TGF-β信号缺陷是否是人类癌症中的致命弱点?

癌细胞中的存活信号可激活mTOR-哺乳动物雷帕霉素靶蛋白。mTOR可抑制TGF-β信号,后者可使细胞周期停滞于G1后期,因此,活化后的mTOR可防止细胞周期停滞于TGF-β介导的检验点。雷帕霉素可重新激活TGF-β信号,从而导致G1期细胞停滞。在人类癌症中,TGF-β信号通常发生缺陷,相反,在雷帕霉素作用下,TGF-β信号缺陷的癌细胞不发生G1期停滞,而发生凋亡。因此,在基于雷帕霉素的抗癌治疗策略中,TGF-β信号缺陷可能是癌细胞的致命弱点。     

TGF-β信号缺陷是否是人类癌症中的致命弱点?

癌细胞中的存活信号可激活mTOR-哺乳动物雷帕霉素靶蛋白.mTOR可抑制TGF-β信号,后者可使细胞周期停滞于G1后期,因此,活化后的mTOR可防止细胞周期停滞于TGF-β介导的检验点.雷帕霉素可重新激活TGF-β信号,从而导致G1期细胞停滞.在人类癌症中,TGF-β信号通常发生缺陷,相反,在雷帕霉素作用下,TGF-β信号缺陷的癌细胞不发生G1期停滞,而发生凋亡.因此,在基于雷帕霉素的抗癌治疗策略中,TGF-β信号缺陷可能是癌细胞的致命弱点.     

哺乳动物雷帕霉素靶蛋白的反馈激活机制在肿瘤中的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）作为生长因子和氨基酸特别是亮氨酸所激发的信号通路的汇合点,在肿瘤细胞中起中心调控作用.近些年,人们逐渐认识到mTOR的反馈激活机制是影响雷帕霉素及其类似物抗肿瘤疗效的重要因素之一.因此,针对mTOR的反馈激活机制及联合应用相关抑制剂协同阻断这一机制的研究成为肿瘤防治的新热点.     

雷帕霉素靶蛋白与白血病治疗

雷帕霉素靶蛋白（mTOR）广泛存在于各种生物细胞中,近年来研究发现mTOR信号通路的活化与肿瘤的发生、发展密切相关,并参与包括血液系统恶性肿瘤在内的许多肿瘤细胞的增生和分化。研究表明其抑制剂雷帕霉素及其衍生物等均有抗肿瘤作用。现就mTOR的结构功能、信号通路,在白血病发病机制中的主要上游调节因子及其抑制剂在白血病中的应用进行简述。     

雷帕霉素耐药机制及其逆转途径

雷帕霉素靶蛋白(mTOR)信号通路与肿瘤细胞的增殖、周期调控等多种病理过程密切相关.雷帕霉素通过抑制mTOR起到抗肿瘤作用,但其容易产生耐药等缺点导致临床应用受限,耐药机制主要与mTOR受抑后负反馈激活磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-Akt)有关.mTOR通路相关蛋白的双重抑制剂等药物有望逆转其耐药.     

弥漫大B细胞性淋巴瘤中mTOR信号通路的激活

0引言 mTOR(mallmalian target of rapamycin)属于丝/苏氨酸激酶家族,在细胞生长和增殖控制中发挥着关键作用.在上游,生长信号激活的Akt激酶诱导其磷酸化而活化.下游其磷酸化核糖体蛋白S6激酶(S6 kinase,S6K1,p70S6K)而刺激蛋白质翻译和核糖体形成[1-2].近年来研究表明,多种恶性肿瘤中存在mTOR信号通路的激活[1-2],该通路因此被视为癌症靶向治疗的新的潜在靶点.雷帕霉素作为免疫抑制剂首先应用于预防器官移植排异反应的研究,但随后发现其能通过调节mTOR激酶活性,抑制信号通路的激活而对抗细胞的增殖,因此被视为一种潜在的抗肿瘤药物,临床上,其衍生物CCI-779(Temsirolmus)已被批准用于晚期肾细胞癌的治疗.     

mTOR结合蛋白的研究进展

mTOR(mammalian target of rapamycin,mTOR)是雷帕霉素在哺乳动物细胞内作用的蛋白激酶,通过PI3K/Akt信号磷酸化激活而调控细胞分裂、促进转录、信号翻译等。研究表明,mTOR在肿瘤的形成和发展中扮演着非常重要的角色,并参与肿瘤的侵袭和转移。目前,以mTOR为治疗靶点成为肿瘤治疗的研究新热点。本文就近年来有关mTOR靶标及其结合蛋白研究进展作一综述。     

哺乳动物雷帕霉素靶蛋白及其信号通路在胃癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法.     

哺乳动物雷帕霉素靶蛋白及其信号通路在胃癌中的研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)及其信号通路控制着蛋白质合成、细胞的生长和代谢以及血管的生成等.其信号通路在胃癌中常被高度激活,与胃癌进展及预后密切相关.雷帕霉素及其衍生物可通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并能与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法.     

mTOR信号通路与胃癌的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）及其信号通路调控蛋白质的合成,细胞生长、迁移、凋亡以及血管形成等,该信号通路在胃癌中常被高度激活,并与胃癌的复发、转移等临床病理特性密切相关。雷帕霉素及其衍生物通过阻断mTOR通路的信号传递,抑制胃癌细胞生长,促进肿瘤坏死,并与其他化疗药物产生协同作用,有望为胃癌预防和治疗提供有效的方法。     

EPHA2通过增强Akt/mTOR信号通路促进SGC-7901细胞的增殖

背景与目的：EPHA2能够促进胃癌细胞中Cyclin D1的表达及胃癌细胞的细胞周期进程,从而增强胃癌细胞的增殖能力,但EPHA2调控胃癌细胞中Cyclin D1的表达及胃癌细胞的细胞周期进程的分子机制依然不明确。Akt/mTOR信号通路能够通过促进胃癌细胞中Cyclin D1的表达及胃癌细胞的细胞周期进程增强胃癌细胞的增殖能力,且有研究表明EPHA2能够激活Akt/mTOR信号通路。基于此,该研究探讨了Akt/mTOR信号通路在EPHA2促胃癌细胞增殖中的作用。方法：采用蛋白[质]印迹法(Western blot)检测过表达EPHA2和敲低EPHA2表达对SGC-7901细胞中Akt、mTOR和4EBP1磷酸化的影响。使用Akt抑制剂MK2206和mTOR抑制剂RAD001分别处理转染空载体病毒的SGC-7901-NC细胞和过表达EPHA2的SGC-7901-EPHA2细胞,分别通过CCK8、流式细胞术和Western blot检测细胞增殖、细胞周期及周期相关蛋白Cyclin D1的表达。结果：过表达EPHA2增强SGC-7901细胞中Akt、mTOR和4EBP1的磷酸化,敲低EPHA2的表达抑制SGC-7901细胞中Akt、mTOR和4EBP1的磷酸化。MK2206和RAD001处理细胞时,EPHA2过表达对SGC-7901细胞增殖、细胞S期和Cyclin D1表达的促进作用被显著抑制。结论：EPHA2通过增强Akt/mTOR信号通路促进胃癌细胞SGC-7901的增殖能力,提示我们将来针对EPHA2高表达的胃癌患者或许可以采用Akt抑制剂和mTOR抑制剂予以个体化治疗。     

mTOR和VEGF在胃癌中的表达及与预后关系的研究

目的：观察mTOR和VEGF在胃癌中的表达，探讨它们在胃癌发生发展中的意义和对胃癌患者预后的影响。方法：采用组织芯片和免疫组化检测mTOR和VEGF在1072例胃癌中的表达。结果：mTOR和VEGF在胃癌中总表达率分别为50．8％和59．4％。mTOR过度表达与肿瘤部位（贲门、胃底）、腺癌、高／中分化、T1／T2、Ⅰ／Ⅱ期以及PCNA表达有关；VEGF过度表达与年龄（〉60岁）、男性、肿瘤部位（贲门、胃底）、腺癌、高／中分化、肿瘤浸润（T3～T4）、淋巴结转移、PCNA表达以及p53表达有关。mTOR和VEGF共表达率为39．6％。Cox模型结果显示，mTOR和VEGF是胃癌独立的预后因素。结论：mTOR／VEGF信号通路在胃癌中高度激活，mTOR和VEGF的表达是胃癌预后的重要影响因素，可作为胃癌治疗的靶点。     

胃癌分子靶向药物治疗的研究进展

胃癌是最常见的恶性肿瘤之一,手术切除是胃癌首选的治疗方法,但由于缺乏典型早期症状,多数患者就诊时已有远处转移,失去手术治疗的机会.目前,晚期胃癌的治疗主要是以化疗联合靶向治疗为主的综合治疗.过去几十年,随着肿瘤生物学的快速发展以及肿瘤分子标志物的不断涌现,使众多靶向药物应运而生,如表皮生长因子(EGFR)、血管生成、免疫关键位点阻滞剂、细胞周期、细胞凋亡、关键酶、C-MET、mTOP等信号通路,以及胰岛素样生长因子受体(IGF-IR)等.分子靶向药物作用机制的深入研究将为胃癌的治疗提供新的认识.     

Increased T‐helper 17 cell differentiation mediated by exosome‐mediated microRNA‐451 redistribution in gastric cancer infiltrated T cells

MicroRNA (miR)‐451 is a cell metabolism‐related miRNA that can mediate cell energy‐consuming models by several targets. As miR‐451 can promote mechanistic target of rapamycin (mTOR) activity, and increased mTOR activity is related to increased differentiation of T‐helper 17 (Th17) cells, we sought to investigate whether miR‐451 can redistribute from cancer cells to infiltrated T cells and enhance the distribution of Th17 cells through mTOR. Real‐time PCR was used for detecting expression of miR‐451 in gastric cancer, tumor infiltrated T cells and exosomes, and distribution of Th17 was evaluated by both flow cytometry and immunohistochemistry (IHC). Immunofluorescence staining was used in monitoring the exosome‐enveloped miR‐451 from cancer cells to T cells with different treatments, and signaling pathway change was analyzed by western blot. miR‐451 decreased significantly in gastric cancer (GC) tissues but increased in infiltrated T cells and exosomes; tumor miR‐451 was negatively related to infiltrated T cells and exosome miR‐451. Exosome miR‐451 can not only serve as an indicator for poor prognosis of post‐operation GC patients but is also related to increased Th17 distribution in gastric cancer. miR‐451 can redistribute from cancer cells to T cells with low glucose treatment. Decreased 5′ AMP‐activated protein kinase (AMPK) and increased mTOR activity was investigated in miR‐451 redistributed T cells and the Th17 polarized differentiation of these T cells were also increased. Exosome miR‐451 derived from tumor tissues can serve as an indicator for poor prognosis and redistribution of miR‐451 from cancer cells to infiltrated T cells in low glucose treatment can enhance Th17 differentiation by enhancing mTOR activity.     

哺乳动物雷帕霉素靶蛋白在胃癌的研究进展

 哺乳动物雷帕霉素靶蛋白(mTOR)在调节细胞增殖、生长、能量代谢等方面起重要作用,在很多肿瘤中表达过量,通过mTOR抑制剂雷帕霉素等可以起到抑制胃癌发展的作用。联合mTOR上下游通路研究对胃癌的早期诊断、监测疗效及预后价值更大。     

Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model

The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1alpha (HIF-1alpha). Since mTOR is an upstream regulator of HIF-1alpha, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1alpha activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1alpha activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy.