Androgen-regulated and highly tumorigenic human prostate cancer cell line established from a transplantable primary CWR22 tumor.
Androgen-regulated and highly tumorigenic human prostate cancer cell line established from a transplantable primary CWR22 tumor.
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DOI：
10.1158/1078-0432.ccr-08-0979
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发表时间：
2008-10-01
期刊：
影响因子：
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通讯作者：
Nevalainen MT
中科院分区：
文献类型：
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作者：
Dagvadorj A;Tan SH;Liao Z;Cavalli LR;Haddad BR;Nevalainen MT
了解前列腺癌生长从雄激素依赖性向激素难治状态转变的分子机制的主要障碍之一是缺乏雄激素调节和致瘤的人类前列腺癌细胞系。我们已经建立并鉴定了一种新的人类前列腺癌细胞系 CWR22Pc，该细胞系源自原代 CWR22 人类前列腺异种移植肿瘤。 CWR22Pc 细胞的生长受到二氢睾酮 (DHT) 的显着诱导，并且 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 细胞中的 PSA 表达受到雄激素的调节。 Stat5a/b、Stat3、Akt 和 MAPK 在 CWR22Pc 细胞中具有组成型活性或细胞因子诱导型。 CWR22Pc 细胞中的 AR 包含 H874Y 突变，但不包含外显子 3 重复或其他突变。当皮下接种到补充 DHT 的去势裸鼠时，20/20 小鼠中迅速形成大肿瘤，而没有循环 DHT 的小鼠中没有肿瘤形成。此外，血清PSA水平与肿瘤体积相关。当从裸鼠体内生长的 CWR22Pc 肿瘤中去除雄激素时，肿瘤最初缩小，但重新生长为雄激素非依赖性肿瘤。这种雄激素调节的致瘤人类前列腺癌细胞系为研究前列腺癌细胞的雄激素调节以及当雄激素从生长环境中撤出时促进前列腺癌生长的分子机制提供了有价值的工具。 CWR22Pc 细胞为研究前列腺癌细胞中突变 H874YAR 转录活性的调节提供了模型系统。
One of the major obstacles in understanding the molecular mechanisms underlying the transition of prostate cancer growth from androgen dependency to 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 (DHT), 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 MAPK 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 DHT-supplemented castrated nude mice, large tumors formed rapidly in 20/20 mice whereas no tumors developed in mice without circulating DHT. 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 When androgens were withdrawn from the CWR22Pc tumors grown in nude mice, the tumors initially shrank but re-grew back as androgen-independent tumors.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 provide a model system for studies on the regulation of transcriptional activity of mutated H874YAR in a prostate cancer cell context.