非编码RNA调节肝癌干细胞的研究进展

肝癌是一种侵袭性极强的恶性肿瘤，临床预后极差。肝癌干细胞（liver cancer stem cells,LCSCs）是肝癌细胞中一类具有自我更新和多向分化潜能的细胞亚群，具有极强的侵袭、迁移能力，与肝癌的发生、进展、转移密切相关。非编码RNA(non-coding RNAs,ncRNAs)是癌症干细胞(cancer stem cells,CSCs)亚群的关键调节因子，参与了CSCs的自我更新、侵袭、耐药和分化等过程。全文对ncRNAs在LCSCs发生、维持和调节中的功能及作用机制等近年来研究进展作一综述：通过ncRNAs寻找肝癌治疗新靶点，以期选择性消除LCSCs，最终改善肝癌患者的预后。     

上皮间质转化和肿瘤干细胞

最近,两个新的概念出现在肿瘤生物学中：上皮间质转化（epitheilal-mesenchymal transition,EMT）和肿瘤干细胞（cancer stem cells,CSCs）。EMT不仅赋予细胞迁移和侵袭特征,还可使肿瘤细胞获得自我更新能力而具有干细胞的特性,从而促进CSCs的产生。本文讨论EMT和CSCs之间的联系、EMT获得干细胞特征促进CSCs产生、EMT是形成CSCs的重要环节及二者在干细胞巢中的转化,并分析影响EMT和CSCs的因素。研究EMT在肿瘤发生中的作用,与CSCs理论相融合,从而可能发现新的肿瘤靶向治疗。     

非黏附性球培养在肿瘤干细胞研究中的应用现状

肿瘤干细胞(cancer stem cells,CSCs)理论的提出为肿瘤靶向治疗研究提供了新的思路,靶向杀灭CSCs将可能有效消除肿瘤。有效、特异地分离和培养CSCs是开展CSCs研究的前提。非黏附性球培养最初应用于成体干细胞的研究,后来应用于CSCs自我更新能力的研究,近来已成为富集肿瘤干细胞的常用方法之一。本文综述非黏附性球培养CSCs的应用原理、关键问题以及相关研究进展。     

肿瘤微环境中的起始细胞

探索肿瘤发生的起始阶段是理解肿瘤生物学的关键,肿瘤起始细胞（cells of origin）的研究已显示出这个领域的进步。现综述肿瘤前期细胞（progenitor cells）、祖细胞（progenitorcells）、癌前干细胞（pre-cancerous stem cells,pCSCs）和肿瘤干细胞（cancer stem cells,CSCs）等肿瘤起始细胞研究的新进展,讨论微环境对肿瘤起始细胞研究的影响。     

上皮源性卵巢癌干细胞的研究进展

肿瘤干细胞(cancer stem cells,CSCs)是肿瘤组织内具有自我更新能力以及无限增殖和多向分化潜能的一群细胞,对化疗药物耐受.卵巢癌干细胞(epithelial ovarian cancer stem cells,EOCSCs)在卵巢癌的发生发展、侵袭转移和耐药复发过程中都起到了重要作用.传统的肿瘤细胞减灭术联合顺铂、紫杉醇全身化疗对减小肿瘤体积,缓解临床症状具有一定的作用,但治疗后残留的EOCSCs能够短时间内重建肿瘤组织,是卵巢癌复发和难治的根本原因.深入了解EOCSCs的生物学特性,探索EOCSCs的发生发展机制,研究针对EOCSCs的靶向治疗药物,是抗肿瘤治疗的关键.     

肝癌干细胞的研究进展

肝细胞癌（HCC）是常见的恶性肿瘤之一,是世界上第五大常见癌症,死亡率仅次于肺癌和结肠癌.预计未来20年,其发病率死亡率还会成倍上升.目前关于肝癌发生的细胞学机制仍不明确.随着对肿瘤和干细胞的研究逐渐深入,Hamburger和Salmon提出肿瘤干细胞学说[3],该学说认为：肿瘤组织中仅有一小部分（＜1.0％）肿瘤细胞有致瘤性,绝大多数肿瘤细胞没有或仅有有限的增殖能力,这小部分肿瘤细胞因具有一些与干细胞相似的自我更新、增殖、分化等特性,被称为肿瘤干细胞（cancer stem cells,CSCS）.肿瘤的形成和发展为该细胞主导过程.在此后大量实验中证实乳腺癌、胰腺癌、肺癌、前列腺癌及脑肿瘤等均存在肿瘤干细胞.于是推测出肝癌中也存在着肝癌干细胞（liver cancer stem cells,LCSCs）.肝癌干细胞是近年来的研究热点,若能证实其在肝癌发病中起到的作用,则将会对肝癌的诊断和治疗产生重大的意义.本文对近年来的肝癌干细胞研究进展做一综述.     

肿瘤细胞群

肿瘤是由不同类型组成的异质体,包含有标志物和功能不同的肿瘤起始细胞（ tumor-initiating cells,TICs）、肿瘤干细胞（ cancer stem cells,CSCs）、肿瘤细胞、转移起始细胞（ metastasis-initiating cells,MICs）和循环肿瘤细胞（ circulating tumor cells,CTCs）。分析这些细胞群的标志和功能可以帮助我们寻找更有效的肿瘤治疗靶点。     

上皮间质转化和肿瘤干细胞

最近,两个新的概念出现在肿瘤生物学中:上皮间质转化(epitheilal-mesenchymal transition,EMT)和肿瘤干细胞(cancer stem cells,CSCs)。EMT不仅赋予细胞迁移和侵袭特征,还可使肿瘤细胞获得自我更新能力而具有干细胞的特性,从而促进CSCs的产生。本文讨论EMT和CSCs之间的联系、EMT获得干细胞特征促进CSCs产生、EMT是形成CSCs的重要环节及二者在干细胞巢中的转化,并分析影响EMT和CSCs的因素。研究EMT在肿瘤发生中的作用,与CSCs理论相融合,从而可能发现新的肿瘤靶向治疗。     

肿瘤微环境中间充质干细胞与癌症干细胞的关系及其在乳腺癌进展中的作用

乳腺癌是女性最高发的恶性肿瘤,在治疗过程中复发、转移、耐药等将显著降低患者的疗效,因此解决复发转移和耐药问题成为研究者关注的方向。近年来,癌症干细胞（cancer stem cells,CSCs）和间充质干细胞（mesenchymal stem cells,MSCs）在肿瘤微环境中调控癌症发生和发展的作用被广泛研究。本文就MSCs和CSCs在乳腺癌进展中的作用以及两者的潜在联系进行阐述,为后续开发新的治疗方案以改善乳腺癌患者预后提供方向和借鉴。     

肿瘤细胞群

肿瘤是由不同类型组成的异质体,包含有标志物和功能不同的肿瘤起始细胞（tumor-initiating cells,TICs)、肿瘤干细胞（cancer stem cells,CSCs)、肿瘤细胞、转移起始细胞（metastasis-initiating cells,MICs）和循环肿瘤细胞（circulating tumor cells,CTCs）。分析这些细胞群的标志和功能可以帮助我们寻找更有效的肿瘤治疗靶点。     

肝癌干细胞与肝癌的研究进展

肿瘤起源于干细胞的假说已在人类许多实体瘤中得到证实,近来亦发现肝癌中存在肝癌干细胞.肿瘤干细胞被认为是肿瘤产生的根源,对肿瘤的发生、发展、转移、复发及耐药具有关键作用.因此,如何分离鉴定肝癌干细胞对于改善预防方法、促进早期检测以及研发新的治疗方法都是一个非常紧迫的课题.本文就肝癌干细胞的来源、表面标志、分选方法、应用前景及存在的问题作一综述.     

Cancer stem cells and cancer therapy

Cancer stem cells (CSCs) are a subpopulation of tumour cells that possess the stem cell properties of self-renewal and differentiation. Stem cells might be the target cells responsible for malignant transformation, and tumour formation may be a disorder of stem cell self-renewal pathway. Epigenetic alterations and mutations of genes involved in signal transmissions may promote the formation of CSCs. These cells have been identified in many solid tumours including breast, brain, lung, prostate, testis, ovary, colon, skin, liver, and also in acute myeloid leukaemia. The CSC theory clarifies not only the issue of tumour initiation, development, metastasis and relapse, but also the ineffectiveness of conventional cancer therapies. Treatments directed against the bulk of the cancer cells may produce striking responses but they are unlikely to result in long-term remissions if the rare CSCs are not targeted. In this review, we consider the properties of CSCs and possible strategies for controlling the viability and tumourigenecity of these cells, including therapeutic models for selective elimination of CSCs and induction of their proper differentiation.     

肿瘤干细胞疫苗的研究进展

目前已知的绝大多数癌症治疗方法如化疗、放疗、免疫靶向治疗等主要以肿瘤细胞为靶目标,但很多肿瘤并不能被完全治愈且治疗后伴随很多并发症。一群高度耐药的肿瘤细胞能够使肿瘤重新聚集并转移到新的部位,使肿瘤继续发生发展。如果可以基于它们的表型或功能特征来鉴定具有干细胞样特征的癌细胞,从而找到肿瘤干细胞特异性抗原制成干细胞疫苗,进而激活机体内特异的免疫应答,以达到靶向清除肿瘤干细胞的目的,就能一定程度上控制肿瘤的复发及转移,杀灭肿瘤干细胞甚至可以消除肿瘤对放化疗的拮抗性及耐药性。因此肿瘤干细胞疫苗即靶向肿瘤干细胞的主动免疫疗法的研究与发展对恶性难治性肿瘤的治疗有着重要意义,本篇综述将对近年来肿瘤干细胞及其疫苗的发现、发展与研究结果进行概述。     

Insights into the cell of origin in breast cancer and breast cancer stem cells

The precise cell types that give rise to tumors and mechanisms that underpin tumor heterogeneity are poorly understood. There is increasing evidence to suggest that diverse solid tumors are hierarchically organized and may be sustained by a distinct subpopulation of cancer stem cells (CSCs). The CSC hypothesis provides an attractive cellular mechanism that can account for the therapeutic refractoriness and dormant behavior exhibited by many tumor types. Breast cancer was the first solid malignancy from which CSCs were identified and isolated. Direct evidence for the CSC hypothesis has also recently emerged from mouse models of mammary tumorigenesis, although alternative models to explain heterogeneity also seem to apply. Our group has found that the luminal epithelial progenitor marker CD61/β3 integrin identified a CSC population in mammary tumors from MMTV‐wnt‐1 mice. However, no CSCs could be identified in the more homogeneous MMTV‐neu/erbB2 model, suggesting an alternate (clonal evolution or stochastic) model of tumorigenesis. It seems likely that both paradigms of tumor propagation exist in human cancer. From a clinical perspective, the CSC concept has significant implications. Quiescent CSCs are thought to be more resistant to chemotherapy and targeted therapy. Enrichment of putative CSCs has been noted in studies of chemotherapy‐treated patients, lending support to the CSC hypothesis and their potential role in chemoresistance. Although many unresolved questions on CSCs remain, ongoing efforts to identify and characterize CSCs continue to be an important area of investigation, with the potential to identify novel tumor targeting strategies.     

长链非编码RNA调控肝癌干细胞的作用

目前常规疗法对晚期、转移或复发肝癌患者疗效差。肝癌干细胞(LCSCs)参与肝癌的发展、侵袭、转移和耐药,与不良预后密切相关,被认为是肝癌治疗的重要靶点。长链非编码RNA(LncRNA)在肝癌中异常表达。最近的研究表明,lncRNAs可能在调控LCSCs的生物学功能中发挥重要作用。全文总结lncRNA调控LCSCs作用的研究现状。     

Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells

Energy metabolism is the foundation of survival for all organisms, and mitochondria are the most important energy-supplying organelles in eukaryotic cells. However, the mitochondrial and energy/metabolism-related properties of cancer stem cells (CSCs), the stem cell-like subpopulation in tumor masses, remain unknown. In our study, we compared the masses of mitochondria and mitochondrial DNA (mtDNA), the mitochondrial membrane potential (Δψm), oxygen/glucose consumption, and the concentration of reactive oxygen species (ROS) and ATP between lung CSCs (LCSCs) and non-LCSCs. In addition, the change in features during differentiation was examined. Some mitochondrial and energy metabolism-related properties, such as perinuclear mitochondrial distribution, a lower quantity of mtDNA, higher Δψm, lower oxygen/glucose consumption, and lower intracellular concentrations of ROS and ATP, can be used as indicators of LCSCs.     

肝癌干细胞研究进展与方向

近年来随着“干细胞”的概念被引入肿瘤学研究,肿瘤干细胞学说逐渐形成。该学说认为,导致肿瘤发生和维持肿瘤生长的是一小群叫做“肿瘤干细胞”的细胞;这些细胞在肿瘤组织中数量极少,具有自我更新、分化及抗治疗能力等干细胞样特性。在过去的数年中,研究者分别通过侧群细胞技术及CD133、CD90、OV6、EpCAM等标志鉴定和分离得到具有很强的体外克隆形成及体内成瘤能力的小群肝癌细胞,为肝癌干细胞的存在提供了有力证据。本文对肿瘤干细胞理论和肝癌干细胞相关研究进展进行了综述,对肝癌干细胞在肝癌诊断和治疗方面的重要性进行了讨论,并对我们面临的有关挑战、机遇和未来的研究方向进行了分析。     

Tumor‐derived spheroids: Relevance to cancer stem cells and clinical applications

Recently, many types of in vitro 3‐D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3‐D culture methods aim to preserve the biological characteristics of original tumors better than conventional 2‐D monolayer cultures, and include tumor‐derived organoids, tumor‐derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3‐D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor‐derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell‐related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC‐related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor‐derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor‐derived spheroids may prove to be instrumental for a high‐throughput screening platform or for the cultivation of CSC‐related tumor cells found in the circulation or body fluids.     

非编码RNA调控乳腺癌干细胞干性的研究进展

随着高通量技术的发展和表观遗传学的深入研究,人们发现基因组大量的非编码RNA(noncoding RNA,ncRNA)转录本,其能从基因组上转录而来但并不翻译成蛋白,在多水平、多途径的调节基因表达,参于生物各个层面的重要生物学行为,与肿瘤发生发展关系密切,是肿瘤研究领域热点。乳腺癌干细胞在乳腺癌的发生发展中起着非常重要的作用。目前研究已经证实了一些ncRNA与乳腺癌动态干性相关,ncRNA被发现作为影响干性的崭新靶点。本文就ncRNA在调控乳腺癌干细胞干性的的相关研究进展作一综述。     

Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo

Breast cancer stem cells (BCSCs) are pan-resistant to different anticancer agents and responsible for cancer relapse. Disulfiram (DS), an antialcoholism drug, targets CSCs and reverses pan-chemoresistance. The anticancer application of DS is limited by its very short half-life in the bloodstream. This prompted us to develop a liposome-encapsulated DS (Lipo-DS) and examine its anticancer effect and mechanisms in vitro and in vivo.The relationship between hypoxia and CSCs was examined by in vitro comparison of BC cells cultured in spheroid and hypoxic conditions. To determine the importance of NFκB activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NFκB p65 transfected cell lines. The effect of Lipo-DS on the NFκB pathway, CSCs and chemosensitivity was investigated in vitro and in vivo.The spheroid cultured BC cells manifested CSC characteristics and pan-resistance to anticancer drugs. This was related to the hypoxic condition in the spheres. Hypoxia induced activation of NFκB and chemoresistance. Transfection of BC cells with NFκB p65 also induced CSC characters and pan-resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted the CSC population in vivo and showed very strong anticancer efficacy. Mice tolerated the treatment very well and no significant in vivo nonspecific toxicity was observed.Hypoxia induced NFκB activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NFκB pathway and CSCs. Further study may translate DS into cancer therapeutics.