Cicchini Michelle, Buza Elizabeth L, Sagal Kyra M, Gudiel A Andrea, Durham Amy C, Feldser David M
Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Rosenthal Bldg., Philadelphia, PA 19104, USA.
Cell Rep. 2017 Feb 21;18(8):1958-1969. doi: 10.1016/j.celrep.2017.01.069.
Expression of oncogenic Kras initiates lung adenomas in a mitogen-activated protein kinase (MAPK) signal-dependent manner from only a subset of cell types in the adult mouse lung. Amplification of MAPK signaling is associated with progression to malignant adenocarcinomas, but whether this is a cause or a consequence of disease progression is not known. To better understand the effects of MAPK signaling downstream of Kras expression, we capitalized on the ability of Braf inhibition to selectively amplify MAPK pathway signaling in Kras-expressing epithelial cells. MAPK signal amplification indeed promoted the rapid progression of established adenomas to malignant adenocarcinomas. However, we observed, surprisingly, a greater number of overall tumor-initiating events after MAPK signal amplification, due to induced proliferation of cell types that are normally refractory to Kras-induced transformation. Thus, MAPK signaling in the lung is thresholded not only during malignant progression but also at the moment of tumor initiation.
致癌性Kras的表达以丝裂原活化蛋白激酶（MAPK）信号依赖的方式，仅从小鼠成年肺脏中的一部分细胞类型引发肺腺瘤。MAPK信号的放大与向恶性腺癌的进展相关，但这是疾病进展的原因还是结果尚不清楚。为了更好地理解Kras表达下游的MAPK信号传导的作用，我们利用了Braf抑制在表达Kras的上皮细胞中选择性放大MAPK途径信号传导的能力。MAPK信号放大确实促进了已建立的腺瘤快速进展为恶性腺癌。然而，令人惊讶的是，我们观察到MAPK信号放大后总体肿瘤起始事件的数量更多，这是由于通常对Kras诱导的转化具有抗性的细胞类型的诱导增殖所致。因此，肺中的MAPK信号传导不仅在恶性进展期间而且在肿瘤起始时刻都存在阈值。
