Different tumoricidal effects of interferon subclasses and p53 status on hepatocellular carcinoma development and neovascularization.
Interferon (IFN) is known as a multifunctional cytokine. The aim of this study was to examine the different effects of IFN subclass; namely, IFN-alpha and IFN-beta, on hepatocellular carcinoma (HCC) growth especially in conjunction with angiogenesis that is known to play a pivotal role in the tumor growth. Furthermore, we also examined whether the p53 status in the tumor would alter the anti-tumoral effect of IFN against HCC growth since the p53 status reportedly affected the therapeutic effect of anti-angiogenic agents against cancer. When compared with IFN-alpha, IFN-beta exerted a more potent inhibitory effect on HCC growth, even after the tumor was established, along with suppression of neovascularization in the tumor. A single treatment with clinically comparable low doses of IFN-beta significantly inhibited HCC growth whereas the same dose of IFN-alpha did not. IFN-beta also significantly suppressed the tumor growth both in the p53-wild and p53-mutant HCC cells. Our in vitro study revealed that IFN-beta showed a more potent inhibitory effect on the endothelial cell proliferation than IFN-alpha as in the in vivo study. Collectively, IFN may be an alternative anti-angiogenic agent against HCC since it exerted a significant tumoricidal effect regardless of the host p53 status even at a low dose. A cautious approach may be also required in the clinical practice since even in a same IFN subclass (class-I), IFN-alpha and IFN-beta exert tumoricidal effects of different magnitudes on HCC.
Noguchi
Ryuichi
R
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Yoshiji
Hitoshi
H
Ikenaka
Yasuhide
Y
Kitade
Mitsuteru
M
Kaji
Kosuke
K
Yoshi
Junichi
J
Yanase
Koji
K
Namisaki
Tadashi
T
Yamazaki
Masaharu
M
Tsujimoto
Tatsuhiro
T
Akahane
Takemi
T
Uemura
Masahito
M
Fukui
Hiroshi
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D016898:Interferon-alpha; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D016899:Interferon-beta