The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision.
The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision.
复制标题
DOI：
10.1371/journal.pone.0003940
复制
发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Jirik FR
中科院分区：
文献类型：
--
作者：
Luchman HA;Benediktsson H;Villemaire ML;Peterson AC;Jirik FR
PTEN肿瘤抑制因子的缺失在人类前列腺癌中是常见的，特别是在晚期疾病中。与其作为磷脂酰肌醇3-激酶信号通路的关键上游调节剂的作用一致，实验诱导的鼠前列腺中Pten缺失总是导致肿瘤形成。然而，与前列腺肿瘤发生可能在数十年内演变的人类不同，组成性Pten缺陷小鼠前列腺中的疾病进展相对较快，在青春期后数周内达到浸润性癌症的顶峰。考虑到前列腺在青春期经历快速的雄激素依赖性生长，并且在此期间切除Pten可能特别具有致瘤性，我们假设将前列腺特异性Pten缺失延迟到青春期后立即进行可能会改变肿瘤发生的速度。为此，我们产生了小鼠与他莫昔芬诱导的Cre重组酶转基因，使时间控制前列腺特异性基因的改变。然后将该品系与携带floxed Pten等位基因的小鼠杂交。尽管有证据表明，在Pten缺陷的上皮细胞中，Akt/mTOR/S6 K轴活性在早期时间点增加，但在青春期后（6周龄）前列腺中诱导的切除产生了一系列病变的逐渐获得。这些进展从癌前病变（核增生，局灶性增生）和低级别前列腺上皮内瘤（PIN）在16-20周后，他莫昔芬暴露，到明显的恶性病变，由高级别PIN和微浸润癌的特点。相比之下，当Pten切除在青春期前（2周龄）前列腺中触发时，瘤形成在更短的时间范围内发展，具有一系列癌前病变，以及在他莫昔芬暴露后10-12周出现明显的PIN和微浸润癌。这些结果表明，Pten缺失诱导的发育阶段决定了PIN发育的速度。
Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16–20 wks post-tamoxifen exposure, to overtly malignant lesions by ∼1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10–12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.
登录
查看更多内容
影响因子：
50.3
作者：
Wang, SY;Gao, J;Wu, H
通讯作者：
Wu, H
DOI：
10.1073/pnas.0712021105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Ratnacaram, Chandrahas Kouimar;Teletin, Marius;Metzger, Daniel
通讯作者：
Metzger, Daniel
影响因子：
11.5
作者：
Carver, Brett S.;Pandolfi, Pier P.
通讯作者：
Pandolfi, Pier P.
影响因子：
50.3
作者：
Memarzadeh, Sanaz;Xin, Li;Witte, Owen N.
通讯作者：
Witte, Owen N.
DOI：
10.1073/pnas.92.8.3439
发表时间：
1995-04-11
影响因子：
11.1
作者：
GREENBERG, NM;DEMAYO, F;ROSEN, JM
通讯作者：
ROSEN, JM