1998 Fiscal Year Final Research Report Summary
Elucidation of Mechanisms for the Growth of hepato-cellular carcinoma (HCC) with androgen receptor and development of new hormone therapy for HCC
| Project/Area Number |
08457325
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Shimane Medical University |
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Principal Investigator |
NAGASUE Naofumi Shimane Medical University, Second Department of Surgery, Professor, 医学部, 教授 (40117198)
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| Co-Investigator(Kenkyū-buntansha) |
YAMANOI Akira Shimane Med.Univ., Surg.Dept., Assistant, 医学部, 助手 (70281152)
KUBOTA Hirofumi Shimane Med.Univ., Surg.Dept., Lecturer, 医学部, 講師 (00205147)
KOHNO Hitoshi Shimane Med.Univ., Surg.Dept., Assoc.Prof., 医学部, 助教授 (60145951)
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| Project Period (FY) |
1996 – 1998
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| Keywords | hepatocellular carcinoma / androgen / androgen receptor / tumor angiogenesis / growth factors / 5alpha-reductase / dihydrotestosterone / hormone therapy |
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| Research Abstract |
Using 50 surgical specimens of hepatocellular carcinoma (HCC), cell proli-ferative activity and apoptosis were evaluated in terms of transforming growth factor (TGF)-alpha and TGF-beta1 . It was elucidated that TGF-beta1 was associated with decreased proliferative activity in HGCs smaller than 5 cm but such mechanism was disrupted in larger tumors. The clinicopathologic significance of microvessel density (MVD) of HCC was evaluated in terms of vascular endothelial growth factor (VEOF) and platelet-derived endothelial cell growth factor (PD-ECGF). Although both angiogenic factors were not associated with tumor MVD, VEOF was related with angiogenesis of cirrhotic liver and PD-ECGF was associated with angiogenesis of hepatitis C virus induced chronic liver disease. Density of relatively large tumor vessels stained with Factor 8 antibody was an independent risk factor for intra-hepatic tumor recurrence following curative hepatic. resection.
The growth of androgen receptor (AR) positive HCC
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was suppressed when transplanted in normal female and castrated male nude mice, but the tumor growth in castrated male mice was completely recovered by the supplemen-tation of dihydrotestosterone (DHT). An AR inhibitor cyproterone acetate (CPA) suppressed or inhibited the growth of AR-positive HCC dose-dependently. CPA induced overexpression of TGF-beta1 in the tumor which possibly, caused cell cycle arrest at G1 phase and in addition apoptosis.
Following studies have not been accomplished as yet but are in progress at present. 5 alpha -reductase converts testosterone in target cells to dihydro-testosterone (DHT) which has a higher affinity to AR compared with testo-sterone and the highest hormonal activity among all androgens. Provided that DHT is most responsible for the growth of AR-positive HCC, the inhibition of 5alpha -reductase could be effective in prophylaxis and treatment of HCC.So far, we have found that a 5 alpha -reductase inhibitor FK143 is effective in suppressing the growth of AR-positive HCC in vivo and in vitro as well as the hepatocarcinogenic process in the Solt-Farber model in rats. Less
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