糖酵解在巨噬细胞促肿瘤进展过程中的作用机制研究

Glycolysis is an important metabolic process for energy acquisition in most tumors, but the mechanism of glycolysis and its effect on malignant biological behavior of cancer are not clear. Our previous studies have confirmed that macrophages (Mφ) mainly exhibited activated phenotypes in the invading edge of hepatocellular carcinoma (HCC), and induced angiogenesis and tumor metastasis. We recently found that the expression of key glycolytic enzymes was positively correlated with the densities of Mφ in the same region. Interestingly, Mφ educated by tumor microenvironments acquired the ability to induce glycolysis in hepatoma cancer cells, but not normal phenotype. These finding indicated that tumor-activated macrophages might be an important regulator for increasing cancer cell glycolysis, which promote the malignant progression. To confirm this hypothesis, we will use HCC as model, and combine experimental studies and clinical sample analysis to: 1) Clarify the role of Mφ in tumor glycolysis and elucidate its key regulatory signal; 2) Explore the tumor glycolytic possible role of macrophage-mediated progression of HCC, focusing on angiogenesis, metastasis and tissue remodeling; 3) Confirm the expression and clinical significance of relative mechanisms or regulators obtained through the above experiments in HCC samples. The results will reveal the mechanism and function of glycolysis in tumors, and provide theoretical basis for new therapeutic schemes targeting cell metabolism and cancer immunity.

糖酵解是大多数肿瘤获取能量的重要代谢方式，但其在肿瘤中的发生机制及对肿瘤恶性生物学行为的影响均未清楚。前期证实：在肝癌侵袭边缘，巨噬细胞（Mφ）发生显著的促炎症反应；这些活化Mφ随后诱导肿瘤转移和血管生成。我们新近发现：肝癌中肿瘤细胞表达糖酵解关键酶基因的水平竟与同一区域中Mφ密度呈正相关；有趣的是，活化而非正常表型Mφ才具备诱导肿瘤细胞糖酵解发生的能力。由此推测，活化Mφ是引起肿瘤细胞选择糖酵解的重要因素，该过程很可能导致肿瘤恶性转化。本课题拟以肝癌为模型，结合临床样本检测和实验模型，明确Mφ在肿瘤细胞糖酵解发生中的作用及潜在调控信号；以血管生成、转移以及组织重塑等为重点，探讨糖酵解在Mφ介导肝癌恶性转化中的作用及调控机制；验证上述调控因素或相应分子在肝癌中表达及临床意义。所得结果将揭示肿瘤中糖酵解的发生机制及功能，为建立以调控代谢和免疫微环境为靶标的新型肿瘤治疗策略提供理论。

糖酵解是大多数肿瘤获取能量的重要代谢方式，但其在肿瘤中的发生机制及对肿瘤恶性生物学行为的影响均未清楚。我们在前期研究发现：肝癌中肿瘤细胞表达糖酵解关键酶基因的水平竟与同一区域中巨噬细胞密度呈正相关；有趣的是，活化而非正常表型巨噬细胞才具备诱导肿瘤细胞糖酵解发生的能力。提示：活化巨噬细胞是引起肿瘤细胞选择糖酵解的重要因素，该过程很可能导致肿瘤恶性转化。但巨噬细胞诱导肿瘤糖酵解的作用机制及调控网络仍未清楚。在青年科学基金项目的资助下，我们以肝癌为研究模型，开展了糖酵解在巨噬细胞促肿瘤进展过程中的作用机制研究，发现：1）活化的巨噬细胞能够产生大量的炎症因子IL-1β，通过激活肿瘤细胞内JNK信号通路来诱导糖酵解的发生。2）活化巨噬细胞介导的肿瘤糖酵解通过产生ROS来抑制H2AX的表达，继而促进肝癌基因不稳定性导致化疗耐受。3）除了肿瘤细胞外，肝癌中巨噬细胞也选择进行糖酵解，它不仅能够提供能量，更可通过激活NF-κB通路促进其分泌更多的细胞因子TNF-α、IL-1β和IL-10等；这些细胞因子一方面作用于自身诱导DC-SIGN的表达来促进巨噬细胞失能，同时还可通过炎性信号重塑肿瘤恶性生物学行为，从而促进肿瘤的恶性进展。项目的研究发现在国际上率先揭示了巨噬细胞介导的糖酵解相关反应网络在人肝癌进展及治疗中的重要性：糖酵解一方面促进巨噬细胞M2b极化来促进肿瘤免疫耐受，同时还能直接改造肿瘤的恶性生物学行为，最终加快肝癌的恶性进展。