HSP90生物学特征及其在泌尿系统肿瘤中作用机制的研究进展北大核心

HSP90作为热休克蛋白家族中最重要的成员,HSP90不仅可以作为癌基因的分子伴侣发挥其重要作用,而且在肿瘤的生长,进展阶段中扮演着重要角色,HSP90在多种癌蛋白的信号通路及信号转导中起着至关重要的作用。HSP90的高表达与泌尿系统肿瘤的发生,发展也密切相关。在肾癌、膀胱癌和前列腺癌中,HSP90均高表达,并且促进这三大肿瘤的发展。抑制HSP90的水平在泌尿系统肿瘤的治疗中也具有重要的研究意义。现对HSP90的生理学特征及其在泌尿系统肿瘤中的作用机制作一综述。     

90K在非霍奇金淋巴瘤组织中的表达及其临床意义

背景与目的:90K是一种分泌性糖蛋白,在一些肿瘤患者中,肿瘤组织90K表达与预后相关,非霍奇金淋巴瘤肿瘤组织90K表达和预后的关系尚未见报道。本研究检测90K在初治非霍奇金淋巴瘤肿瘤组织中的表达水平,并探讨其临床意义。方法:采用免疫组化的方法检测90K在110例非霍奇金淋巴瘤肿瘤组织中的表达,回顾性分析90K表达与CHOP方案的近期疗效和远期生存的关系。结果:110例非霍奇金淋巴瘤中,90K阴性36例,弱阳性27例,较强阳性17例,强阳性30例,阳性率67.3%(74/110),其表达与性别、年龄、IPI以及临床病理特征等均无相关性(P>0.05)。109例初治患者采用标准CHOP方案化疗,90K高表达组(较强阳性和强阳性)CHOP方案化疗的近期有效(CR PR)率65.2%(30/46)低于低表达组(阴性和弱阳性)的有效率82.5%(52/63),差异有显著性(P=0.039),但90K表达和远期生存无相关性(P>0.05)。结论:90K在非霍奇金淋巴瘤肿瘤组织中的表达对预测CHOP方案的近期疗效有一定临床价值,能否成为预测非霍奇金淋巴瘤预后的肿瘤标志物还有待进一步研究。     

非霍奇金淋巴瘤血清90K/Mac-2BP水平的测定及临床意义

背景与目的：90K／Mac-2BP是-种分泌性糖蛋白，有研究报道在-些肿瘤血清90K／Mac-2BP水平升高与肿瘤预后有关。本研究分析90K／Mac-2BP作为非霍奇金淋巴瘤（non-Hodgkin’s lymphoma，NHL）肿瘤标志物的临床价值。方法：采用酶联免疫吸附（ELISA）的方法测定30例正常人、160例（30例缓解、30例复发以及100例初治）NHL患者血清90K／Mac-2BP水平，分析90K／Mac-2BP在NHL患者不同疾病时期（初治治疗前、缓解、复发治疗前）血清水平的差异，以及初治治疗前NHL患者血清90K／Mac-2BP水平和临床病理特征之间的关系：结果：初治组治疗前、复发组治疗前血清90K／Mac-2BP的水平高于正常组和缓解组，差异具有显著性（P〈0．05），初治组治疗前和复发组治疗前血清90K水平无显著性差异（P〉0．05），正常组和缓解组血清90K／Mac-2BP差异也无显著性（P〉0．05）；初治治疗前NHL患者血清90K／Mac-2BP水平与年龄、性别、病理分型、体力状态、临床分期、IPI、LDH、骨髓侵犯以及有无巨大包块均无相关性（P〉0．05）。结论：血清90K／Mac，2BP水平住NHL不同疾病时期有差异，能否成为NHL的一个肿瘤标记物还需进-步研究。     

PI3K/AKT信号通路轴在肿瘤上皮细胞间质转化中作用的研究进展

肿瘤上皮间质转化（epithelial-mesenchymal transition,EMT）与肿瘤耐药、侵袭、迁移、发生远处转移等生物学行为密切相关.肿瘤微环境中多种细胞因子及其激活的信号通路均参与细胞的EMT.近年来,越来越多的文献报道PI3K/AKT信号转导途径在肿瘤细胞发生EMT过程中的作用尤为重要.本文将重点讨论PI3K/AKT途径在对E-钙黏蛋白（E-cadherin,E-Cad）的调控及其与其他信号通路协同诱发EMT过程中的作用,并对PI3 K/AKT抑制剂在肿瘤治疗的研究进行回顾.     

PI3K/Akt信号通路在肿瘤化疗耐药中的作用

磷脂酰肌醇3-激酶-蛋白激酶B(PI3K/Akt)信号通路在细胞内发挥重要的作用,参与了许多生理和病理活动.目前研究发现在许多肿瘤中过度激活的PI3K/Akt信号通路与肿瘤化疗耐药的产生密切相关,体外研究显示采用PI3K/Akt信号通路抑制剂可以逆转肿瘤细胞的耐药.本文简要介绍了PI3K/Akt信号通路的基本组成结构,并重点介绍其在肿瘤化疗耐药中的作用.     

维生素K抗肿瘤作用的研究进展

维生素K作为凝血辅助因子参与凝血过程,近年来其抗肿瘤作用已成为研究重点。维生素K对多种肿瘤细胞的生长具有抑制作用或细胞毒性作用。维生素K通过提高肿瘤细胞的氧化应激水平、促凋亡、抑制细胞周期、促进细胞自噬作用,达到抑制肿瘤细胞生长、促进肿瘤细胞死亡的目的。维生素K应用于临床抗肿瘤治疗中,主要用于血液和消化系统肿瘤,与其他化疗药物联合应用,可提高预防和治疗肿瘤的效果。随着维生素K新衍生物和新型制剂的研发,维生素K在肿瘤治疗中展现出良好的应用前景。本文针对维生素K抗肿瘤作用机制及临床应用进行综述。     

mTOR抑制剂在乳腺癌内分泌治疗耐药中的研究进展

PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。      

LSD1在肿瘤中的研究进展及其抑制剂的开发现状

在肿瘤的发生、发展过程中,遗传物质的异常改变发挥了重要作用,但随着表观遗传学的出现,改变了人类对遗传信息的认知,表观遗传学逐渐成为肿瘤研究领域中的热点。组蛋白去甲基化酶1(LSD1)是第1个被发现的组蛋白去甲基化酶,依赖于FAD的单胺氧化酶,可以催化组蛋白赖氨酸H3K4和H3K9去甲基化,启动或抑制基因的转录。目前研究证实,LSD1在多种肿瘤中高表达并与肿瘤的发生及预后密切相关。LSD1对肿瘤的增殖、侵袭和转移起重要的调控作用,因此逐渐成为潜在的抗肿瘤靶点。本文将对LSD1在肿瘤领域的研究进展及其抑制剂在肿瘤中的应用作一综述。     

热休克蛋白90抑制剂研究进展

热休克蛋白90(HSP90)抑制剂能够抑制HSP90，促使在肿瘤生长信号通路中起重要作用的HSP90效应蛋白通过泛素化降解，从而阻断肿瘤增殖生长信号通路的多个靶点，有效阻止肿瘤的生长。现综述近年来有关HSP90抑制剂在肿瘤治疗方面的研究进展。     

热休克蛋白90抑制剂研究进展

热休克蛋白90(HSP90)抑制剂能够抑制HSP90,促使在肿瘤生长信号通路中起重要作用的HSP90效应蛋白通过泛素化降解,从而阻断肿瘤增殖生长信号通路的多个靶点,有效阻止肿瘤的生长.现综述近年来有关HSP90抑制剂在肿瘤治疗方面的研究进展.     

High expression of 90K (Mac-2 BP) is associated with poor survival in node-negative breast cancer patients not receiving adjuvant systemic therapies

90K (Mac-2 BP) expression was evaluated by immunohistochemistry in paraffin-embedded tissue from a consecutive series of lymph-node negative breast cancer patients who did not receive adjuvant systemic treatment. An independent series of patients served as validation set. The association of 90K expression with risk of recurrence and death was examined in survival analyses together with known prognostic factors. High levels of 90K expression (IHC score>8) were observed in 43 (25.3%) of 170 tumors examined. We found elevated risks of distant recurrence and overall mortality in patients with high 90K expression compared with patients with low 90K expression in their tumors. This increase persisted after adjusting for other prognostic factors in multivariate analysis (hazard ratio=4.084; p<0.001 for recurrence; hazard ratio=4.298; p<0.001 for death). These findings were confirmed in the validation set. Therefore, evaluation of 90K expression may be beneficial to identify lymph-node negative breast cancer patients at lower risk of disease recurrence and death.     

Measurement of a breast cancer associated antigen detected by monoclonal antibody SP-2 in sera of cancer patients

An enzyme-linked immuno-absorbent assay has been developed for the detection of a circulating tumor-associated antigen, 90K, recognized by murine monoclonal antibody SP-2 (Iacobelli et al., Cancer Res 46: 3005-3010, 1986). This assay was found to be simple and reproducible. Using this method, 6% of 165 apparently healthy individuals and 15% of 91 patients with benign breast disease showed 90K levels above 1.7 units/ml. Approximately 50% of 129 patients with advanced breast cancer demonstrated serum antigen levels above 1.7 units/ml. All histological types of breast cancer were positive, and no association between the incidence of elevated 90K levels and other prognostic variables could be detected. The titers of 90K were significantly higher in sera from advanced-stage (3 and 4) patients than in those from patients with limited-stage (1 and 2) disease. Elevated 90K levels were also observed in patients with carcinomas of other sites, including gastrointestinal, gynecological, and lung tumors. By means of the immune blotting technique, the antigenic components carrying the determinants in serum and extracts of breast cancer cells have been identified. The levels of 90K did not correlate with those of CA 15-3 or CEA. The measurement of 90K in sera appears to be a useful adjunct to other available assays for the detection and monitoring of breast cancer and other malignant tumors.     

A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles

PURPOSE: Integrin alpha(v)beta(3) and vascular endothelial growth factor receptor 2 (Flk-1) have been shown to be involved in tumor-induced angiogenesis. Selective targeting of upregulated alpha(v)beta(3) and Flk-1 on the neovasculature of tumors is a novel antiangiogenesis strategy for treating a wide variety of solid tumors. In the studies described here, we investigated the potential therapeutic efficacy of two three-component treatment regimens using two murine tumor models. METHODS AND MATERIALS: The treatment regimens used nanoparticle (NP) based targeting agents radiolabeled with (90)Y. The small molecule integrin antagonist (IA) 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]-benzoyl-2-(5)-aminoethylsulfonylamino-beta-alanine, which binds to the integrin alpha(v)beta(3), and a monoclonal antibody against murine Flk-1 (anti-Flk-1 MAb) were used to target the NPs. Murine tumor models K1735-M2 (melanoma) and CT-26 (colon adenocarcinoma) were used to evaluate the treatment efficacy. RESULTS: In K1735-M2 and CT-26 tumors, a single treatment with IA-NP-(90)Y (14.2 microg/g IA, 5 or 6 microCi/g (90)Y) caused a significant tumor growth delay compared to untreated control tumors, as well as tumors treated with IA, IA-NP, and NP-(90)Y, respectively (p < 0.025, Wilcoxon test). In K1735-M2 tumors, a single treatment with anti-Flk-1 MAb-NP-(90)Y (0.36 microg/g anti-Flk-1 MAb, 5 microCi/g (90)Y) also caused a significant tumor growth delay (p < 0.05, Wilcoxon test) compared to untreated tumors, as well as tumors treated with anti-Flk-1 MAb, anti-Flk-1 MAb-NP, and conventional radioimmunotherapy with (90)Y-labeled anti-Flk mAb. Anti-CD31 staining showed a marked decrease in vessel density in tumors treated with anti-Flk-1 MAb-NP-(90)Y, which was associated with a high level of apoptotic death in these tumors, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. CONCLUSIONS: The present studies provide proof of principle that targeted radiotherapy works using different targeting agents on a nanoparticle, to target both the integrin alpha(v)beta(3) and the vascular endothelial growth factor receptor. These encouraging results demonstrate the potential therapeutic efficacy of the IA-NP-(90)Y and anti-Flk-1 MAb-NP-(90)Y complexes as novel therapeutic agents for the treatment of a variety of tumor types.     

Measurement of a monoclonal-antibody-defined antigen (90K) in the sera of patients with ovarian cancer

Serum levels of CA125 and 90K, a new tumor-associated antigen, were measured in 73 ovarian cancer patients and 70 patients with benign gynecological conditions. Abnormally high serum CA 125 and 90K levels were found in 49% and 78% of these patients, respectively. When a combination of the two markers was used, the sensitivity increased to 86%. The percentage of 90K positivity did not significantly correlate with stage of disease or with histological type. A statistically significant correlation was found between 90K positivity rate and grade of tumor differentiation. Elevated serum CA 125 and 90K levels were present in 32% and 29% of patients with benign ovarian tumors, respectively. Only 1 case out of 26 with endometriosis had high 90K levels, compared to 7 patients with abnormal CA 125 levels. Serial measurements of 90K concentrations were found to be correlated with the clinical behaviour of the disease during chemotherapy. Moreover, rising levels of 90K preceded the clinical detection of recurrence with a median lead-time of 3 months. In 2 of these cases the serial changes in 90K values were better correlated with the course of disease than changes in CA 125 levels. Our data suggest that 90K combined with CA 125 may be applied for the detection and monitoring of ovarian cancer.     

Suppression of progression and metastasis of established colon tumors in mice by intravenous delivery of short interfering RNA targeting KITENIN, a metastasis-enhancing protein

KITENIN promotes invasion of mouse colon adenocarcinoma (CT-26) cells in vivo. Here, we studied the effects of in vivo KITENIN ablation on established tumors by using pSUPER vectors (pSUPER-KITENIN) producing short interfering RNA (siRNA). When pSUPER-KITENIN was given weekly or semiweekly for 1 month into tail vein of syngeneic mice that have established colon tumors, tumor size regressed markedly and metastases were inhibited. In mice injected with pSUPER-KITENIN, serum interleukin-2 (IL-2) and IFN-gamma increased and CD4+ and CD8+ T cells infiltrated in the regressed tumor tissues. These effects, observed beginning 2 days after i.v. injection, imply that immune response is involved in the antitumor action of pSUPER-KITENIN. Using a yeast two-hybrid assay, we identified two KITENIN-interacting proteins for the possible mediators of these actions: 90K protein, a known immune modulatory glycoprotein, and protein kinase C inhibitor (PKCI). 90K was increased in the culture medium from CT-26/antisense KITENIN/90K cells. Double culture of accessory cells with CT-26/antisense KITENIN/90K cells revealed increased secretion of IL-1 and IL-6. Overexpression of 90K in CT-26/antisense KITENIN cells further delayed tumor growth compared with that of CT-26/antisense KITENIN cells. Actin arrangement was distorted in CT-26/antisense KITENIN and CT-26/antisense PKCI cells, whereas overexpression of PKCI resulted in increased invasiveness to fibronectin. Thus, antitumor effects of KITENIN siRNA derives from both the generation of a tumor-specific immune response in vivo through increased 90K secretion from tumor cells and the suppression of tumor invasion in which PKCI is related to increased invasiveness. Moreover, siRNA targeting of KITENIN can function as a chemotherapeutic strategy against colon cancer.     

Expression of 90K (Mac-2 BP) correlates with distant metastasis and predicts survival in stage I non-small cell lung cancer patients

90K, also known as Mac-2 binding protein, is a secreted glycoprotein that binds galectins, beta1-integrins, collagens, and fibronectin, and has some relevance in cell-cell and cell-extracellular matrix adhesion. Previous studies have shown that serum levels of 90K have prognostic value in several neoplasms. In the present study, the role of the expression of 90K as an adverse prognostic indicator in 72 pathological stage I non-small cell lung cancer patients was investigated immunohistochemically. All of the patients underwent complete surgical removal of the tumor. The median length of follow-up care was 54 months. High level of 90K expression (90K staining of > or =50% of the neoplastic cells) was observed in 20 of the 72 (28%) tumors. Expression of 90K was confirmed by ELISA. The results showed that a high expression of 90K correlates with adverse prognosis. Among patients with high 90K expression, the disease-free and overall survival rates were significantly lower than the same rates of those with low expression (P = 0. 0001 and P = 0. 0003, respectively). The incidence of distant metastases in the patients with high 90K expression (60%; 12 of 20 patients) was significantly higher than that of in the patients with low expression (21%; 11 of 53 patients; P = 0.0038). The results of multivariate analysis confirmed that a high 90K expression was a significant factor to predict poor prognosis. We suggest that 90K expression could be a useful prognostic factor in patients with stage I non-small cell lung cancer, likely as an indicator of the metastatic propensity of the tumor.     

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

The abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been validated by epidemiological and experimental studies as an essential step toward the initiation and maintenance of human tumors. Notable in this regard are the prevalent somatic genetic alterations leading to the inactivation of the tumor suppressor gene PTEN and gain-of-function mutations targeting PIK3CA--the gene encoding the catalytic phosphosinositide-3 kinase subunit p110 alpha. A number of the intracellular components of this pathway have been targeted as anticancer drug discovery activities leading to the current panoply of clinical trials of inhibitors of PI3K, Akt and HSP90 in man. This review summarizes current preclinical knowledge of modulators of the PI3K/Akt pathway in which drug discovery and development activities have been advanced focusing on both the relevant clinical stage inhibitors and other disclosed tool compounds targeting PI3K, PDK1, Akt and HSP90.     

Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis

Minichromosomal maintenance protein 7 (MCM7) is an essential component of the replication helicase complex (MCM2-7) required for DNA replication. Although this function is highly conserved among eukaryotes, additional functions for the MCM molecules continue to be described. Minichromosomal maintenance protein 7 is a marker for proliferation and is upregulated in a variety of tumors including neuroblastoma, prostate, cervical and hypopharyngeal carcinomas. To further investigate the general role of MCM7 in tumorigenesis, we generated a mouse model with deregulated MCM7 expression targeted to the basal layer of the epidermis using the keratin 14 (K14) promoter (K14.MCM7). When subjected to a two-stage chemical carcinogenesis protocol (dimethylbenz[alpha]anthracene (DMBA) initiation with 12-ortho-tetradecanoylphorbol-13-acetate promotion), K14.MCM7 mice showed significantly increased incidence and prevalence of tumor development relative to controls. Furthermore, within 40 weeks of treatment over 45% K14.MCM7 mice exhibited tumors that had converted to squamous cell carcinomas versus none in the control group. As predicted from previous skin carcinogenesis studies using DMBA as the initiating agent, Ras mutations where found in more than 90% of tumors isolated from K14.MCM7 mice. Whereas previous studies have shown that MCM7 is useful as a proliferation marker, our data suggest that deregulated MCM7 expression actively contributes to tumor formation, progression and malignant conversion.     

Recombinant human leukocyte interferon-α 2b stimulates the synthesis and release of a 90k tumor-associated antigen in human breast cancer cells

We have previously reported the production of a new monoclonal antibody (MAb) (SP-2) recognizing a 90-kDa tumorassociated antigen, termed 9OK, which is increased in the serum of many cancer patients. Treatment of CG5 human breast cancer cells with recombinant interferon-α 2b (rlFN-α 2b) can increase the synthesis and release, in culture medium, of the 90K. The effect of rIFN-α 2b was dose-related and occurred at concentrations which did not affect cell proliferation. The increase of 90K expression was due to de novo protein synthesis since cycloheximide, added within 3 hr of the beginning of rIFN-α 2b stimulation treatment, completely abolished the effect of rlFN-α 2b. The stimulatory effect of rIFN-α 2b was already evident after 24 hr treatment. Finally, an increase in serum 90K levels was observed in 3 patients with advanced breast cancer receiving a short course of rIFN-α 2b (Intron A). No effect of rIFN-α 2b was seen in 3 normal women. The ability of rIFN-α 2b to increase the synthesis and release of 9OK both in vitro and in vivo may be of clinical importance in the early detection of tumors.