胰腺癌细胞群通过活性氧系统相互竞争促进肿瘤进展的实验性研究

乏营养压力可诱导肿瘤微环境中不稳定的分子活性氧(ROS)，通过损伤DNA和激活癌基因的方式促进肿瘤发生，但是细胞内的高水平ROS实际上又抑制肿瘤生长。某些胰腺癌细胞能够抵抗乏营养胁迫，我们推测该抗性可能是由于部分癌细胞K-Ras突变诱导Nrf2表达，增加了细胞内抗氧化系统活性后，消减了ROS的毒性，从而使其在癌细胞亚群相互竞争中获得生存优势，在整体水平促进肿瘤演进。本研究应用临床病理、体外癌细胞亚群共培养以及裸鼠原位胰腺癌模型等手段，运用流式细胞术、激光共聚焦、qRT-PCR、Western blot、小动物活体成像等方法从组织学、细胞学、分子生物学等水平，通过双向调节Nrf2蛋白，探究其在肿瘤微环境乏营养压力下对细胞生存的选择作用，从另一角度理解胰腺癌发生进展机制，为治疗研究提供新依据。

Background: Starvation of pancreatic cancer cells induced oxidative stress, a condition in which an imbalance results between the production and inactivation of reactive oxygen species, in tumor microenvironment. Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. The enhanced reactive oxygen species can best be described as double-edged swords: while they play an essential role in carcinogenesis via activation of oncogene and DNA damage; on the other hand, they contribute to cellular dysfunction and inhibition of proliferation in cancer cells under conditions of oxidative stress. Evidences reveal that there are some special subsets of pancreatic cancer cells in the bulk of tumor have the potential capability to resist the detriment of high level of ROS in the starved stress. Thus, we hypothesize that the expression of Nrf2, the transcript factor which has the function of antioxidant program, is increased induced by activation of K-Ras in these subsets of cells. Due to the enhanced Nrf2 expression, the harm of ROS for cell is eliminated. As the result of this ROS-antioxidant system, these special subset of pancreatic cancer cells gain the considerable advantage to survive in competition and the entire bulk of tumor cells have the evolution forward to more aggravation. Objectives:This study aimed to determine the function of the Nrf2 which induced by K-Ras in the different subset of pancreatic cancer cells under condition of starve stress in tumor microenviroment.