The endothelin system in Morris hepatoma‐7777: an endothelin receptor antagonist inhibits growth in vitro and in vivo

Abstract

1 Plasma concentrations of endothelin are increased in patients with hepatocellular cancer as well as in patients with liver metastasis. However, the impact of these findings remains uncertain. 2 We thus analyzed the endothelin system in a rat hepatoma model (Morris hepatoma 7777) in vitro and in vivo. 3 Our study revealed that tissue concentrations of endothelin-1 (ET-1) and big-ET-1, the precursor of ET-1, were significantly elevated in Morris hepatoma 7777 as compared to normal liver. The ETA receptor density was significantly elevated, whereas the density of the ETB receptor was decreased in Morris hepatoma 7777.4 We could also demonstrate that hepatoma cells secrete ET-1. 5 Exogenously added ET-1 enhances hepatoma cell growth in a dose-dependent manner. Endothelin receptor antagonists (ETA and combined ETA/ETB receptor antagonists) inhibit tumor cell growth in vitro. Since the combined ETA/ETB receptor antagonist was more effective in vitro, we used this compound also for in vivo studies and could demonstrate that a combined ETA/ETB receptor antagonist is able to reduce hepatoma growth in vivo. 6 In conclusion, the endothelin system is activated in Morris hepatoma 7777 and contributes to hepatoma growth. Since endothelin receptor antagonists are well-tolerated upcoming clinically used drugs without major side effects, our data might provide a new pharmacological approach to reduce hepatoma growth in vivo.

T2relaxation times of13C metabolites in a rat hepatocellular carcinoma model measuredin vivousing13C-MRS of hyperpolarized [1-13C]pyruvate

“…We found the alanine to total carbon ratio is significantly higher in HCC tumors than in normal livers. This may be related to the reported high ALT level in the Morris HCC rat model (35,36). Even though the same amount of hyperpolarized 13 C-pyruvate solution was injected in each animal, the up-take of 13 C-pyruvate by each HCC tumor varies, as indicated by the wide range of total carbon signal found in HCC tumors (Fig.…”

“…Therefore, we hypothesized that the 13 C-lactate signal relative to the injected 13 C-pyruvate, which was quantified as the total 13 C signal (or total carbon) in this work, may not differentiate HCC tumor and normal liver. However, in some liver diseases, including hepatoma (35,36), the enzyme catalyzing pyruvate conversion to alanine, Alanine Transaminase (ALT), is elevated and we postulated a potential difference in 13 C-alanine. In this study, hyperpolarized 13 C-pyruvate was injected into both normal and HCC rats to measure both the signal levels and T 2 's of 13 C-lactate and 13 C-alanine.…”

Overexpression of Endothelin 1 Triggers Hepatocarcinogenesis in Zebrafish and Promotes Cell Proliferation and Migration through the AKT Pathway

“…Endothelin 1 (EDN1) is a 21-amino acid peptide that exerts a wide range of biological activities. It is recognized as a vasoconstrictor peptide and has been implicated in the growth regulation of several tumors [12] , [13] . EDN1 has been found to enhance tumor growth by promoting angiogenesis [14] , [15] .…”

“…EDN1 secretion in hepatoma cells has been described [26] , [27] . Hepatoma cell growth increases upon the exogenous addition of EDN1 in a dose-dependent manner [12] . The tissue concentrations of EDN1, big ET-1, and the ETA receptor were significantly increased in hepatoma tissue compared to normal liver tissue [12] .…”

Functions of endothelin-1 in apoptosis and migration in hepatocellular carcinoma

“…ET-1 secretion in HCC is stimulated by various cytokines and growth factors (13). Elevated levels of ET-1 have been observed in HCC tissues compared with corresponding normal liver tissues (14). It has previously been demonstrated that ET-1 upregulation increases HCC cell proliferation, invasion and migration, and inhibits apoptosis (15).…”