Ishibashi M, Fujita M, Nagai K, Kako M, Furue H, Haku E, Osamura Y, Yamaji T
Fourth Department of Medicine, Teikyo University School of Medicine, Kawasaki, Japan.
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.
为了阐明肝细胞癌（HCC）是否会产生并分泌内皮素（ET），我们检测了30例HCC患者血浆中ET-1及其前体形式大ET-1的水平。通过特异性酶免疫测定法测定发现，与正常受试者相比，相当数量的患者血浆ET-1和大ET-1水平升高。患者组中ET-1（1.7±0.9 pmol/L）和大ET-1（6.1±4.8 pmol/L）的平均（±标准差）血浆浓度显著（P<0.01）高于对照组（分别为1.0±0.3和2.0±0.8 pmol/L）。血浆大ET-1与甲胎蛋白之间存在显著正相关（r = 0.77，P<0.01）。29例肝硬化患者中部分患者血浆大ET-1水平也有适度升高。肝硬化患者的平均（±标准差）血浆大ET-1浓度（3.1±0.9 pmol/L）显著（P<0.01）高于对照组，尽管两组的平均血浆ET-1水平无显著差异。HCC患者血浆中大ET-1水平升高，ET-1水平升高不太明显，在成功进行经导管动脉栓塞后，随着肿瘤大小的减小和血浆甲胎蛋白水平的降低而下降。在6例患者中，发现肿瘤床处ET-1和大ET-1水平存在动静脉差异，静脉循环中浓度更高。反相高效液相色谱显示，肝静脉血浆中免疫反应性ET-1和大ET-1的主要部分分别与合成的ET-1和大ET-1共洗脱。两名患者HCC组织的免疫组织化学显示HCC细胞ET-1和大ET-1呈阳性，而相邻的非肿瘤肝细胞未发现ET免疫反应性。从这些结果我们得出结论，大量HCC会产生并释放ET，ET可能作为一种自分泌或旁分泌生长因子刺激癌细胞增殖。
