Production and secretion of endothelin by hepatocellular carcinoma.
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.
Ishibashi
M
M
Fourth Department of Medicine, Teikyo University School of Medicine, Kawasaki, Japan.
Fujita
M
M
Nagai
K
K
Kako
M
M
Furue
H
H
Haku
E
E
Osamura
Y
Y
Yamaji
T
T
D000328:Adult; D000368:Aged; D001158:Arteries; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000628:therapy; D002851:Chromatography, High Pressure Liquid; D004621:Embolization, Therapeutic; D019332:Endothelin-1; D016232:Endothelins / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008103:Liver Cirrhosis / Q000097:blood; D008113:Liver Neoplasms / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000097:blood; D014680:Veins; D000509:alpha-Fetoproteins / Q000378:metabolism
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D000509:alpha-Fetoproteins