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首页> 外文期刊>Cell cycle >Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations
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Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

机译：通过直接靶向衰老屏障，可在两个步骤中使正常人类乳腺上皮细胞永生化，而无需进行重大的基因组改变

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Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16(INK4); replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages; in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional passenger errors carried forward into resulting carcinomas; (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se; bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of passenger genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.
机译：端粒酶的激活和永生化对于人类癌症的发展至关重要。然而，对于控制这一关键步骤的机制知之甚少，部分原因是缺乏实验上可处理的模型系统，该系统可以检查人上皮细胞永生化，因为它可能在体内发生。通过直接靶向培养的HMEC遇到的2种主要衰老障碍，我们实现了正常人乳腺上皮细胞（HMEC）的有效非克隆永生化。使用shRNA绕过与应力相关的瘀阻屏障至p16（INK4）;在停滞后的HMEC中，通过c-MYC转导绕过了由于端粒严重缩短而引起的复制衰老。因此，两种与病理相关的致癌剂足以永生地转化正常的HMEC。产生的非克隆永生品系表现出正常的核型。大多数人类癌症都含有基因组不稳定的细胞，首先在体内在恶性前期就发现了广泛的不稳定性。在体外，不稳定性被认为是端粒严重缩短的有限细胞接近复制衰老。我们的结果支持我们的假设：（1）端粒功能障碍引起的恶变前有限细胞中的基因组不稳定性可能会产生端粒酶重新激活和永生化所需的错误，以及许多额外的过客错误会导致癌症。 （2）需要癌症发展过程中的基因组不稳定性来产生克服肿瘤抑制性障碍的错误，但本身不是必需的;通过直接靶向绕过衰老障碍消除了对基因组错误产生永生化的需要。在没有乘客基因组错误的情况下实现有效的HMEC永生化，应有助于检查人类癌症进展过程中端粒酶的调控，并探索可防止永生化的药物。

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