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Clinical significance of alpha-fetoprotein: involvement in proliferation, angiogenesis, and apoptosis of hepatocellular carcinoma.

Research paper by Noboru N Mitsuhashi, Souichi S Kobayashi, Tomoko T Doki, Fumio F Kimura, Hiroaki H Shimizu, Hiroyuki H Yoshidome, Masayuki M Ohtsuka, Atsushi A Kato, Hideyuki H Yoshitomi, Satoshi S Nozawa, Katsunori K Furukawa, Dan D Takeuchi, Kosuke K Suda, Seiki S Miura, Masaru M Miyazaki

Indexed on: 10 May '08Published on: 10 May '08Published in: Journal of Gastroenterology and Hepatology



Abstract

Hepatocellular carcinoma is one of the most common cancers. alpha-Fetoprotein is strongly expressed in most patients with hepatocellular carcinoma, and high levels of alpha-fetoprotein expression have been reported as an independent prognostic factor. However, there have been few reports on the reasons for poor prognosis.We analyzed the correlation between serum alpha-fetoprotein levels and clinicopathological findings in 37 hepatocellular carcinoma patients undergoing curative surgery. alpha-Fetoprotein mRNA expression in tissue samples was analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR), while protein expression was assessed by immunohistochemistry. To assess the mechanistic correlations between alpha-fetoprotein and tumor progression, we further analyzed cell proliferation (Ki-67), angiogenesis (CD34), and apoptosis (TdT-mediated dUTP-biotin nick end labeling [TUNEL] assay).Post-operative serum alpha-fetoprotein levels were correlated with disease-free and overall survival, and were an independent prognostic factor for survival. alpha-Fetoprotein expression, as assessed by immunohistochemistry, was strong and heterogeneous in hepatocellular carcinoma. Control livers did not express alpha-fetoprotein and there was weak expression of alpha-fetoprotein in adjacent regions in hepatocellular carcinoma patients. The Ki-67 labeling index in the high serum alpha-fetoprotein cases was significantly higher than in alpha-fetoprotein-negative cases (P = 0.042). The alpha-fetoprotein-positive cases also showed a significantly higher microvessel density than alpha-fetoprotein-negative cases (P = 0.035), whereas hepatocellular carcinoma without alpha-fetoprotein overexpression had a higher apoptotic index when compared to hepatocellular carcinoma with alpha-fetoprotein overexpression (P = 0.033).These results indicate that the poor prognosis associated with high alpha-fetoprotein is due to high cell proliferation, high angiogenesis, and low apoptosis.