Production and secretion of endothelin by hepatocellular carcinoma

J Clin Endocrinol Metab. 1993 Feb;76(2):378-83. doi: 10.1210/jcem.76.2.7679399.


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.

MeSH terms

  • Adult
  • Aged
  • Arteries
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / therapy
  • Chromatography, High Pressure Liquid
  • Embolization, Therapeutic
  • Endothelin-1
  • Endothelins / biosynthesis*
  • Endothelins / blood
  • Endothelins / metabolism
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Liver Cirrhosis / blood
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / therapy
  • Male
  • Middle Aged
  • Protein Precursors / blood
  • Veins
  • alpha-Fetoproteins / metabolism


  • Endothelin-1
  • Endothelins
  • Protein Precursors
  • alpha-Fetoproteins