谷氨酰胺酶2在肿瘤中作用的研究现状和进展

正肿瘤细胞可出现多种表型的改变,而代谢异常是肿瘤细胞的一项主要特征~([1])。肿瘤细胞异常代谢机制的研究可为抗肿瘤治疗提供新的潜在治疗靶点和思路。谷氨酰胺可为细胞生长提供代谢所需的能量,为合成各种大分子物质如脂肪、蛋白质、核酸等提供原料,而异常代谢的肿瘤细胞消耗大量的谷氨酰胺,因而谷氨酰胺在肿瘤代谢过程中起到重     

不平衡氨基酸在综合治疗进展期胃肠道肿瘤中的意义

近年来不少研究从蛋白质和氨基酸代谢的观点出发，探索抑制肿瘤生长的营养支持方法，。即通过除去或增加氮源中某种氨基酸组分或改变酶活恶性循环 的方法，造成体内某种特定氨基酸含量过剩或不足，使之有利于营养不良的改善而又有碍于肿瘤细胞的扩增。目前认为对肿瘤生长有影响的氨基酸为谷氨酰胺（Ｇｌｎ）、甲硫氨酸（Ｍｅｔ）和精氨酸（Ａｒｇ）．Ｇｌｎ是快速生长组织利用的燃料，肿瘤正是Ｇｌｎ的主要消耗者，并因此而可改变宿     

谷氨酰胺与肿瘤免疫、化学治疗、放射治疗(文献综述)

谷氨酰胺是机体内含量最丰富的氨基酸 ,在荷瘤机体常出现谷氨酰胺的缺乏。本文拟对谷氨酰胺在荷瘤机体中的代谢及在肿瘤免疫、化学治疗、放射治疗中的应用新的进展作一综述。     

含谷胺酰胺TPN对择期腹部手术后节省肌肉游离谷氨酰胺、增加肌肉蛋白合成和改善氮平衡的作用

谷氨酰胺是体内最丰富的氨基酸,它虽然不是必需氨基酸,但在体内氨基酸代谢中起着关键作用。谷氨酰胺是由谷氨酸在肌肉和肾内生成。动物实验已经发现谷氨酰胺浓度与肌肉蛋白合成率呈正相关。本实验选其它系统正常的择期胆囊切除者22名,随机分成两组。术后早期三天用同热卡(135kJ/kg/24 h)和同氮量(0.2g/kg/24 h)的TPN。对照组(13人)供普通氨基酸液Vamin;实验组(9人)在此氨基酸液内再加入谷氨酰胺(0.285 g/kg/24 h),但使总氮     

谷氨酰胺与肿瘤免疫、化学治疗、放射治疗（文献综述）

谷氨酰胺是机体内含量最丰富的氨基酸，在荷瘤机体常出现谷氨酰胺的缺乏。本文拟对谷氨酰胺在荷瘤机体中的代谢及在肿瘤免疫、化学治疗、放射治疗中的应用新的进展作一综述。     

肿瘤代谢:肝癌精准诊疗新视角

代谢重编程是肿瘤的重要特征之一。肝脏是体内三大营养物质糖、脂质、氨基酸代谢的重要枢纽。肝细胞癌(HCC)中可呈现多种特征性代谢改变,如有氧糖酵解增加、脂肪从头合成增强、谷氨酰胺消耗和氧化代谢失衡等,从而为快速生长和增殖的肿瘤细胞提供能量和生物大分子合成原料。肿瘤代谢重编程过程受代谢酶活性改变、基因表达异常、信号转导通路失调等多因素调节。高通量代谢组学技术的进步为发现新的HCC生物标志物和代谢靶点提供了平台。深入研究HCC的代谢特征及调控机制对于以肿瘤代谢为靶点的新型抗代谢药物的研发至关重要。     

谷氨酰胺在胃肠肿瘤患者术后的应用进展

谷氨酰胺是一种条件性必需氨基酸,是血浆中含量最高的氨基酸,约占全身游离氨基酸的60％,在正常血浆浓度为0.6～0.9 mmol/L.近年来,随着谷氨酰胺在临床营养领域研究的不断深入,已从过去单纯的营养支持治疗逐步转为免疫营养治疗的概念.谷氨酰胺能够改善机体的蛋白质营养水平,保护胃肠道黏膜,提高免疫功能,降低感染发病率,减轻机体炎症反应,降低化疗的不良反应,增强肿瘤对化疗药物的敏感性,促进胃肠肿瘤患者术后恢复,减少手术并发症.本文对谷氨酰胺在胃肠肿瘤患者术后的应用研究方面做一综述.     

lncRNA调控肿瘤能量代谢机制的研究进展

目的总结近年来lncRNA肿瘤能量代谢机制的最新研究进展。方法计算机检索Pub Med、Springer、High Wire等数据库中的相关文献,就近年来长链非编码RNA(lncRNA)调控肿瘤能量代谢机制的研究进展进行综述。结果恶性肿瘤最主要的能量代谢特点就是有氧糖酵解(Warburg效应),lncRNA能够通过对肿瘤细胞糖代谢、谷氨酰胺代谢和脂类代谢途径中的关键环节进行调节,导致肿瘤细胞对葡萄糖摄取增加、谷氨酰胺分解增强及脂质生成增加,从而促进肿瘤的发生和发展。结论目前,大多数lncRNA在肿瘤细胞能量代谢中的功能和调控机制尚不完全清楚,进一步认识和了解肿瘤细胞中与lncRNA相关的能量代谢异常表现出的恶性生物学行为,将有助于为肿瘤的诊断和治疗提供有效的证据及新的思路和途径。     

肿瘤代谢异常与侵袭转移研究进展

肿瘤的侵袭转移是导致患者死亡的主要因素之一,肿瘤细胞的物质代谢过程与正常细胞差异明显,这种异常的物质代谢途径与肿瘤的侵袭转移能力密切相关.本文主要对糖类、脂质、蛋白质三类物质的异常代谢在肿瘤侵袭转移中的作用及机制进行综述,为从肿瘤代谢角度发现新的侵袭转移调控手段提供研究基础.     

谷氨酰胺与肿瘤

谷氨酰胺与肿瘤第二军医大学长海医院普外科（上海，２００４３３）刘连杰综述屠岳，叶必远审阅谷氨酰胺（ｇｌｕｔａｍｉｎｅ，ＧＬＮ）对正常机体是一种非必需氨基酸，占体内游离氨基酸池的６０％，正常血浆中浓度为０．６～０．９ｍｍｏｌ／Ｌ，可在细胞内氧化供能并为...     

Normalization of tumor-induced increases in hepatic amino acid transport after surgical resection.

BACKGROUND: The liver of the host with cancer requires increased amounts of amino acids to support the synthesis of glucose and key defense proteins. To study the effect of the growing tumor on hepatic amino acid uptake, the authors measured hepatic transport activity in tumor-bearing rats and in rats at various times after tumor resection. METHODS: Fischer-344 rats were implanted subcutaneously with methylcholanthrene-induced fibrosarcoma cells (MCA sarcoma). When the tumors reached 10% of body weight, hepatic amino acid transport activity was assayed or the animals underwent surgical removal of the tumor. In animals that underwent tumor excision, livers were removed at 1, 3, or 5 days post-resection, and hepatic plasma membrane vesicles (HPMVs) were prepared. Nontumor-bearing pair-fed rats undergoing sham implantation or sham resection served as controls. System N (glutamine), System A (MeAIB), and System y+ (arginine) transport activity were assayed, which allowed the authors to compare differences in tumor-induced rates of transport and the influence of resection on transport activity. RESULTS: System A transport activity was unaltered by tumor growth. In contrast, the presence of the growing tumor increased arginine and glutamine uptake by the liver. Hepatic glutamine transport remained elevated for 5 days after tumor resection, although by postoperative day 5 there was a trend toward normalization. In contrast, arginine transport remained increased by twofold onpost-resection day 1 and had normalized by postoperative day 3. The enhanced arginine transport was a result of an increase in maximal transport velocity (Vmax) rather than a change in carrier affinity. CONCLUSIONS: Increases in hepatic amino acid transport normalize within several days of tumor resection, indicating a key role for the tumor in the induction of this response. The observation that hepatic glutamine transport activity remains augmented after tumor resection longer than any other transporter studied suggests a key role for this amino acid in overall hepatic nitrogen metabolism and may partially explain the persistent glutamine depletion that is characteristic of the tumor-bearing host.     

p55PIK N末端24个氨基酸抑制甲状腺癌细胞增殖的研究

目的 观察P55PIK的N端的24个氨基酸抑制甲状腺癌细胞增殖的作用.方法 构建含有P55PIK-N端24个氨基酸的腺病毒载体Ad-N24-p55PIK-GFP及对照病毒Ad-GFP,以其感染甲状腺癌YTC236细胞,流式细胞仪检测细胞周期进程,应用BrdU掺人的方法 检测其对细胞DNA合成的影响,通过建立体内肿瘤裸鼠移植瘤模型,进一步证实Ad-N24p55PIK-GFP的抗肿瘤作用.结果 对照腺病毒Ad-GFP感染的细胞中G0/G1期细胞为(69.83±3.50)%,S期和G2/M期细胞数分别为(18.56±3.10)%和(11.61±2.90)%,而带有插入目的 基因的腺病毒Ad-N24p55PIK-GFP感染后的细胞G0/G1期细胞减少为(45.81±2.10)%,S期和G2/M期细胞增加至(30.12±2.60)%和(24.07±2.90)%,BrdU掺入显示BrdU阳性的细胞数由(21.2±3.0)%降至(8.1±2.2)%,FTC236细胞裸鼠移植瘤模型局部应用Ad-N24p55PIK-GFP后肿瘤生长显著减慢.结论 在FTC236细胞中,过表达p55PIK的N末端的24个氨基酸可有效阻滞细胞周期进程,抑制细胞DNA合成,体外有效抑制甲状腺癌裸鼠移植瘤模型的肿瘤生长.     

Malignant prolactinoma with multiple intracranial metastases studied with positron emission tomography

A rare case of a patient with multiple intracranial metastases from a prolactin-secreting pituitary neoplasm is described. At the age of 14 years, the patient had been operated on for a sellar tumor; he presented 12 years later with severe headache, at which time computed tomographic and magnetic resonance imaging scans revealed multiple intracranial metastases. Histopathology examination showed pituitary neoplastic cells with positive immunostaining for prolactin. The patient was investigated with positron emission tomography (PET) and dopamine D2-receptor binding, and the amino acid metabolism of the tumor was characterized in vivo. High dopamine D2-receptor binding and high amino acid metabolism were found in the tumor. The patient was subsequently treated with bromocriptine injections that resulted in a decrease in serum prolactin levels, decreased dopamine D2-receptor binding, reduced amino acid metabolism, and a reduction in tumor volume. This case demonstrates a beneficial effect of bromocriptine treatment in a patient with prolactinoma with multiple intracranial metastases. It also illustrates the great potential of PET in the in vivo characterization of the D2-binding and the high sensitivity of 11C-labeled L-methionine in the follow-up of treatment in patients with pituitary adenomas.     

microRNA调控肿瘤细胞能量代谢机理的研究进展

目的 总结近年来microRNA对肿瘤细胞能量代谢调控的最新研究进展。方法 根据PUBMED检索获取的相关资料,就近年来关于microRNA对肿瘤细胞能量代谢调控机理的研究进展进行综述。结果 有氧糖酵解（Warburg效应）是恶性肿瘤最主要的能量代谢特点,microRNA能够通过对肿瘤细胞葡萄糖摄取、糖酵解途径、三羧酸循环以及脂代谢和氨基酸代谢与三羧酸循环的联系等途径中的关键环节进行调控,结果使肿瘤细胞对葡萄糖的摄取和糖酵解处于增高状态。可见,葡萄糖、脂肪酸、氨基酸转运和代谢对肿瘤细胞至关重要,且与肿瘤患者的不良预后有关。结论 研究microRNA对肿瘤细胞能量代谢的调控,为破解肿瘤细胞基于能量代谢异常而表现出的恶性生物学行为提供了重要线索,也为肿瘤的诊断和治疗提供了有力的证据及新的思路和途径。就目前关于microRNA对肿瘤细胞能量代谢调控方面的研究进展来看,必须要揭示清楚的是microRNA异常表达引起肿瘤细胞代谢变化后,能够直接引发肿瘤生物学行为变化的肿瘤细胞代谢因素有哪些。     

A Novel Approach for the Identification of Unique Tumor Vasculature Binding Peptides Using an E. coli Peptide Display Library

Background: Tumor neovascularization is necessary for continued tumor growth and metastasis. During the process of endothelial cell (EC) recruitment and tumor infiltration, specific molecular markers unique for this interaction are expressed on the EC surface. Targeting these molecular markers would, in effect, allow for specific tumor targeting. Tripeptide sequence motifs have previously been reported that will bind to angiogenic tumor ECs. These sequences were identified from in vivo phage peptide display libraries. The purpose of this study was to use a more simplified bacterial peptide display library in an in vitro system to seek out peptide motifs with unique binding to tumor microvasculature.Methods: FliTrx is a bacterial peptide display library containing the entire repertoire of possible random dodecapeptides expressed on the flagella tip of E. coli. Two EC populations were used for the screening process, Matrigel invading cells (MAGIC) and tumor–derived endothelial cells (TDEC). MAGIC are obtained from ECs that infiltrate a subcutaneous fibroblast growth factor–containing Matrigel deposit, and TDEC are ECs selectively obtained from tumor vasculature. FliTrx cells were incubated with MAGIC at 4°C to remove any potential clones displaying peptides that will bind to nonspecific EC surface targets. The non–binding cells were then incubated with TDEC, allowing for clones displaying potential binding peptides to bind tumor specific targets on TDECs. The bacterial population was then expanded and this panning process was carried out a total of five times. Peptide insert sequences from 100 bacterial colonies were analyzed for potential repetitive peptide motifs.Results: Recurring peptide sequences were detected that were 3–mers (13 sequences) and 4–mers (4 sequences). Of the 3–mers, four repeated 3 times, whereas none of the 4–mers repeated more than twice. All of the repeated sequences were basic in charge, and arginine was the most commonly seen amino acid. A tripeptide basic–basic–nonpolar amino acid arrangement was the most prevalent charge sequence in all repetitive motifs (17 repeat sequences). Two test peptides showed TDEC binding specificity, and both conformed to the basic–basic–nonpolar motif.Conclusions: We report peptide sequences derived from panning an in vitro system designed to detect tumor–EC specific markers. These putative motifs may serve as molecular determinants for a novel therapeutic modality aimed at specifically targeting tumors through tumor angiogenic vessels.     

Renal amino acid transport: cellular and molecular events from clearance studies to frog eggs

This article reviews recent advances in the mechanisms of renal amino acid transport. Renal amino acid transport is necessary to efficiently reclaim approximately 450 mmol amino acids from the glomerular ultrafiltrate each day in man. In general, individual amino acids are transported across the epithelial membrane of the proximal tubule by a sodium (Na⁺) dependent mechanism. This cotransport process utilizes the energy of the Na⁺ gradient to enter the cell. The amino acid then exits the basolateral surface and Na⁺ is pumped out by the Na⁺–K⁺-ATPase located in the basolateral membrane. In addition to the cellular accumulation of amino acids across the luminal membrane, these compounds may be taken up by the cell from the basolateral surface. Most amino acids are transported both individually and in a series of seven group specific processes. Human disorders of amino acid transport have been described for six to the seven transport systems. The process of ontogeny of amino acid accumulation by the proximal tubule is a complex one and will be further discussed in this review. A number of factors including pH, ion dependency, electrogenicity of transport process, as well as a variety of hormonal factors, may contribute to the regulation of amino acid transport. Gene expression of several amino acid transporters has been successfully performed using the oocyte of the frogXenopus laevis. Using this system, a number of transporters have been cloned. Such a strategy will permit the cloning of virtually all transporter molecules, and thus we can anticipate the elucidation of the structure of the transporters. However, for a comprehensive understanding of cytoskeletal interactions protein phosphorylation and phospholipid domains and their linkage to the primary structure of the transporter need to be studied. The future for research in this area is indeed a bright one.     

ProAgio靶向诱导胰腺导管腺癌中活化胰腺星状细胞凋亡的可能机制

目的总结肿瘤微环境中整合素、肿瘤代谢和肿瘤细胞与胰腺星状细胞的关系,旨在为胰腺导管腺癌的治疗及药物研发提供靶点和思路。方法对国内外以胰腺星状细胞、整合素、氨基酸代谢等作为胰腺导管腺癌治疗靶点的研究文献进行综述。结果针对胰腺导管腺癌的靶向药物研究目前正蓬勃开展,但均停留在动物及临床试验阶段。ProAgio作为一种新的治疗性蛋白,对胰腺导管腺癌微环境中整合素αvβ3的表达、胰腺星状细胞的活化及其分泌、丙氨酸代谢等具有抑制作用,从而达到抗纤维化及抗肿瘤的双重作用。结论活化的胰腺星状细胞、ProAgio、整合素αvβ3、丙氨酸代谢等在胰腺导管腺癌中的作用已部分阐明,但具体作用机制仍需进一步研究,并可能成为全新的治疗靶点。     

Functional Domains of the BRCA1 and BRCA2 Proteins

The BRCA1 and BRCA2 genes encode large unrelatedproteins that presumably function as tumor suppressorsin normal epithelial cells of the breast. However, theprimary amino acid sequences of these proteins provide few insights into the mechanisms bywhich BRCA1 and BRCA2 inhibit tumor development.Nevertheless, recent studies have uncovered manysimilarities in the biological properties of BRCA1 andBRCA2, raising the prospect that these proteins mayfunction in a common pathway of tumor suppression andthat inactivation of either gene may represent anequivalent step in the development of breast cancer. Several lines of evidence now suggest a rolefor BRCA1 and BRCA2 in the cellular response to DNAdamage, possibly by virtue of their relationship withproteins required for the recombinational repair of double-strand DNA breaks. Accordingly, the lossof BRCA1 or BRCA2 function might accelerate tumordevelopment by allowing cells to accumulate DNA lesionsthat are potentially oncogenic.