肿瘤微环境因子Lactic acidosis在肿瘤细胞耐受葡萄糖剥夺中的作用机制研究

Solid tumor is largely short of glucose supply, due to its disorganized vasculature and dysfunctional capillary bed. The mechanism underlies adaptation of solid tumor to glucose shortage is an important theoretical issue, which is not clarified yet. Lactic acidosis, defined as high lactate anion and proton concentration, is one of the hallmarks of tumor microenvironment, and is significantly corelatted with tumor metastasis and prognosis. Recent research show that lactic acidosis could inhibit the proliferation and cytokine production of human cytotoxic T lymphocytes, or oxidized by some tumor cells to provide energy or nutrient. The function of lactic acidosis already becomes an hotspot in tumoral biology research. We recently revealed that lactic acidosis allow cancer cells to develop resistance to glucose deprivation-induced death and dramatically prolong cell's survival time, which was not dependent on lactate anion's oxidation; and cells resumed proliferation almost immediately after glucose is replenished. We further found that lactic acidosis could induce autophagy and inhibit apoptosis of cancer cells. Based on these previous studies, we sought to indentify the molecular target of lactic acidosis and reveal that how lactic acidosis regulates autophagy and apoptosis machinery, which shall provide theoretical foundation for the lactic acidosis signaling pathway-targeting anticancer drug design.

肿瘤由于血管结构功能紊乱，内部常常处于葡萄糖饥饿状态。肿瘤细胞如何适应该环境是一个重要的理论问题，目前尚未得到解决。Lactic acidosis（高乳酸根离子和氢离子浓度）是肿瘤微环境的一个重要特征，与肿瘤转移和预后都有显著的相关性。研究表明lactic acidosis可以抑制细胞毒性T淋巴细胞的活性，也可以通过乳酸根的氧化为某些肿瘤细胞提供能量，已经成为研究的热点之一。我们在前期研究中证实lactic acidosis可以使得肿瘤细胞耐受葡萄糖剥夺从而长期存活，该作用并不依赖于乳酸作为营养物质被利用。进一步研究发现lactic acidosis激活了肿瘤细胞的自噬并抑制凋亡。本项目将在前期工作的基础上，鉴定lactic acidosis使得肿瘤细胞耐受糖剥夺的作用靶点并阐明其通过该靶点调节细胞自噬和凋亡的具体机理，为发展以该信号通路为靶点的抗肿瘤创新药物提供理论基础。

乳酸是实体肿瘤内的重要微环境因子，可以使得肿瘤细胞在葡萄糖剥夺的环境中长期存活，其作用机理包括了抑制肿瘤细胞周期，抑制肿瘤细胞的凋亡，并有限地激活细胞的自噬。本研究通过组学和生物信息学方法筛选到了乳酸使得肿瘤细胞耐受葡萄糖剥夺的重要靶点分子乳酸脱氢酶。在lactic acidosis条件下，乳酸脱氢酶可以产生大量的氧自由基。乳酸脱氢酶在高乳酸条件下，受其酶学平衡常数的影响，其反应平衡向丙酮酸产生方向移动，从而使得肿瘤细胞的有氧糖酵解途径受到抑制。本研究还发现，lactic acidosis可以使得肿瘤细胞从物质代谢和能量代谢两个方面从有氧磷酸化为主的代谢模式，即Warburg 代谢模式向氧化磷酸化为主的代谢模式进行转化。本研究发现，使用碳酸氢钠中和乳酸环境，可以抑制肿瘤的生长。并且在临床试验中，利用同样的原理，极大提高了中晚期干细胞肝癌的治疗效果。