IL6和肺干/始祖细胞在肺转移龛形成中的作用和调控机理

转移微环境或龛作为转移的关键因素，为转移癌细胞提供了丰富的“土壤”环境。炎症与肺转移紧密相关，但具体机制还有待阐明。我们发现：肺癌抑制基因Gprc5a缺失造成小鼠肺组织慢性炎症，激活的NF-kB信号介导了肺干/始祖细胞的异常扩增和IL6表达升高；分泌增加的IL6一方面正反馈进一步激活NF-kB，另一方面通过招募髓系抑制细胞（MDSCs）促进肺组织预转移龛形成和肺转移。我们假设IL6也可诱导肺干/始祖细胞的扩增，两者均为肺转移龛形成之必要条件，协同促进了肺转移。基于此，我们获得了Gprc5a-ko/Il6-ko和Gprc5a-ko/SPC-dnIkBa小鼠。在这项研究中，我们拟从细胞、动物和肺癌临床样本中展开研究，揭示炎症引起的IL6和肺干/始祖细胞促进肺转移龛形成的调控机制，阐明炎症促进肺转移的具体机制，不仅可为肺转移龛的形成提出新的见解，还有望为炎症介导的肺转移防治提供新的思路。

Metastatic microenvironment or niche is a key factor of metastasis which provides rich "soil" environment for metastasis cancer cells. Inflammation is closely related to lung metastasis, but the specific mechanism remains to be elucidated. We found that mice with deletion of Gprc5a, a lung cancer suppressor gene, resulted in chronic inflammation in lung tissues and activated NF-kB signaling, which mediated the abnormal expansion of lung stem/progenitor cells and the increase of IL6 expression; On the one hand, the increased secretion of IL6 further activated NF-kB by a positive feedback loop, on the other hand, it further promoted the formation of pre-metastatic niche and lung metastasis by recruiting myeloid-derived suppressor cells (MDSCs). We hypothesize that IL6 can also induce the expansion of lung stem/progenitor cells, both of which are requisite element for lung metastatic niche and synergistically promotes lung metastasis. Accordingly, we obtained Gprc5a-ko/Il6-ko and Gprc5a-ko/SPC-dnIkBa mice models. In this study, we will use cell lines, animal models and clinical samples of lung cancer to reveal the regulatory mechanism of IL6 and lung stem/progenitor cells induced by inflammation in the formation of lung metastatic niche, and clarify the specific mechanism of inflammation in promoting lung metastasis. Our work can not only brings new insights in the formation of lung metastatic niche, but also provides new ideas for the prevention and treatment of lung metastasis mediated by inflammation.