分子显像监测TIGAR调节微环境诱导肿瘤转移及分子机制

Targeting metabolic reprogramming has become an important strategy for tumor treatment. Tumor growth and metastasis of tumor bearing mice with different TIGAR expression condition was observed by the 18F-FDG micro PET/CT.The correlation between tumor metastasis and expression of TIGAR protein was analysed. Angiogenesis of tumor bearing mice with different TIGAR expression condition was observed by 99Tcm-3PRGD2 imaging. The relationship between molecular expression of TIGAR protein and tumor angiogenesis was explored. The carbon flow and Extracellular acid change of the different expression of TIGAR state change of tumor cells was determined by isotope labeled glucose flow analysis techology and XF24 Extracellular Flux Analyzer for Cellular Bioenergetics. It is was explored that correlation and molecular mechanism between the changes of expression of TIGAR protein and cell acid environment. Establishment of the theoretical system between targeting tumor cells glycolysis level and inhibit angiogenesis induced migration, which lays a theoretical foundation for the clinical application of combined anti-metabolism drugs and anti angiogenesis drugs in the treatment of cancer.

靶向代谢重组已经成为抗肿瘤治疗的一个重要策略。本课题通过18F-FDG micro PET/CT观察荷瘤小鼠不同TIGAR表达状态下，肿瘤组织生长与转移能力的变化，研究TIGAR蛋白表达与肿瘤细胞转移生物学行为之间相关性。通过99Tcm-3PRGD2显像观察荷瘤小鼠不同TIGAR表达状态下，肿瘤组织新生血管表达变化，研究TIGAR蛋白表达与肿瘤新生血管生成之间相关性及分子机制。通过同位素标记葡萄糖流量分析和海马生物能量测定仪观察不同TIGAR表达状态下肿瘤细胞碳流量变化、细胞酸环境变化，研究TIGAR蛋白表达与细胞酸环境变化之间相关性及分子机制。建立通过靶向肿瘤细胞调节糖酵解水平抑制肿瘤细胞血管生成诱导转移的理论体系，为临床联合应用抗代谢药物和抗血管生成药物治疗肿瘤奠定理论基础。

肿瘤转移是90%以上的肿瘤死亡病例的病因，而代谢可塑性使得肿瘤细胞能够灵活应对各种微环境改变，促进其在远处形成转移灶。TIGAR促进代谢流量从糖酵解途径转向磷酸戊糖途径，一方面有利于克服肿瘤细胞脱离原发灶时发生的“失巢凋亡”，另一方面给转移灶的快速增殖提供大量的核酸原材料。本课题组通过18FDG micro PET/CT观察不同TIGAR表达状态对肿瘤侵袭转移的影响，发现敲减TIGAR肿瘤转移灶数量和增殖能力明显下调。通过划痕、Trans-well侵袭、细胞黏附实验分别检测TIGAR对迁移、侵袭、基质黏附能力的影响，并检测TIGAR对上皮间质化的影响，发现TIGAR促进肿瘤迁移、侵袭、上皮间质化；通过放射性同位素示踪技术和海马生物能量测定以及乳酸、ROS检测，发现TIGAR在氧化应激条件下对细胞周围酸性微环境和细胞氧化还原稳态的维持具有重要作用。对临床肺癌组织样本分析发现，TIGAR和Met表达具正相关，与肿瘤TNM分期、淋巴结转移、肿瘤进展密切相关，两者共高表达患者预后明显差于共低表达，分子实验表明TIGAR可能通过转录后调控Met表达来促肿瘤侵袭转移。本课题组的研究发现提示TIGAR/Met通路可能为非小细胞肺癌治疗的新靶点，Met抑制剂可能对高表达TIGAR的非小细胞的肺癌患者有效。