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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Wnt/beta-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.
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Wnt/beta-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.

机译：Wnt/β-catenin 信号转导通过在肺上皮上施加胚胎远端祖细胞表型来加速小鼠肺肿瘤发生。

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摘要

Although mutations in Kras are present in 21 of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/beta-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/beta-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/beta-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/beta-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/beta-catenin signaling. Together, these data suggest that activation of Wnt/beta-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.
机译：尽管 21% 的肺肿瘤存在 Kras 突变，但具有类似突变的肺癌患者的表型和结果存在高度异质性，这表明其他途径很重要。Wnt/β-catenin 信号转导是一种已知的致癌途径，在结肠癌和皮肤癌中起着明确的作用;然而，它在肺癌中的作用尚不清楚。我们在这里已经表明，成年小鼠肺细支气管上皮中Wnt / β-catenin的激活本身不会促进肿瘤的发展。然而，与单独使用 KrasG12D 相比，Wnt/β-catenin 信号转导和组成型活性 Kras 突变体 （KrasG12D） 的表达同时激活导致总体肿瘤数量和大小显着增加。Wnt/β-catenin 信号转导的激活改变了 KrasG12D 肿瘤表型，导致表型从细支气管上皮转移到胚胎肺中发现的高度增殖的远端祖细胞。这与细胞表面的 E-钙粘蛋白表达降低有关，这可能是具有活性 Wnt/β-catenin 信号转导的肿瘤转移增加的基础。总之，这些数据表明，Wnt/β-catenin 信号转导的激活可以与肺上皮中的其他致癌途径结合，通过施加胚胎远端祖细胞表型和降低 E-钙粘蛋白表达来产生更具侵袭性的肿瘤表型。

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