Dagvadorj Ayush, Tan Shyh-Han, Liao Zhiyong, Cavalli Luciane R, Haddad Bassem R, Nevalainen Marja T
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Clin Cancer Res. 2008 Oct 1;14(19):6062-72. doi: 10.1158/1078-0432.CCR-08-0979.
One of the major obstacles in understanding the molecular mechanisms underlying the transition of prostate cancer growth from androgen dependency to a hormone-refractory state is the lack of androgen-regulated and tumorigenic human prostate cancer cell lines.
We have established and characterized a new human prostate cancer cell line, CWR22Pc, derived from the primary CWR22 human prostate xenograft tumors.
The growth of CWR22Pc cells is induced markedly by dihydrotestosterone, and CWR22Pc cells express high levels of androgen receptor (AR) and prostate-specific antigen (PSA). Importantly, PSA expression in CWR22Pc cells is regulated by androgens. Stat5a/b, Stat3, Akt, and mitogen-activated protein kinase were constitutively active or cytokine inducible in CWR22Pc cells. The AR in CWR22Pc cells contains the H874Y mutation, but not the exon 3 duplication or other mutations. When inoculated subcutaneously into dihydrotestosterone-supplemented castrated nude mice, large tumors formed rapidly in 20 of 20 mice, whereas no tumors developed in mice without circulating dihydrotestosterone. Moreover, the serum PSA levels correlated with the tumor volumes. When androgens were withdrawn from the CWR22Pc tumors grown in nude mice, the tumors initially shrank but regrew back as androgen-independent tumors.
This androgen-regulated and tumorigenic human prostate cancer cell line provides a valuable tool for studies on androgen regulation of prostate cancer cells and on the molecular mechanisms taking place in growth promotion of prostate cancer when androgens are withdrawn from the growth environment. CWR22Pc cells also provide a model system for studies on the regulation of transcriptional activity of mutated H874YAR in a prostate cancer cell context.
理解前列腺癌生长从雄激素依赖状态转变为激素难治性状态背后分子机制的主要障碍之一是缺乏雄激素调节且具有致瘤性的人前列腺癌细胞系。
我们建立并鉴定了一种新的人前列腺癌细胞系CWR22Pc，它源自原发性CWR22人前列腺异种移植肿瘤。
二氢睾酮可显著诱导CWR22Pc细胞的生长，且CWR22Pc细胞表达高水平的雄激素受体（AR）和前列腺特异性抗原（PSA）。重要的是，CWR22Pc细胞中PSA的表达受雄激素调节。Stat5a/b、Stat3、Akt和丝裂原活化蛋白激酶在CWR22Pc细胞中持续激活或可被细胞因子诱导。CWR22Pc细胞中的AR含有H874Y突变，但不存在外显子3重复或其他突变。当皮下接种到补充二氢睾酮的去势裸鼠中时，20只小鼠中有20只迅速形成了大肿瘤，而在没有循环二氢睾酮的小鼠中未形成肿瘤。此外，血清PSA水平与肿瘤体积相关。当从裸鼠中生长的CWR22Pc肿瘤中撤除雄激素时，肿瘤最初缩小，但随后又重新生长为雄激素非依赖型肿瘤。
这种雄激素调节且具有致瘤性的人前列腺癌细胞系为研究雄激素对前列腺癌细胞的调节以及从生长环境中撤除雄激素时前列腺癌生长促进过程中发生的分子机制提供了有价值的工具。CWR22Pc细胞还为在前列腺癌细胞背景下研究突变型H874YAR转录活性的调节提供了一个模型系统。
