Elucidation of Mechanisms for the Growth of hepato-cellular carcinoma (HCC) with androgen receptor and development of new hormone therapy for HCC

阐明雄激素受体肝细胞癌（HCC）的生长机制并开发新的 HCC 激素疗法

基本信息

批准号：
08457325
负责人：
NAGASUE Naofumi
金额：
$ 3.84万
依托单位：
Shimane Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

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 … More 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

使用50个肝细胞癌（HCC）WTH因子（TGF） - α和TGF-Beta1的手术标本。根据血管界面的基质生长因子（VEOF）和血小板衍生的界面的界面型骨细胞细胞生长因子（PD-ECGF）Althooth Althooth两种血管生成因子与肿瘤MVD无关，VEOF与Cirrhotic肝脏和ECGF WASSOCF WASSSOCF相关，肝炎的血管生成是一种独立的风险。由供应者 - taTatostosterone（DHT）恢复。。 - 还原酶抑制剂FK143可有效抑制大鼠Solt -Farber模型中AR阳性HCC的生长以及氧化烷的生长。