肿瘤干细胞与非激素依赖性前列腺癌的形成

项目名称： 肿瘤干细胞与非激素依赖性前列腺癌的形成

项目编号： No.30872587

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 牛远杰

作者单位： 天津医科大学

项目金额： 30万元

中文摘要： 采用人前列腺癌细胞系LNCaP和VCaP原位种植于裸鼠前列腺前叶，或将人体前列腺癌标本种植于NOD-SCID鼠肾被膜下，获得前列腺癌动物模型。通过将上述前列腺癌小鼠去势，得到激素非依赖性前列腺癌动物模型。并且采用flox-cre基因敲除系统，通过Probasin-cre敲除TRAMP前列腺癌上皮细胞的雄激素受体。在上述非激素依赖性前列腺癌动物模型的基础上，并用流式细胞技术和磁珠分离技术获得了前列腺肿瘤干细胞。通过肿瘤干细胞及非干细胞在裸鼠体内成瘤能力的不同，并鉴定了肿瘤干细胞。用基因芯片和磷酸化蛋白组学技术，筛选了激素非依赖性前列腺癌特异性的细胞内信号调节系统的差异。对初步筛选出的五个分子做了鉴定。研究了这些分子与前列腺癌激素非依赖发生发展的关系。最后用临床雄激素阻断治疗前列腺癌和非激素依赖性前列腺癌标本验证了这些分子的临床意义。通过上述研究我们探讨了激素非依赖性前列腺癌的分子形成机制。

中文关键词： 肿瘤干细胞；前列腺癌；激素非依赖性前列腺癌；雄激素受体

英文摘要： We successfully generated the animal model for human prostate cancer and castration resistant prostate cancer by several approaches, including 1)transplanted human prostate tumor cell lines, LNCaP and VCaP cells, into the anterial lobes of nude mice; 2)transplanted human prostate tumor clinical samples beneath the capsule of the kidney of NOD-SCID mice; 3)knocked out AR specifically from the epithelium of TRAMP prostate by flox - cre strategy. Using the tumor samples from these models, we separated the cancer stem cells by flow-cytometry and MACS. By comparing the stem-like tumor cells with the non-stem tumor cells, we screened the specific molecules and signal pathways for the cancer stem cells by gene-chip assay and phosphor-proteomics assay. We fortunately screened out 5 molecules of two pathways from more than 300 molecules. We verified the clinical significants of these molecules by examinate their expression in different stages of prostate cancer samples and castration-resistant prostate cancer samples. Though these above studies, we proposed the molecular mechanism of the formation of castration-resistant prostate cancer.

英文关键词： Cancer stem cell; Prostate cancer; Castration-resistant prostate cancer; Androgen receptor