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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma
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Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma

机译：在成年小鼠前列腺上皮中暂时控制PTEN的消融可产生浸润性前列​​腺癌模型

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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-ER~(T2) mice that express the tamoxifen-dependent Cre-ER~(T2) 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-ER~(T2)-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-ER~(T2)-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.
机译：缺乏合适的小鼠模型阻碍了前列腺癌发病机理和新疗法发展的研究。我们已经产生了在前列腺上皮细胞中选择性表达三苯氧胺依赖性Cre-ER〜（T2）重组酶的PSA-Cre-ER〜（T2）小鼠，从而使我们能够在成年小鼠完全分化的前列腺的上皮细胞中选择性地靶向固定基因并调节转基因细胞的数量。我们目前的小鼠模型在青春期后通过Cre-ER〜（T2）介导的肿瘤抑制基因PTEN的体细胞双等位基因切除来引发前列腺癌，它紧密地模拟了人类癌症的形成过程。实际上，突变小鼠在PTEN消融后4周内出现前列腺上皮增生，在2-3个月内在所有肺叶中出现前列腺上皮内瘤变（PIN），在背外侧叶中发生率最高，这被认为与外周血最相似人前列腺的区域，其中腺癌优先位于其中。 PTEN消融后8到10个月，背外侧叶的一些PIN已发展为腺癌，但在PTEN消融后直至20个月未发现远处转移，这表明转移至转移需要进一步的突变。有趣的是，在成年前列腺的上皮细胞中由等位基因Cre-ER〜（T2）介导的PTEN消融也产生局灶性增生和PIN，但仅在背外侧叶中产生，数量少得多，且潜伏期长。但是，未观察到进展为腺癌。由于从这些PIN在上皮细胞中无法检测到PTEN表达，因此PTEN功能的丧失似乎是不受控制的细胞增殖的允许事件。

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