Cells; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Transgenic; RGS Proteins; RNA, Small Interfering; Signal Transduction

MicroRNA-1 (miR-1) has been demonstrated as a tumor-suppressive miRNA, which shows a down-regulated pattern in several human malignancies including hepatocellular carcinoma (HCC). However, the pathophysiologic roles of miR-1 and their mechanisms in HCC tumorigenesis are still not totally elucidated.. Pre-miR-1 was cloned into pSuper plasmid to overexpress the miR-1 in hepatoma cells. Real-time PCR and Western blot were applied to detect miR-1, ET-1 mRNA and protein levels respectively. Dual luciferase reporter assay was conducted to investigate the binding site of miR-1 on 3'UTR of ET-1 mRNA. Proliferation of hepatoma cells was evaluated by MTT assay.. We observed that over-expression of miR-1 by miRNA-expressing plasmid transfection in HepG2 and Hep3B cells significantly reduced the proliferation of these cells. To explore the mechanism, we examined the potential target genes of miR-1 by bioinformatics. A potent mitogen, Endothelin-1 (ET-1), attracted our attention. Elevated expression of ET-1 but reduced miR-1 level was detected both in human liver cancer tissues and in hepatoma cell lines using Western Blot and miRNA real-time PCR respectively. By the over-expression and inhibition of miR-1 in HepG2 and Hep3B, we confirmed that miR-1 negatively regulated ET-1 expression in hepatoma cells. A luciferase reporter assay showed that miR-1 regulation was established by pairing to a complementary binding site within the ET-1 3'UTR. Finally, attenuated proliferation of hepatoma cells by over-expression of miR-1 could be partially restored by exogenous ET-1 treatment.. Our findings demonstrate that miR-1 could inhibit ET-1 expression to attenuate the proliferation of hepatoma cells.

Topics: Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Endothelin-1; Hep G2 Cells; Humans; Liver Neoplasms; Luciferases; MicroRNAs; Real-Time Polymerase Chain Reaction

In the event of diffuse hepatic metastases, hepatic artery embolization (HAE) can be a successful treatment option in patients with well-differentiated neuroendocrine tumours (NET). However, embolization causes hypoxia which stimulates angiogenesis and therefore tumour growth. This study investigates angiogenesis activity following HAE by measuring vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and C-terminal proendothelin-1 (proET-1) in blood. Twelve patients with well-differentiated NET and liver metastases underwent HAE. VEGF, ET-1 and proET-1 were measured before embolization and the days following treatment during hospitalization. Mean levels during treatment were compared with those at baseline. From 12 patients, 90 blood samples were obtained before and daily for 8 days following HAE. Mean (± SE) VEGF level at baseline was 116 (± 33)ng/l which increased after HAE to 313 (± 46)ng/l at day 6, followed by a gradual decrease. ProET-1 showed a similar pattern, with a mean baseline level of 9.2 (± 2.0)pmol/l and the highest level of 40.8 (± 5.7)pmol/l at day 6. Some fluctuations were observed for ET-1, with maximum levels at day 3 compared to baseline levels. In patients with well-differentiated NET who underwent hepatic arterial embolization, angiogenic growth factors increase temporarily. This implies a need to investigate the effect of anti-angiogenic drugs as an adjuvant therapy to embolization.

Topics: Adult; Aged; Embolization, Therapeutic; Endothelin-1; Female; Hepatic Artery; Humans; Intercellular Signaling Peptides and Proteins; Liver Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Neuroendocrine Tumors; Peptide Fragments; Vascular Endothelial Growth Factor A

Topics: Carcinoma, Hepatocellular; Endothelin-1; Female; Humans; Liver Neoplasms; Male; Neovascularization, Pathologic; Nitric Oxide; Vascular Endothelial Growth Factors

The absence of perivascular nerves in tumour vessels suggests that endothelium derived vasoactive substances [nitric oxide (NO) and endothelin-1 (ET-1)] may be key factors in controlling tumour blood flow during tumour growth and metastasis. We have studied the ultrastructural distribution and immunoreactivity of different NO synthase (NOS) isoforms and ET-1 in human colorectal metastatic liver tumour tissues using pre-embedding peroxidase-anti-peroxidase and post-embedding immunoelectron microscopic triple gold labelling techniques. Dramatically lower NOS 1 immunoreactivity was observed in tumour vascular endothelium (1-3% and 15-20% in tumour and normal groups, respectively). As compared to control groups there were significantly less NOS3 immunopositive EC in metastatic tumour vessels (45-50% and 1-3% in normal and tumour groups, respectively). A striking rise in NOS2 was observed in tumour vessel endothelium (< 1% in normal and 65-70% in tumour vessel endothelium). ET-1 immunoreactivity levels were also significantly higher in tumour vessel endothelium (85-90% in tumour, 15-20% in normal group). This increased expression of NOS2 and ET-1 immunoreactivity was accompanied by the increased expression of three NOS isoforms and ET-1 immunoreactivity in liver parenchymal cells. These data suggest that metastatic tumour vessel endothelium is characterized by increased expression of NOS2 and ET-1 and by decreases in NOS1 and NOS3. These characteristics are associated with the overexpression of all three NOS isoforms and ET-1 immunoreactivity in non-vascular cells.

Topics: Aged; Colorectal Neoplasms; Endothelin-1; Endothelium, Vascular; Hepatocytes; Humans; Immunohistochemistry; Liver Neoplasms; Middle Aged; Nitric Oxide Synthase

A balance between endothelins (ET) and nitric oxide (NO) might interfere with liver haemodynamics and disease progression in various liver diseases. Increased levels of endothelin 1 (ET-1) and nitrites and nitrates (NOx, the end products of NO metabolism) have been reported in hepatocellular carcinoma (HCC), but the balance has not been studied. The purpose of this study was to assess the ratio of NOx to ET-1 in patients with virus-related hepatocellular carcinoma and to investigate its correlation with the extent of the disease. Eighteen patients with virus-related HCC (six Okuda stage I, six Okuda stage II and six Okuda stage III) were included in the study and were compared with 22 patients with viral cirrhosis (14 decompensated, eight compensated) and seven normal controls. ET-1 was measured with an ELISA assay and NOx with a modification of the Griess reaction. Patients with virus-related HCC had the highest levels of circulating ET-1 and NOx (13.24 +/- 0.82 pg/ml and 112.28 +/- 18.56 micromol/l) compared to compensated cirrhosis (9.47 +/- 0.50 pg/ml, P < 0.004 and 54.47 +/- 2.36 micromol/l, P < 0.01), decompensated cirrhosis (9.57 +/- 0.32 pg/ml, P < 0.001 and 90.20 +/- 11.23 micromol/l, NS) and normal controls (8.84 +/- 0.61 pg/ml, P < 0.001 and 51.17 +/- 6.18 micromol/l, P < 0.01). There was a significant increase of ET-1 and NOx at HCC stage III compared to HCC stages I and II, cirhotics and controls. HCC stage III patients also had a NOx/ET-1 ratio that was higher than HCC stages I and II patients, normal controls and patients with compensated cirrhosis. Virus-related HCC patients have high levels of circulating ET-1, compared to compensated or decompensated cirrhosis. Highest levels of ET-1 are produced in Okuda III tumours. NOx are also increased but only in Okuda stage III tumours. The NOx/ET-1 ratio is increased in virus-related HCC and DC. This increase may account for the known increase in tumour blood flow.

Topics: Carcinoma, Hepatocellular; Endothelin-1; Female; Hepacivirus; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Nitrates; Nitrites

Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =10) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ET(A) and ET(B), on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 +/- 1.4, 4.5 +/- 1.5, vs. 2.75 +/- 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ET(A) antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET(A) receptors. ET(A) antagonists are indicated as potential anti-cancer agents.

Topics: Adult; Aged; Aged, 80 and over; Animals; Colon; Colorectal Neoplasms; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Immunohistochemistry; Liver Neoplasms; Male; Middle Aged; Neoplasm Transplantation; Neoplasms, Experimental; Oligopeptides; Peptides, Cyclic; Pyrrolidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B

The aim was to assess the role of plasma Big Endothelin (ET) 1 levels as a marker of disease presence and stage in colorectal adenocarcinoma.. Big ET-1 was measured in the plasma of 37 patients with colorectal cancer. Preoperative systemic plasma levels of Big ET-1 in patients with cancer were compared with levels in 20 age- and sex-matched controls. Portal plasma samples were collected at operation in addition to peripheral venous samples. Immunohistochemical staining for Big ET-1 was performed on a selection of primary tumour specimens and liver metastases.. Median (range) preoperative systemic plasma levels of Big ET-1 were significantly higher in patients with cancer than in controls (1.0 (0.3-9.7) versus 0.2 (0.0-6.0) fmol/ml; P = 0.0001). Intraoperative portal plasma levels of Big ET-1 were significantly higher in patients with Dukes' 'D' disease than in patients with Dukes' A, B and C disease (2.1 (1.4-10.0) versus 1.2 (0.3-6.6) fmol/ml; P = 0. 01). Similarly, systemic plasma levels were significantly higher in patients with Dukes' 'D' disease than in those with localized disease (1.9 (1.2-9.7) versus 1.2 (0.2-8.3) fmol/ml; P = 0.01). The presence of microvascular invasion in the tumour specimens was associated with a significantly raised portal plasma level of Big ET-1 (1.6 (1.5-2.1) versus 1.1 (0.8-1.3) fmol/ml; P = 0.04). Immunohistochemistry localized Big ET-1 to the cancer epithelial cells.. The plasma level of Big ET-1 is significantly raised in patients with colorectal cancer. Patients with liver metastases have significantly higher levels than those with localized disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Endothelin-1; Endothelins; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Precursors

Endothelin 1 (ET-1), a vasoconstrictor peptide, has been implicated as a tumour growth stimulator and an angiogenesis factor.. To assess the involvement of ET-1 in colorectal cancer, immunoelectron microscopy for ET-1 was performed in colorectal liver metastases and normal liver (n = 6). ET-1 plasma levels were measured by radioimmunoassay in patients with colorectal cancer, with (n = 18) and without (n = 12) liver metastases, and in controls (n = 22).. In normal liver, ET-1 was present in endothelial cells; in tumour, it was observed in endothelial cells, tumour cells and myofibroblasts. Mean(s.d.) plasma ET-1 levels were 2.75 (1.37) pg/ml in controls, 4.53(1.61) pg/ml in patients with colorectal liver metastases (P = 0.001) and 3.92(1.32) pg/ml in patients without metastases (P = 0.02).. ET-1 was present in various cell types within colorectal liver metastases and raised levels were found in the plasma of patients with colorectal cancer. ET-1 may not only modulate tumour vascular tone but also act on tumour growth and angiogenesis, both locally and systemically.

Topics: Aged; Biomarkers, Tumor; Colorectal Neoplasms; Endothelin-1; Female; Humans; Liver Neoplasms; Male; Microscopy, Immunoelectron; Middle Aged; Radioimmunoassay; Thrombomodulin

In order to clarify the characteristics of cellular localization of ET-1/big ET-1 in liver tissues, we carried out immunohistochemical study on 30 normal, 87 cirrhosis (LC) and 55 hepatocellular carcinoma (HCC) liver specimens using anti-ET-1 antibody and anti-big ET-1 antibody and further performed in situ hybridization on 5 LC liver specimens. Positive immunostaining of hepatocytes of normal and LC livers, and tumor cells of HCC was obtained. The frequency of positive cells for ET-1 and big ET-1 of normal liver was very low. In contrast, LC hepatocytes were stained much more frequently for both ET-1 and big ET-1 than those of normal liver (P < 0.01). In the HCC livers hepatoma cells showed intermediate frequency of positive cells between normal and LC livers. Big ET-1, not ET-1, expression in HCC was significantly high compared with that of normal liver (P < 0.01). Specific signals for ET-mRNA were not detected in hepatocytes of LCs by in situ hybridization. ETs detected in hepatocytes by immunohistochemistry, therefore, seem not to have been synthesized locally. The origin of ETs is not clear but they might have been taken up from the circulation through ET receptors on hepatocytes. Although the clearance mechanism of ETs by ET-converting enzyme or other peptidases in liver has not been elucidated, the mechanisms seem to be absent or impaired in LC and/or HCC liver since the frequency and intensity of ET-positivity in the diseased hepatocytes are significantly high than those of normal liver. In addition, a disturbance of ET excretion into the bile may be also responsible for the ET storage. Elevation of serum ET levels in LC may be caused by disturbance of ET degradation and/or leakage of bile into the blood, as the ET is excreted through the biliary system.

Topics: Carcinoma, Hepatocellular; Endothelin-1; Endothelins; Humans; Immunohistochemistry; In Situ Hybridization; Liver; Liver Cirrhosis; Liver Neoplasms; Protein Precursors; RNA, Messenger; RNA, Neoplasm

Regionally administered vasopressors might increase tumour chemotherapy uptake by differentially constricting normal and tumour blood vessels, leading to a selective increase in blood flow to the tumour. In this study, we compared the effects of the vasopressors angiotensin II, vasopressin and endothelin I and the vasodilator calcitonin gene-related peptide (CGRP) by continuously measuring liver parenchymal and tumour blood flow during a 30-min regional vasoactive infusion in a rat HSN liver metastasis model. Vasopressin and angiotensin II produced a vasoconstriction that decreased despite continued infusion, while endothelin I infusion led to prolonged vasoconstriction with a more gradual onset. CGRP infusion resulted in increased vessel conductance but a reduction in blood flow due to systemic hypotension. The tumour to normal flow ratio (TNR) was transiently increased during infusion of all pressors, but only endothelin I produced sufficient change to result in a rise in average TNR throughout pressor infusion. Continuous liver and tumour blood flow measurement throughout vasoactive infusion demonstrated that the extent and the duration of blood flow change varied with the agents assessed. No vasoactive agent increased tumour blood flow, but endothelin I had the most suitable vasoactive properties for enhancing tumour uptake of continuously infused chemotherapy.

Topics: Angiotensin II; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Disease Models, Animal; Endothelin-1; Infusions, Intra-Arterial; Laser-Doppler Flowmetry; Liver Circulation; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins

To clarify whether hepatocellular carcinoma (HCC) may produce and secrete endothelin (ET), we measured plasma levels of ET-1 and big ET-1, a precursor form of ET-1, in 30 patients with HCC. When compared to normal subjects, a substantial number of patients had elevated plasma ET-1 and big ET-1 levels, determined by specific enzyme immunoassays. The mean (+/- SD) plasma concentrations of ET-1 (1.7 +/- 0.9 pmol/L) and big ET-1 (6.1 +/- 4.8 pmol/L) in patients' group were significantly (P < 0.01) higher than those (1.0 +/- 0.3 and 2.0 +/- 0.8 pmol/L, respectively) in control group. There was a significant positive correlation between plasma big ET-1 and alpha-fetoprotein (r = 0.77, P < 0.01). Some of the 29 patients with liver cirrhosis also had modestly elevated plasma big ET-1 levels. The mean (+/- SD) plasma big ET-1 concentration (3.1 +/- 0.9 pmol/L) in patients with liver cirrhosis was significantly (P < 0.01) higher than that in control group, although there was no significant difference between the mean plasma ET-1 levels of both groups. Raised plasma big ET-1 and, less markedly, ET-1 levels in patients with HCC decreased after successful transcatheter arterial embolization concomitantly with a reduction in tumor sizes and a decrease in plasma alpha-fetoprotein levels. In six patients, an arteriovenous difference in ET-1 and big ET-1 levels across the tumor bed with a higher concentration in the venous circulation was found. Reverse-phase high performance liquid chromatography revealed that major portions of immunoreactive ET-1 and big ET-1 in hepatic venous plasma coeluted with synthetic ET-1 and big ET-1, respectively. Immunohistochemistry of HCC tissues from two patients demonstrated HCC cells positive for ET-1 and big ET-1, whereas no ET immunoreactivity was found in adjacent nontumorous hepatocytes. We conclude from these results that ET is produced by and released from a substantial number of HCC, which may stimulate proliferation of carcinoma cells as an autocrine or paracrine growth factor.

Topics: Adult; Aged; alpha-Fetoproteins; Arteries; Carcinoma, Hepatocellular; Chromatography, High Pressure Liquid; Embolization, Therapeutic; Endothelin-1; Endothelins; Female; Humans; Immunoenzyme Techniques; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Veins