Fina F, Muracciole X, Rocchi P, Nanni-Métellus I, Delfino C, Daniel L, Dussert C, Ouafik L 'H, Martin P M
Université de la Méditerranée, Aix-Marseille II, Laboratoire de Transfert d'Oncologie Biologique, Assistance Publique--Hôpitaux de Marseille (AP-HM), Faculté de Médecine Secteur nord, Bd Pierre Dramard, 13916 Marseille Cedex, France.
J Steroid Biochem Mol Biol. 2005 Sep;96(5):355-65. doi: 10.1016/j.jsbmb.2005.04.041. Epub 2005 Jul 25.
After castration or therapeutic hormone deprivation, most cancer of the prostate (CaP) cells develop androgen-independent (AI) growth. In this work, we studied the effect of androgen depletion (castration) on the growth of experimental model LuCaP 23.1 xenograft. A total of 101 nude mice were implanted and analysed for their growth profile before experimental period 1 (11 weeks) and after castration experimental period 2 (15 weeks). For specific periods, tumors were harvested and assessed for molecular marker expression specific for CaP. Taking into account tumor dynamic growth, prior to castration we found 37 fast growing (FG) tumors (948.9+/-76.9 mm3) and 63 slow growing (SG) tumors (229.6+/-18.4 mm3). Real-time quantitative RT-PCR showed that in comparison to SGs, FGs contained elevated expression of epidermal growth factor receptor type 1 (HER1), urokinase plasminogen activator (uPA), thymidine phosphorylase (TP) and thymidilate synthase (TS) mRNAs expression and low levels of 5alpha-reductase 2 (5alpha-R2) mRNA. After castration all FG tumors progressed rapidly (by 5 weeks) to AI growth (FG-P). In SG castrated tumors, 66% of tumors showed retarded progression (by 12 weeks) to AI (SG-P), whereas 34% responded to castration (SG-R). Molecular analysis demonstrated distinct molecular profiles integrating different pathways associated with AI progression. The progressive tumors FG-P, and some tumors of SG-P subgroup, presented significantly high levels of HER1, epidermal growth factor receptor type 2 (HER2), TS, uPA, TP, tumor necrosis factor superfamily member 6 (FAS) and peptidylglycine alpha-amidating mono-oxygenase (PAM) mRNA all of which correlated with androgen receptor (AR) mRNA. The second subgroup of SG-P tumors showed a high expression of the anti-apoptotic gene Bcl-2. A third subgroup of SG-P tumors showed significant expression of hypoxia-related genes such as adrenomedullin (AM) after castration. LuCaP 23.1 xenograft represent a useful dynamic model to study pre-clinically new therapeutic molecules and evaluate non-randomized therapeutics protocols combining different target inhibition specific to each AI pathways.
去势或治疗性激素剥夺后，大多数前列腺癌（CaP）细胞会发展为雄激素非依赖性（AI）生长。在本研究中，我们研究了雄激素剥夺（去势）对实验模型LuCaP 23.1异种移植瘤生长的影响。总共植入了101只裸鼠，并在实验期1（11周）前和去势实验期2（15周）后分析其生长情况。在特定时间段，采集肿瘤并评估CaP特异性分子标志物的表达。考虑到肿瘤的动态生长，在去势前，我们发现37个快速生长（FG）肿瘤（948.9±76.9 mm3）和63个缓慢生长（SG）肿瘤（229.6±18.4 mm3）。实时定量RT-PCR显示，与SG肿瘤相比，FG肿瘤中表皮生长因子受体1型（HER1）、尿激酶型纤溶酶原激活剂（uPA）、胸苷磷酸化酶（TP）和胸苷酸合成酶（TS）的mRNA表达升高，而5α-还原酶2（5α-R2）的mRNA水平较低。去势后，所有FG肿瘤迅速（5周内）进展为AI生长（FG-P）。在SG去势肿瘤中，66%的肿瘤进展迟缓（12周内）至AI（SG-P），而34%对去势有反应（SG-R）。分子分析显示了整合与AI进展相关的不同途径的独特分子谱。进展性肿瘤FG-P以及SG-P亚组的一些肿瘤中，HER1、表皮生长因子受体2型（HER2）、TS、uPA、TP、肿瘤坏死因子超家族成员6（FAS）和肽基甘氨酸α-酰胺化单加氧酶（PAM）的mRNA水平均显著升高，所有这些均与雄激素受体（AR）mRNA相关。SG-P肿瘤的第二个亚组显示抗凋亡基因Bcl-2高表达。SG-P肿瘤的第三个亚组在去势后显示缺氧相关基因如肾上腺髓质素（AM）的显著表达。LuCaP 23.1异种移植瘤是一个有用的动态模型，可用于临床前研究新的治疗分子，并评估结合针对每个AI途径的不同靶点抑制的非随机治疗方案。
