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


METHODS
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).


RESULTS
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).


CONCLUSIONS
These results indicate that the poor prognosis associated with high alpha-fetoprotein is due to high cell proliferation, high angiogenesis, and low apoptosis.
Mitsuhashi
Noboru
N
Section for Medical Nanotechniques, Research Center for Frontier Medical Engineering, Chiba University, Chiba, Japan. nmitsuhashi@faculty.chiba-u.jp
Kobayashi
Souichi
S
Doki
Tomoko
T
Kimura
Fumio
F
Shimizu
Hiroaki
H
Yoshidome
Hiroyuki
H
Ohtsuka
Masayuki
M
Kato
Atsushi
A
Yoshitomi
Hideyuki
H
Nozawa
Satoshi
S
Furukawa
Katsunori
K
Takeuchi
Dan
D
Suda
Kosuke
K
Miura
Seiki
S
Miyazaki
Masaru
M
D000368:Aged; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D000509:alpha-Fetoproteins / Q000032:analysis* / Q000235:genetics
C097353:AFP protein, human; D012333:RNA, Messenger; D000509:alpha-Fetoproteins