Dynamic Metabolic Transformation in Tumor Invasion and Metastasis in Mice with LM-8 Osteosarcoma Cell Transplantation

While extensive evidence indicates that tumor cells shift their global metabolic programs, the molecular details of the metabolic transformation in tumor invasion, progression, and metastasis remain largely unknown. Characterization of the time-dependent metabolic shift during the tumor invasion, development, and metastasis will describe an important aspect of tumor phenotypes and potentially allow us to design therapies that inhibit tumor cell movement. In this study, a metabonomic study was performed to characterize the global metabolic changes during the process of tumor invasion and metastasis to lung in a mouse model with subcutaneous transplantation of murine osteosarcoma cell line (LM8). The serum metabolic profiling revealed that many key metabolites in glycolysis and tricarboxylic acid (TCA) cycle, as well as most of the amino acids were elevated at rapidly growing stage of tumor, presumably resulting from a high energy demand and turnover of anabolic metabolism during the tumor cell proliferation. Serum levels of succinic acid and proline significantly increased (with fold change FC = 10.75 and 4.43, relative to controls) among all the metabolites in the third week. The serum metabolic profile of lung metastasis at week 4 was different from that at week 3, in that most of previously increased serum metabolites were found decreased, except for cholesterol and several free fatty acids, suggesting lowered carbohydrate and amino acids metabolism, but an elevated lipid metabolism associated with tumor metastasis.尽管已有大量研究证实肿瘤细胞会重塑其整体代谢程序，但肿瘤侵袭、进展及转移过程中代谢转化的分子机制仍未完全阐明。阐明肿瘤侵袭、发生及转移过程中随时间动态变化的代谢特征，可揭示肿瘤表型的重要维度，亦有望为开发抑制肿瘤细胞迁移的治疗策略提供思路。本研究通过小鼠皮下接种小鼠骨肉瘤细胞系（LM8）构建的移植瘤模型，开展代谢组学（metabonomic）研究，以表征肿瘤侵袭及肺转移过程中的整体代谢变化。血清代谢组学分析结果显示，在肿瘤快速增殖阶段，糖酵解（glycolysis）、三羧酸循环（tricarboxylic acid cycle, TCA）中的多种关键代谢物以及大部分氨基酸水平均显著升高，这大概率源于肿瘤细胞增殖过程中旺盛的能量需求与合成代谢（anabolic metabolism）周转。在接种后第3周的所有检测代谢物中，琥珀酸与脯氨酸的血清水平显著升高（相较于对照组，其倍数变化（fold change, FC）分别为10.75与4.43）。第4周肺转移模型小鼠的血清代谢谱与第3周存在显著差异：此前升高的多数血清代谢物水平均出现回落，仅胆固醇与数种游离脂肪酸（free fatty acids）水平仍维持升高，这提示伴随肿瘤肺转移，机体碳水化合物与氨基酸代谢水平降低，而脂质代谢则被激活。