糖皮质激素受体β表达与结肠癌细胞激素敏感相关性的实验观察

目的:观察结肠癌组织糖皮质激素受体表达及地塞米松(dexamethasone,Dex)体外对结肠癌细胞的作用,探讨糖皮质激素受体β(GRβ)亚型表达在结肠癌细胞激素反应中的作用。方法:免疫组化检测GR在结肠癌组织和细胞株中的表达,MTT和annexinⅤ-FITC/PI双染检测糖皮质激素对结肠癌细胞的作用,RT-PCR检测糖皮质激素作用过程中GRα和GRβ的mRNA表达变化,si RNA沉默GRβ的表达对细胞激素敏感性的影响。结果:在57.3%的结肠癌组织标本中糖皮质激素受体呈阳性表达,在四种结肠癌细胞株中只有LoVo和HCT116表达糖皮质激素受体,HT29和SW480细胞不表达。在体外实验中地塞米松对糖皮质激素受体阳性的LoVo和HCT116细胞有较强的增殖抑制和促凋亡作用;在Dex作用过程中GRα和GRβ表达均升高,但是GRβ升高更明显;转染GRβ的小分子干扰片断后,Lo-Vo细胞GRβ的mRNA表达下降67.3%,Dex诱导的细胞凋亡率则从(34.7±1.8)%上升至(45.4±4.3)%(P<0.05)。结论:糖皮质激素对结肠癌细胞有增殖抑制和凋亡诱导作用,细胞GRβ表达增加抑制结肠癌细胞对糖皮质激...     

糖皮质激素受体与肿瘤

糖皮质激素受体(GR)是肿瘤细胞信号传导、相关基因表达和细胞凋亡等多环节中的一个重要调节因素.GR具有自身结构的特殊性及与糖皮质激素(GC)结合的专一性,使其可在转录及翻译水平调节肿瘤相关基因的转录与表达,发挥调节肿瘤细胞代谢的生物学效应.现就此方面研究进展综述如下.     

糖皮质激素受体在肝癌细胞生长中的作用机制

糖皮质激素受体(GR)在癌细胞的信号转导、相关基因表达及凋亡中发挥十分关键的作用。肝癌具有侵袭性强、死亡率高的特征, 在关于GR与肝癌关系的探索中, 大量研究表明GR对肝癌细胞的生长有抑制作用, 这为临床治疗肝癌提供了新思路和新方法。     

肝细胞癌患者外周血性激素受体和糖皮质激素受体的含量

为探讨性激素受体(Sex Hormone Receptor)和糖皮质激素受体(Glucocorticoid Receptor.GR)与肝细胞癌(Hepa- tocelular carcinoma.HCC)的关系及其意义,应用放射配体测定13例HCC患者及23例正常人外周血淋巴细胞雌激素受体(Es- trogen Receptor.ER)和雄激素受体(Androgen Receptor.AR)及外周血细胞GR水平.正常人ER和AR分别为616±106和687±109位点/细胞;GR为5360±1684位点/细胞.HCC患者ER和AR分别为968±120和2903±860位点/细胞.HCC伴肝硬化GR为3112±1130位点/细胞、不伴肝硬化为4536±1201位点/细胞.AR水平明显高于对照组,提示HCC可能为雄激素依赖性肿瘤;GR水平与肝硬化负相关,提示GR下降反映肝硬化的程度.     

泌尿系统肿瘤的基因治疗研究进展

基因治疗作为一种新的治疗手段，在泌尿系统肿瘤的治疗应用中主要集中在肾脏、膀胱及前列腺三方面的恶性肿瘤，除部分已进入临床试验阶段外，目前主要为基础研究，有些实验取得了明显的治疗效果。本文综述了近年来泌尿系统恶性肿瘤基因治疗的实验结果及临床资料。     

糖皮质激素受体与肿瘤

糖皮质激素受体(GR)是肿瘤细胞信号传导、相关基因表达和细胞凋亡等多环节中的一个重要调节因素。GR具有自身结构的特殊性及与糖皮质激素(GC)结合的专一性，使其可在转录及翻译水平调节肿瘤相关基因的转录与表达，发挥调节肿瘤细胞代谢的生物学效应。现就此方面研究进展综述如下。     

地塞米松诱导结肠癌细胞凋亡的实验研究

目的:研究糖皮质激素受体(GR)在结肠癌细胞株Lovo、HCT-116、HT-29和SW-480中的表达,观察地塞米松(Dex)在体外对结肠癌细胞株的增殖抑制和凋亡诱导作用。方法:采用免疫组化、RT-PCR检测糖皮质激素受体(GR)在结肠癌细胞株中的表达;MTT、DNALadder和流式细胞仪等方法进行增殖抑制和细胞凋亡检测。结果:在4种结肠癌细胞株中只有Lovo和HCT-116表达GR。地塞米松在体外作用后,对4种细胞的增殖均有抑制作用,其中对Lovo和HCT-116细胞作用最显著。在Lovo细胞可检测到特征性的凋亡细胞DNA梯带。在流式细胞仪检测显示经1×10-4mol/LDex诱导72h后,在Lovo和HCT-116细胞检测到细胞凋亡,分别为(34.8±1.9)%和(33.6±1.4)%,明显高于未加Dex对照组的Lovo(2.9±0.4)%和HCT-116(6.4±1.3)%,差异有统计学意义(t值分别为28.934和22.980,P值均为0.000)。结论:结肠癌细胞株Lovo和HCT-116表达GR,地塞米松体外抑制Lovo和HCT-116细胞增殖,并诱导其发生凋亡,可能与GR相关。     

GR基因片段的克隆和可诱导的目标载体的构建

为了构建针对小鼠糖皮质激素受体基因第2 外显子的可诱导目标载体,我们对小鼠糖皮质激素受体基因第2 外显子及其侧翼区域的基因组DNA 片段进行了结构分析,和部分片段的亚克隆,然后以pF1ox 质粒为框架构建了可诱导的目标载体。这一载体的构建为进一步建立诱导型GR 基因剔除小鼠奠定了基础,而且对于深入研究GR 基因的表达调控也很有帮助。     

养阴抗毒胶囊对放射损伤大鼠肾组织热休克蛋白70与糖皮质激素受体表达的影响

目的:研究养阴抗毒胶囊对放射性损伤大鼠肾热休克蛋白70(HSP70)与糖皮质激素受体的表达的影响及作用机制.方法:40只雄性SD大鼠随机分成4组,即正常对照组(A)、放射对照组(B)、放射+养阴抗毒组(C)和放射+桂附地黄组(D),以6GyX射线照射大鼠造成重度造血型放射损伤模型,用蛋白印迹法(Western Blot)检测肾组织热休克蛋白70与糖皮质激素受体(GR)的表达情况.结果:HSPT0在放射对照组(B)、放射+养阴抗毒组(C)和放射+桂附地黄组(D)均有高表达,以B组最为明显,D组其次,C组最弱.而GR在C组表达最明显,其次在D组.结论:养阴抗毒胶囊能显著降低放射损伤大鼠肾组织中HSP70的表达,而桂附地黄丸的此作用相对较弱,养阴抗毒胶囊能明显提高糖皮质激素受体的表达.     

激酶Kinome和糖皮质激素诱导的凋亡

糖皮质激素(glucocorticoid,GC)信号系统和激酶Kinome之间有着复杂的相互作用,其中,在GC处理后,由Kinome最终决定细胞的命运.当细胞表达足够水平的糖皮质激素受体(glucocorticoid receptor,GR)和Bim,以及有利于GSK3激活的Kinome时,就会继发细胞凋亡.通过防止Bim的上调和/或抑制GSK3的蛋白激酶,可在细胞内产生GC抵抗.通过抑制JNK、Src、P13K、Akt或mTOR存活通路,可以克服T淋巴系统和B淋巴系统恶性肿瘤中的GC抵抗.最近已证明星状孢子素和雷帕霉素可以对GC诱导细胞凋亡相抵抗的恶性T淋巴细胞和B淋巴细胞加以有效致敏.这在理论上论证了通过改变细胞的Kinome提高CC疗效的可行性.     

Corticosteroid-induced chemotherapy resistance in urological cancers

PURPOSE: Glucocorticoids such as dexamethasone are widely used for medication of urological diseases, e.g., as cotreatment of advanced prostate cancer, to improve appetite, weight loss, fatigue, relieve bone pain, diminish ureteric obstruction, to reduce the production of adrenal androgens, as an antiemetic in patients undergoing chemo- and/or radiotherapy together with serving as "standard" therapy arm in randomized studies. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumor therapy in lymphoid cells are well studied, the impact to growth of prostate and other urological carcinomas is unknown. METHODS: We isolated cells from surgical resections of 21 prostate tumors and measured apoptosis and viability in these primary cells and 17 established cell lines from human prostate, bladder, renal cell and testicular carcinomas. RESULTS: We found that dexamethasone induces resistance regarding exposure to several cytotoxic agents such as taxol, gemcitabine, cisplatin, 5-FU and gamma-irradiation in 86% of the freshly isolated prostate tumors and in 100% of the established urological cell lines. No difference in dexamethasone-mediated protection was found in normal, benign and malignant prostate tumors. CONCLUSIONS: These data show for the first time that dexamethasone induced therapy resistance in urological carcinomas is not the exception but a more common phenomenon and implicate that glucocorticoids may have two faces in cancer therapy, a beneficial and a dangerous one.     

Glucocorticoid receptor expression in breast cancer associates with older patient age

Breast cancer can be classified according to estrogen (ER), progesterone (PR), and HER2 receptor expression. Recent evidence suggests that activation of the glucocorticoid receptor (GR) contributes to breast cell survival, although the incidence of GR expression in primary human breast tumors is not well established. We therefore evaluated ER, PR, HER2, and GR by immunohistochemistry from 231 patients and found that while African American (AA) patient tumors were much more likely to be ER negative compared to tumors from non-AA patients, GR expression was significantly higher in tumors from patients ≥50 regardless of ancestry. Prospective examination of GR expression in tumors should be considered to determine whether GR contributes to long-term clinical outcome.     

Positron emission tomography: clinical applications in oncology. Part 2

This review continues from a previous review on this topic, which was published in the December issue. In that review, the role of positron emission tomography in lung cancer, lymphoma, breast cancer, head and neck cancer, gastroesophageal cancer, colorectal cancer, malignant melanoma, bone tumors and ovarian cancer was discussed. In this review, the role of positron emission tomography in other malignancies, such as gynecological malignancies other than ovary, pancreatic cancer, hepatocellular cancer, gastrointestinal tumors, urological malignancies, neuroendocrine tumors, adrenocortical tumors, soft-tissue sarcomas, pituitary and brain tumors, is discussed.     

Positron emission tomography: clinical applications in oncology. Part 2

This review continues from a previous review on this topic, which was published in the December issue. In that review, the role of positron emission tomography in lung cancer, lymphoma, breast cancer, head and neck cancer, gastroesophageal cancer, colorectal cancer, malignant melanoma, bone tumors and ovarian cancer was discussed. In this review, the role of positron emission tomography in other malignancies, such as gynecological malignancies other than ovary, pancreatic cancer, hepatocellular cancer, gastrointestinal tumors, urological malignancies, neuroendocrine tumors, adrenocortical tumors, soft-tissue sarcomas, pituitary and brain tumors, is discussed.     

C-反应蛋白在肾癌预后评价中的意义

越来越多的证据显示炎症在肿瘤发生发展过程中扮演了极其重要的角色.C-反应蛋白（CRP）作为最具代表性的炎症反应指标,被认为与肾癌等多种肿瘤的预后密切相关.许多研究表明,CRP可以为实施手术、细胞因子治疗和分子靶向治疗的肾癌患者提供有价值的预后信息,并且已有预后模型将CRP纳入其中应用于患者的预后评估.     

大肠癌靶向治疗进展

大肠癌是最常见的恶性肿瘤之一，近年来靶向治疗的成功应用为大肠癌患者带来了新的希望。针对血管内皮生长因子（VEGF）和表皮生长因子受体（EGFR）的单克隆抗体（贝伐单抗和西妥昔单抗）已在临床上广泛应用。本文就目前大肠癌靶向治疗方面的新进展进行综述。     

射频消融治疗恶性肿瘤现状

目前,恶性肿瘤的治疗多强调以手术切除为主的多学科综合治疗,而对于一些不能手术切除的肿瘤患者,微创介入疗法是一种较好的肿瘤姑息治疗手段。射频消融(radiofrequency ablation,RFA)是一种针对肿瘤局部的微创介入性疗法,已被证实是一种有效、安全、并发症少、定位准确的治疗恶性实体肿瘤的微创技术。近年来,此项技术已被广泛应用于多种恶性肿瘤,如肝癌、肺癌、乳腺癌等。随着RFA治疗原理研究的不断深入、射频消融技术的不断改进,局部肿瘤治疗的疗效将进一步提高,但仍需要随机化的研究和长期的随访来证实RFA在肿瘤治疗中的重要意义。     

超声造影在膀胱癌诊治中的应用

超声造影通过对肿瘤微血管的显影,反映膀胱肿瘤的良、恶性程度,提高对膀胱癌诊断的敏感性和特异性.同时还能携带药物和特异性配体对膀胱癌进行靶向治疗.     

嵌合抗原受体T细胞联合免疫检查点抑制剂治疗恶性肿瘤的研究进展

近年来,嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）治疗在恶性肿瘤治疗中取得了较多成果,尤其在血液肿瘤治疗方面有所突破,实体瘤治疗研究前景较为广阔,有望成为更多复发难治性肿瘤患者的选择。免疫检查点抑制剂疗法在肿瘤治疗中同样具有疗效,如肝癌、难治性霍奇金淋巴瘤等多种恶性肿瘤,为晚期肿瘤患者带来了希望。但是上述两种治疗方法均存在不同程度的局限性。CAR-T联合免疫检查点抑制剂会削弱肿瘤微环境的免疫抑制作用,提高CAR-T治疗的有效率,延长生存期。本文旨在对CAR-T细胞和免疫检查点抑制剂治疗及二者联合应用的研究进展予以综述。      

In vivo growth of transitional and renal cell carcinoma cell lines can be suppressed by the adenovirus-mediated expression of a soluble form of vascular endothelial growth factor receptor

Antiangiogenic therapy is a promising strategy for the treatment of cancer since tumor development and metastases require angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most important factors in tumor angiogenesis. In the present study, we investigated the antitumor effect of an adenovirus (AdVEGF-ExR) expressing the extracellular domain of the human VEGF receptor (flt-1) using two different urological tumor/mouse systems. RENCA, a renal cell carcinoma of BALB/c origin, and MBT-2, a poorly differentiated transitional carcinoma of C3H/He origin, were used. Both types of tumor were in vitro infected with AdVEGF-ExR and inoculated subcutaneously into the abdomens of syngenenic mice, and tumor growth was measured twice weekly. In some experiments, BALB/c mice with established RENCA tumors were injected intramuscularly with AdVEGF-ExR as a therapeutic model. The cytotoxicity of spleen cells from the tumor-rejected mice was assessed by 51Cr-release assay. Although the in vitro cell growth of either MBT-2 or RENCA was not affected by infection with AdVEGF-ExR, the in vivo growth of both AdVEGF-ExR-infected tumors was significantly suppressed in the syngeneic mice. In addition, although 2 of 5 mice rejected the AdVEGF-ExR-infected RENCA, tumor-specific cytotoxic T lymphocytes were not generated from their spleen cells, thus suggesting no cellular immune response. In a therapeutic model, intramuscular injections of AdVEGF-ExR at a remote site also significantly suppressed the growth of the subcutaneously established RENCA. These results indicate that the adenovirus-mediated expression of a soluble VEGF receptor can be an effective therapy for urological cancer treatment; however, such VEGF-targeted gene therapy is not necessarily accompanied by subsequent antitumor T cell immunity.