外泌体miRNA在卵巢癌中的研究进展

卵巢癌(ovarian cancer,OC)致死率在女性生殖系统肿瘤中位居第一,因其早期无典型症状,大多数患者在晚期才得到诊断。此外,由于癌细胞易对化疗药物产生耐药,多数患者会出现复发,导致患者预后很差。因此寻找有效的早期诊断及治疗方法对OC的早期预测、疗效评估、预后及复发判断等具有重要意义。外泌体(exosome)是近年来研究的热点,其富含脂质、蛋白质、RNA和DNA,通过与细胞膜融合将内容物释放到细胞外环境,影响相邻或远处细胞的生物学行为。研究认为外泌体可参与肿瘤微环境中细胞间通讯,通过传递癌或抑癌信息分子,影响肿瘤的进程。微小RNA(miRNA)可被包裹在外泌体中传递至受体细胞,影响肿瘤细胞的增殖、转移、耐药等,在肿瘤进展中发挥重要作用。本文对外泌体miRNA在OC中的研究进行综述。     

外泌体在卵巢癌诊断中的研究进展

外泌体(exosomes)是大多数细胞均会分泌的一种直径为30~100 nm的细胞外囊泡,是含有不同类型信息载体[如DNA、微小RNA(miRNA)、长链非编码RNA(lncRNA)和蛋白质等]的通讯工具。外泌体广泛存在于血液、母乳、尿液、胸水、腹水、脑脊液等多种体液中。研究表明外泌体有着介导细胞间通讯的潜在功能,可以激活多种信号通路,这一现象在肿瘤的发生过程中也有所体现。外泌体在肿瘤组织中含量明显多于正常组织。由于缺乏早期诊断的标志物,卵巢癌尤其是上皮性卵巢癌,诊断时多为晚期(FIGOⅢ期或Ⅳ期),且容易对化疗产生耐药,5年生存率显著降低。综述近年来外泌体在卵巢癌诊断中的相关研究,总结研究最为广泛的miRNA和蛋白质,为进一步寻找卵巢癌早期诊断的生物标志物提供思路。     

外泌体在子宫内膜异位症发生发展及诊疗中的意义

外泌体是一种能够稳定存在于多种体液中的囊泡结构,参与许多细胞间的信息传递和信号调节,其携带的微小RNA(miRNA)和蛋白质等在很多病理生理过程中发挥重要作用,因与多种肿瘤等疾病的发生、发展密切相关受到广泛关注。子宫内膜异位症(EMs)是一种好发于育龄期妇女、具有侵袭性强、病变广泛和易复发等特点的疾病,外泌体作为重要的信号调节器与EMs的血管生成、异位子宫内膜细胞的增殖和迁移等有关,在EMs的发生发展、继发病变和恶变等过程中起重要作用,但具体机制尚不明确。现就外泌体在EMs发生发展中的作用进行综述,为EMs的早期诊断及治疗提供新思路。     

外泌体在常见妇科恶性肿瘤诊治中的研究进展

外泌体(exosome)是活细胞分泌的脂质双分子层结构的纳米级囊泡,内含多种DNA、RNA及蛋白质,广泛参与细胞间信息传递和物质交换等多种病理生理过程。外泌体不仅能够反映分泌细胞的生理状态和功能状态,而且在调控肿瘤的发生、发展、侵袭及转移中均能够发挥重要作用。卵巢癌、宫颈癌、子宫内膜癌等常见妇科恶性肿瘤的外泌体可在血液、阴道灌洗液、宫腔灌洗液等各种体液中获取,方法无创且提取的外泌体具有肿瘤细胞特异性,以此进行液体活检捕获肿瘤细胞外泌体来源的微小RNA(mi RNA)等,对肿瘤的早期筛查、确诊及疗效判定具有重要意义。此外,肿瘤细胞通过外泌体排出化疗药物,导致肿瘤对抗肿瘤药物耐药;反之,外泌体也可作为抗肿瘤药物新的给药途径,提高抗肿瘤药物治疗的疗效。     

外泌体在卵巢癌中的研究进展

卵巢癌是女性最常见的恶性肿瘤之一,其发病率及死亡率逐年增加。外泌体是一种由多种类型细胞经胞外分泌到细胞外的直径约30~100 nm的膜囊泡,普遍存在于生物体液中,内含有多种生物活性的分子,包括蛋白质、脂质、RNA、DNA,其特征因细胞类型的不同而不同。外泌体主要参与细胞间的通讯,与肿瘤的形成、发展、转移、浸润和耐药密切相关。外泌体作为肿瘤研究的热点,在卵巢癌的发展、诊断及治疗预后方面具有重要的临床研究价值。随着对外泌体研究的不断深入,外泌体分离和检测方法不断完善发展,外泌体的临床应用将为卵巢癌的诊断、治疗提供新的方向。     

外泌体在子宫内膜异位症发生发展及诊疗中的意义

外泌体是一种能够稳定存在于多种体液中的囊泡结构,参与许多细胞间的信息传递和信号调节,其携带的微小RNA（miRNA）和蛋白质等在很多病理生理过程中发挥重要作用,因与多种肿瘤等疾病的发生、发展密切相关受到广泛关注。子宫内膜异位症（EMs）是一种好发于育龄期妇女、具有侵袭性强、病变广泛和易复发等特点的疾病,外泌体作为重要的信号调节器与EMs的血管生成、异位子宫内膜细胞的增殖和迁移等有关,在EMs的发生发展、继发病变和恶变等过程中起重要作用,但具体机制尚不明确。现就外泌体在EMs发生发展中的作用进行综述,为EMs的早期诊断及治疗提供新思路。     

胎盘外泌体在子宫螺旋动脉重铸不全相关妊娠并发症中的作用

子宫螺旋动脉重铸是胎盘滋养细胞与母体血管内皮、平滑肌细胞、免疫细胞等相互作用下完成的,细胞间信息传递在这一过程中起重要作用。外泌体的发现更新了学者们对细胞间信息传递的思考模式。外泌体是细胞主动分泌的直径40~100 nm的囊泡,可由多种细胞分泌并可从多种体液中分离出来,携带多种蛋白质、mRNA、微小RNA(miRNA)等信号分子,在细胞间通讯起重要作用。研究证明,胎盘滋养细胞能分泌外泌体,在母血中能检测并分离出胎盘外泌体,胎盘外泌体携带滋养细胞信息,作用于母体细胞,调节血管形成,重铸子宫螺旋动脉,调节母体免疫,参与胎盘屏障的形成。综述胎盘外泌体的特征、生物学功能及其在螺旋动脉重铸不全相关妊娠并发症中的变化,探讨胎盘外泌体作为诊断妊娠并发症血清标志物的临床价值。     

胎盘外泌体在子宫螺旋动脉重铸不全相关妊娠并发症中的作用

子宫螺旋动脉重铸是胎盘滋养细胞与母体血管内皮、平滑肌细胞、免疫细胞等相互作用下完成的,细胞间信息传递在这一过程中起重要作用。外泌体的发现更新了学者们对细胞间信息传递的思考模式。外泌体是细胞主动分泌的直径40～100 nm的囊泡,可由多种细胞分泌并可从多种体液中分离出来,携带多种蛋白质、mRNA、微小RNA(miRNA)等信号分子,在细胞间通讯起重要作用。研究证明,胎盘滋养细胞能分泌外泌体,在母血中能检测并分离出胎盘外泌体,胎盘外泌体携带滋养细胞信息,作用于母体细胞,调节血管形成,重铸子宫螺旋动脉,调节母体免疫,参与胎盘屏障的形成。综述胎盘外泌体的特征、生物学功能及其在螺旋动脉重铸不全相关妊娠并发症中的变化,探讨胎盘外泌体作为诊断妊娠并发症血清标志物的临床价值。     

外泌体及其在卵巢癌中的研究进展

卵巢癌是死亡率居首位的妇科恶性肿瘤,多数患者确诊时已处于进展期,预后相对较差。外泌体(exosome)是由细胞内多囊泡体(multi-vesicular body)与细胞膜融合后,释放到胞外基质中的一种直径约40~100nm的膜性囊泡,可由多种不同类型的细胞释放。外泌体作为介导细胞间物质和信息交流的工具,具有广泛的生理作用,可参与免疫应答、抗原提呈、细胞间通讯、蛋白质和RNA的转运等多种生理过程。研究表明,外泌体可能通过调控免疫功能,促进血管新生和肿瘤转移等途径,影响肿瘤的进展。外泌体在卵巢癌的发生发展过程中也有重要的调控作用,其可能成为卵巢癌诊断的新方法和治疗的新靶点。     

微小RNA基因的DNA甲基化在卵巢癌中的研究

微小RNA(microRNA,miRNA)是一类短链非编码RNA,通过降解mRNA或抑制mRNA翻译的方式调控众多基因的表达。已有许多研究表明miRNA与卵巢癌的发生、发展、耐药和预后相关。DNA甲基化是表观遗传学的重要组成部分,与细胞的增殖、癌变等生命现象有着重大的关系,是目前肿瘤中研究最多的表观遗传学机制之一,与肿瘤的发生、发展、耐药和预后相关。研究卵巢癌中miRNA基因的DNA甲基化可能为卵巢癌诊治提供新的分子诊断和预后标记物,为化疗耐药分析和个性化治疗提供新的临床思路。     

miR-375在宫颈癌中的研究进展

宫颈癌是全球第四大最常见的女性恶性肿瘤,且呈年轻化趋势发展,因此早期诊断治疗非常重要。微小RNA(microRNA,miRNA)是由19~23个核苷酸组成的保守的单链非编码小分子RNA。miRNA被证实在许多人类恶性肿瘤中都异常表达,其在恶性肿瘤的发生、发展和转移中起着重要作用。miR-375作为一种高度保守的miRNA,存在于人类的2号染色体,被证实在宫颈癌患者中表达下调,其通过调控下游靶基因的表达,从而参与宫颈癌变的进展过程。血清miR-375的敏感度和特异度均优于传统肿瘤标志物CA125,敏感度优于薄层液基细胞学检测(TCT),miR-375有望成为宫颈癌早期诊断的新的标志物。miR-375可以调控宫颈癌放化疗的敏感性,可作为潜在的有效药物靶点。miR-375的表达缺失促进宫颈癌的发生,亦是促进患者临床分期进展或者复发风险上升的重要因素,miR-375可作为预测宫颈癌预后的生物学标志物。综述miR-375参与宫颈癌进展的机制及其在临床诊断治疗和预后方面的研究进展。     

Current status and implications of microRNAs in ovarian cancer diagnosis and therapy

Ovarian cancer is the fifth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Currently, treatment of ovarian cancer is based on the combination of surgery and chemotherapy. While recurrent ovarian cancer responds to additional chemotherapy treatments, the progression-free interval becomes shorter after each cycle, as chemo-resistance increases until the disease becomes incurable. There is, therefore, a strong need for prognostic and predictive markers to help optimize and personalize treatment in order to improve the outcome of ovarian cancer. An increasing number of studies indicate an essential role for microRNAs in ovarian cancer progression and chemo-resistance. MicroRNAs (miRNAs) are small endogenous non-coding RNAs (~22bp) which are frequently dysregulated in cancer. Typically, miRNAs are involved in crucial biological processes, including development, differentiation, apoptosis and proliferation. Two families of miRNAs, miR-200 and let-7, are frequently dysregulated in ovarian cancer and have been associated with poor prognosis. Both have been implicated in the regulation of epithelial-to-mesenchymal transition, a cellular transition associated with tumor aggressiveness, tumor invasion and chemo-resistance. Moreover, miRNAs also have possible implications for improving cancer diagnosis; for example miR-200 family, let-7 family, miR-21 and miR-214 may be useful in diagnostic tests to help detect ovarian cancer at an early stage. Additionally, the use of multiple target O-modified antagomirs (MTG-AMO) to inhibit oncogenic miRNAs and miRNA replacement therapy for tumor suppressor miRNAs are essential tools for miRNA based cancer therapeutics. In this review we describe the current status of the role miRNAs play in ovarian cancer and focus on the possibilities of microRNA-based therapies and the use of microRNAs as diagnostic tools.     

循环肿瘤DNA在卵巢癌诊治中的研究进展

卵巢癌(ovarian cancer,OC)近年发病率逐渐增高,具有高复发率、高病死率的特点,成为危害女性生命健康的主要疾病之一.目前在卵巢癌的早期检测和筛查、复发监测、治疗评估方面尚缺乏有效的检测手段.循环肿瘤DNA(circulating tumor DNA,ctDNA)是肿瘤细胞释放进入血液循环中的DNA片段,具...     

人附睾分泌蛋白4在妇科肿瘤中的研究进展

人附睾分泌蛋白4（HE4）是近年发现的新妇科肿瘤标记物,其在正常子宫内膜及卵巢中低表达的特性使其在妇科恶性肿瘤中的诊断具有独特的价值。研究表明,HE4在卵巢癌的早期诊断、鉴别诊断等方面已显示出一定的优越性,其在评价卵巢癌的预后以及早期监测复发上可能优于糖类抗原125（CA125）。HE4对子宫内膜癌的诊断也有研究报道。HE4作为一种新肿瘤标记物与CA125联用,对卵巢癌、子宫内膜癌等妇科肿瘤的诊断、鉴别诊断、风险预测均有很好的临床价值。HE4在子宫肌瘤等良性妇科疾病的诊断及鉴别诊断中也具有一定的临床价值。     

Circulating cell-free DNA and circulating tumor cells,the “liquid biopsies” in ovarian cancer

Limited understanding of ovarian cancer (OC) genome portrait has hindered the therapeutic advances. The serial monitoring of tumor genotypes is becoming increasingly attainable with circulating cell-free DNA (cf-DNA) and circulating tumor cells (CTCs) emerging as “liquid biopsies”. They represent non-invasive biomarkers and are viable, as they can be isolated from human plasma, serum and other body fluids. Molecular characterization of circulating tumor DNA (ct-DNA) and CTCs offer unique potentials to better understand the biology of metastasis and resistance to therapies. The liquid biopsies may also give innovative insights into the process of rapid and accurate identification, resistant genetic alterations and a real time monitoring of treatment responses. In addition, liquid biopsies are shedding light on elucidating signal pathways involved in invasiveness and metastasis competence; but the detection and molecular characterization of ct-DNA and CTCs are still challenging, since they are rare, and the amount of available samples are very limited. This review will focus on the clinical potential of ct-DNA and CTCs in both the early and advanced diagnosis, prognosis, and in the identification of resistance mutations in OC.     

Ovarian cancer--modern approach to its origin and histogenesis

Ovarian cancers (OC) belong to a heterogeneous group of pathologies and are traditionally classified with regard to histological type and degree of differentiation. OC was hypothesized to originate from ovarian surface epithelium (OSE) and inclusion cysts epithelium (IC). Unfortunately this theory was never supported by any clinical or molecular evidence linking carcinogenesis with OSE and was refuted. OC subtypes demonstrate morphologic features that resemble Müllerian duct-derived epithelia of the genital tract. Investigations of the HOX gene family Müllerian epithelial differentiation markers, confirmed the HOX genes expression in many subtypes of OC but not in OSE. The first step towards connecting OC origin with other than OSE genital tract structures were epidemiological observations indicating a minor OC risk after tubal ligation in women with the BRCA mutation. The first in situ carcinoma was found in the Fallopian tube fimbriae. Further research confirmed the same mechanism in sporadic OC. Endometriosis and endometrium cells may be a highly probable place of endometrioid OC initiation. Mucinous types share common futures with gastrointestinal tract cancers and there one needs to search for their precursors. Clear cell carcinoma may arise from glandular epithelium of endocervix or from endometrioid foci. The new classification of OC was proposed in 2004, suggesting to divide all OC into two types: I and II. Type II includes serous and endometrioid G3 subtypes, carcinosarcomas and undifferentiated OC. They are responsible for 75% of OC morbidity identified usually in FIGO stages Ill or IV, have poor prognosis and relapse early The remaining hystiotypes, with better prognosis and earlier FIGO stages at time of diagnosis, were classified as type I. Serous and endometrioid poorly differentiated ovarian cancers demonstrate mutation in TP53 gene (type II) and highly differentiated ones, generally in BRAS and KRAS genes (type I). The differences in molecular pathways also confirm different patterns of carcinogenesis of both OC types. Modern approach to OC histogenesis and origin emphasizes the necessity to verify OC screening, detection and treatment methods.     

循环肿瘤细胞在卵巢癌临床应用中的研究进展

液体活检（liquid biopsy,LB）作为新一代检测技术,能更准确地评价肿瘤患者疾病进展,成为具有临床应用价值的管理工具,有望改善卵巢恶性肿瘤疾病的转归。对循环肿瘤细胞（circulating tumor cells,CTCs）动态数量变化或肿瘤生物学特性的监测,可应用于卵巢恶性肿瘤的早期筛查、疗效监测和耐药性评估、复发风险预测、患者预后判断等方面。相比目前依赖于肿瘤标志物的临床管理策略,CTCs的特异度更高,而且可以进行细胞学培养和分析。但CTCs与卵巢肿瘤的疾病进展之间的关系尚不十分明确,此外,适用于卵巢癌CTCs更高级的分子富集策略有待进一步明确。     

Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study.

BACKGROUND AND RATIONALE: Non-curative surgical cytoreduction of advanced tumors is associated with increased proliferation of the remaining tumor cells. Thus, appropriate preoperative chemotherapy should prevent both cell proliferation and the increase of resistant cells. The aim of the present study was to evaluate the efficacy and toxicity of primary chemotherapy (P-CT) in previously untreated patients with stage IV ovarian cancer (OC). PATIENTS AND METHODS: Thirty-four patients with stage IV OC were treated from January 1993 to April 2000 with P-CT. Eligibility criteria included: histologically or cytologically confirmed, unresectable stage IV OC and performance status < or = 3. P-CT consisted of four courses of carboplatin, cyclophosphamide and epirubicin until October 1996, and paclitaxel, carboplatin thereafter. Surgery followed P-CT. After the operation patients received two further courses of chemotherapy that were tailored according to their individual response. Median (M) age was 61 years, range 32-73; median performance status was 2. A total number of 197 courses of CT were administered, median 5.7 per patient. RESULTS: Complete or partial response (CR, PR) was observed in 28 patients (response rate 82%, 95% CI: 65.4% to 93.2%), disease stability and progression (SD, PD) was observed in three and three patients, respectively. Median time to progression was 16.45 months (range 4.8-90.4+), median survival time was 28 months (range 4.5 - 90.4+): 1-year survival rate was 94%. Toxicity according to WHO: nausea and vomiting grade (G) 2, 30% of patients; gastrointestinal G 2-3, 20% of patients; alopecia G 3, 88% of patients; hematological G 3-4, 73% of patients; neurologic G 2, 12% of patients. Nine pathological CRs were observed. CONCLUSION: Neoadjuvant treatment with CBDCA with either CTX and EPI or Taxol is feasible and shows activity in OC.     

微小RNA在卵巢癌中的研究进展

微小RNA（microRNA,miRNA）是一种内源性非编码小RNA,其在转录后水平负调节靶基因的表达。一个肿瘤相关的微小RNA通常可以同时调节几个癌基因和抑癌基因的表达水平,因此miRNA与肿瘤的发生、发展和预后有着密切的联系。研究发现,一些miRNA在正常卵巢组织和上皮性卵巢癌组织中表达水平明显不同,其表达谱可作为潜在的肿瘤标志物对卵巢癌进行早期诊断和预后判断。此外,对某些在卵巢癌中调节异常的miRNA靶基因的探索,不但可有助于了解卵巢癌的发病机制,同时也可为卵巢癌治疗提供新靶点。