Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma
Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma
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DOI：
10.1073/pnas.0712021105
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发表时间：
2008-02-19
影响因子：
11.1
通讯作者：
Metzger, Daniel
中科院分区：
文献类型：
--
作者：
Ratnacaram, Chandrahas Kouimar;Teletin, Marius;Metzger, Daniel
由于缺乏合适的小鼠模型，前列腺癌发病机制的研究和新疗法的开发一直受到阻碍。我们培育了在前列腺上皮中选择性表达他莫昔芬依赖性Cre-ERT2重组酶的PSA-Cre-ERT2小鼠，从而使我们能够在成年小鼠完全分化的前列腺上皮细胞中选择性靶向floxed基因，并调节基因改变细胞的数量。我们目前的小鼠模型，在青春期后通过cre - ert2介导的肿瘤抑制基因PTEN的体细胞双等位基因消融启动前列腺癌，密切模仿人类癌症形成的过程。的确，突变小鼠在PTEN消融后4周内出现前列腺上皮增生，在2-3个月内出现所有肺叶的前列腺上皮内瘤变（PIN），其中背外侧肺叶发病率最高，被认为与人类前列腺外周区最相似，腺癌优先定位于该区域。PTEN消融后8至10个月，一些背外侧叶PINs进展为腺癌，但在PTEN消融后20个月未发现远处转移，表明进展为转移需要额外的突变或突变。有趣的是，单等位基因cre - ert2介导的成人前列腺上皮细胞PTEN消融也产生局灶性增生和pin，但仅在背外侧叶，数量少得多，潜伏期长。然而，未观察到进展为腺癌。由于这些pin在上皮细胞中检测不到PTEN的表达，PTEN功能的丧失似乎是不受控制的细胞增殖的许可事件。
Studies of prostate cancer pathogenesis and development of new therapies have been hampered by a lack of appropriate mouse models. We have generated PSA-Cre-ERT2 mice that express the tamoxifen-dependent Cre-ERT2 recombinase selectively in prostatic epithelium, thus allowing us to target floxed genes selectively in epithelial cells of fully differentiated prostate of adult mice and to modulate the number of genetically altered cells. Our present mouse model, in which prostate carcinogenesis is initiated through Cre-ERT2-mediated somatic biallelic ablation of the tumor suppressor gene PTEN after puberty, closely mimics the course of human cancer formation. Indeed, mutant mice developed prostate epithelium hyperplasia within 4 weeks after PTEN ablation and prostatic intraepithelial neoplasia (PIN) in all lobes within 2-3 months, with the highest incidence in the dorsolateral lobe, which is considered to be the most similar to the peripheral zone of the human prostate, in which adenocarcinoma is preferentially localized. Eight to 10 months after PTEN ablation some PINs of the dorsolateral lobe had progressed to adenocarcinoma, but no distant metastases were found up to 20 months after PTEN ablation, indicating that progression to metastasis requires an additional mutation or mutations. Interestingly, monoallelic Cre-ERT2-mediated PTEN ablation in epithelial cells of adult prostate also generated focal hyperplasia and PINs, but exclusively in the dorsolateral lobe, and in much lower number and after a longer latency. However, no progression to adenocarcinoma was observed. Because PTEN expression was undetectable in epithelial cells from these PINs, loss of PTEN function appears to act as a permissive event for uncontrolled cell proliferation.