1 Stem Cell Program, Division of Hematology/Oncology and Pulmonary and Respiratory Diseases, Children's Hospital Boston, Boston Massachusetts.
2 Department of Genetics, Harvard Medical School, Boston, Massachusetts.
Am J Respir Cell Mol Biol. 2018 Aug;59(2):237-245. doi: 10.1165/rcmb.2017-0210OC.
Metastatic disease is the primary cause of death of patients with lung cancer, but the mouse models of lung adenocarcinoma do not accurately recapitulate the tumor microenvironment or metastatic disease observed in patients. In this study, we conditionally deleted E-cadherin in an autochthonous lung adenocarcinoma mouse model driven by activated oncogenic Kras and p53 loss. Loss of E-cadherin significantly accelerated lung adenocarcinoma progression and decreased survival of the mice. Kras;p53;E-cadherin mice had a 41% lung tumor burden, invasive grade 4 tumors, and a desmoplastic stroma just 8 weeks after tumor initiation. One hundred percent of the mice developed local metastases to the lymph nodes or chest wall, and 38% developed distant metastases to the liver or kidney. Lung adenocarcinoma cancer cell lines derived from these tumors also had high migratory rates. These studies demonstrate that the Kras;p53;E-cadherin mouse model better emulates the tumor microenvironment and metastases observed in patients with lung adenocarcinoma than previous models and may therefore be useful for studying metastasis and testing new lung cancer treatments in vivo.
转移性疾病是肺癌患者死亡的主要原因，但肺癌腺癌的小鼠模型不能准确重现患者中观察到的肿瘤微环境或转移性疾病。在这项研究中，我们在由激活的致癌性 Kras 和 p53 缺失驱动的同源肺腺癌小鼠模型中条件性缺失了 E-钙黏蛋白。E-钙黏蛋白的缺失显著加速了肺腺癌的进展并降低了小鼠的存活率。Kras;p53;E-cadherin 小鼠在肿瘤起始后仅 8 周，肺肿瘤负担就达到了 41%，侵袭性 4 级肿瘤和纤维母细胞性基质。100%的小鼠发生了局部淋巴结或胸壁转移，38%发生了远处肝或肾转移。从这些肿瘤中分离出的肺腺癌细胞系也具有较高的迁移率。这些研究表明，Kras;p53;E-cadherin 小鼠模型比以前的模型更好地模拟了患者肺腺癌中观察到的肿瘤微环境和转移，因此可能有助于在体内研究转移和测试新的肺癌治疗方法。
