Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.
Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.
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DOI：
10.1158/0008-5472.can-11-0595
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发表时间：
2011-09-15
期刊：
影响因子：
11.2
通讯作者：
Bishop JM
中科院分区：
文献类型：
--
作者：
Allen TD;Rodriguez EM;Jones KD;Bishop JM
NOTCH1编码哺乳动物Notch受体家族的典型成员。激活的病变经常影响T细胞急性淋巴细胞白血病(T-ALL)的NOTCH1，最近在非小细胞肺癌(NSCLC)中也发现了NOTCH1。我们通过建立肺泡上皮细胞过度表达活化的NOTCH1转基因小鼠模型，探讨了活化的NOTCH1在肺内的致癌潜能。对激活的NOTCH1的最初反应是增殖和肺泡增生堆积，然后迅速被细胞凋亡清除。然而，经过一段较长的潜伏期后，转基因小鼠中出现了肺腺瘤，但未能进展为癌症。有趣的是，MYC和MYCL1在腺瘤中表达，这表明选择增强的MYC活性可能有助于肿瘤的发生。利用共表达激活的NOTCH1和MYC的小鼠，我们发现补充MYC的表达增加了N1ICD诱导的腺瘤的频率，并使其能够进展为腺癌和转移。合作源于肿瘤细胞周期的协同激活，这一过程显然对抗了MYC和/或激活的NOTCH1诱导的细胞凋亡对肿瘤形成的任何阻力。值得注意的是，合作不依赖于RAS的激活。综上所述，这些数据表明，在NSCLC的发展过程中，激活的NOTCH1替代了RAS的激活，与MYC合作。这些肿瘤模型对于探索激活的NOTCH1在非小细胞肺癌发生中的作用以及测试针对激活的NOTCH1或其下游效应的治疗方法具有重要价值。
NOTCH1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL) and recently have been found in non-small cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated NOTCH1 in the lung by developing a transgenic mouse model in which activated NOTCH1 was overexpressed in the alveolar epithelium. The initial response to activated NOTCH1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas arose in the transgenic mice, but failed to progress to carcinoma. Interestingly, MYC and MYCL1 were expressed in the adenomas, suggesting that selection for enhanced MYC activity may facilitate tumorigenesis. Using mice engineered to co-express activated NOTCH1 and MYC, we found that supplementing MYC expression increased the frequency of N1ICD-induced adenomas and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by MYC and/or activated NOTCH1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated NOTCH1 substitutes for RAS activation in cooperation with MYC in the development of NSCLC. These tumor models should be valuable for exploring the role of activated NOTCH1 in the genesis of NSCLC and for testing therapies targeting either activated NOTCH1 or its downstream effectors.