肿瘤谷氨酰胺代谢变化及诊疗新靶点

Altered glutamine metabolism and therapeutic opportunities for cancer

目的谷氨酰胺是人体内最丰富的非必需氨基酸,多个研究表明其可参与癌细胞的能量代谢、氧化还原平衡、大分子合成和信号传导等过程。这些特征使得谷氨酰胺代谢成为临床上监测和治疗癌症的新靶点。本研究回顾了谷氨酰胺在正常器官和肿瘤组织中的代谢机制、作用及差异,以及谷氨酰胺在肿瘤成像和治疗方面的进展,并讨论其在这些领域面临的挑战及前景。方法应用PubMed、CNKI、万方数据库和维普中文科技期刊数据库检索系统,以"glutamine,tumor,metabolism,therapy"及"谷氨酰胺、肿瘤、代谢、治疗"为关键词,检索2000-01-2018-01相关文献。纳入标准:(1)谷氨酰胺代谢;(2)肿瘤谷氨酰胺代谢相关显像;(3)肿瘤谷氨酰胺代谢抑制治疗。根据纳入标准分析文献43篇(中文2篇,外文41篇)。结果癌细胞代谢重编程有助于谷氨酰胺的摄取和利用。增殖癌细胞可与正常细胞竞争循环谷氨酰胺,各器官的谷氨酰胺代谢可能随着肿瘤的进行性生长而发生显著变化。由于肿瘤的异质性不同肿瘤组织表现出不同水平的谷氨酰胺代谢。通过影像学方法可成功量化人体某器官或肿瘤组织的谷氨酰胺代谢,目前研究最广泛的是18 F-(2S,4R)4-氟谷氨酰胺PET显像。另外,通过阻断转运蛋白谷氨酰胺ASCT2抑制谷氨酰胺摄取是现在癌症治疗剂的研究和开发热点。结论关于谷氨酰胺代谢的深入研究将有助于更准确地了解肿瘤对谷氨酰胺成瘾的决定因素以及谷氨酰胺分解代谢受损时细胞的死亡机制。研究如何安全、高效地抑制谷氨酰胺代谢位点,有望促进以抑制谷氨酰胺代谢为特征的治疗方案的开发。

OBJECTIVE Glutamine is the most abundant,naturally occurring,non-essential amino acid in the human body and several studies have shown that it can participate in the process of energy metabolism,redox balance,macromolecular synthesis and signal transduction of cancer cells.These characteristics make glutamine metabolism an appealing target for new clinical strategies to detect,monitor and treat cancer.This article reviewed the metabolic mechanisms of glutamine in normal organs and tumor tissues and its effect and differences on malignant tumors.We also reviewed recent advances in the imaging and treatment of glutamine in tumors and discuss its challenges and prospects in these areas.METHODS The articles were retrieved in PubMed,CNKI,and Wanfang database from January 2000 to January 2018 using terms"glutamine,tumors,metabolism,treatment"as keywords.Inclusion criteria:(1)metabolic mechanisms of glutamine,(2)metabolic imaging of glutamine in tumor,(3)treatment of glutamine in tumors.According to the inclusion criteria,a total of 43 studies(2 in Chinese and 41 in foreign languages)were included in the analysis.RESULTS Metabolic reprogramming of cancer cells contributes to the uptake and utilization of glutamine.Proliferating cancer cells can compete with normal cells for glutamine,and glutamine metabolism of various organs may change significantly as the tumor progresses progressively.Different tumor tissues exhibit different levels of glutamine metabolism due to tumor heterogeneity.The imaging method can successfully quantify the metabolism of glutamine in an organ or tumor tissue of the human body.The most widely studied is 18 F-(2 S,4 R)4-fluoroglutamine PET imaging.In addition,inhibition of glutamine uptake by blocking the transporter glutamine ASCT2 is a hot spot in the research and development of current cancer therapeutics.CONCLUSIONS Glutamine is an essential nutrient for the survival and growth of most tumors.An in-depth study of glutamine metabolism will help to understand the determinants of tumor glutamine addiction and the mechanism of cell death when glutamine catabolism is impaired more accurately.Finally,research on how to safely and efficiently inhibit glutamine metabolism sites is expected to promote the development of treatments characterized by inhibition of glutamine metabolism.