肝癌干细胞研究现状

原发性肝癌是一种常见而恶性度极大的肿瘤，肝癌起源一直存在争议。肝干细胞是肝脏组织中的一类具有自我更新和向前分化为成熟肝细胞、胆管细胞等的不成熟细胞，这类细胞是生理性肝细胞更新和病理性肝损伤修复的起源细胞。传统认为肝癌起源于肝细胞突变和异常增生，目前观点多倾向于肝癌起源于肝干细胞的异常分化和增生。肝干细胞比成熟肝细胞更有可能成为肝癌癌变的靶细胞。现对当前肿瘤干细胞与肝癌干细胞相关方面的最新研究进展作一概述。     

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。     

干细胞肿瘤干细胞与肝细胞癌发生关系研究进展

越来越多的实验结果证实肿瘤起源于干细胞,诸如白血病、乳腺癌、脑肿瘤等已成功分离出肿瘤干细胞,有关肝干细胞与肝癌的研究较为成熟,理论上应存在肝癌干细胞,但因缺乏特异性标志物,相关的肝癌干细胞分离尚未成功.     

肿瘤干细胞:起源与争论

近年来,随着干细胞理论在肿瘤研究中的广泛应用,人们逐渐认识到在绝大多数癌症中,肿瘤细胞很可能起源于一种肿瘤起始细胞———肿瘤干细胞,它在机体内具有自我更新并形成肿瘤的能力。肿瘤干细胞的存在已在多种肿瘤类型与细胞系中得到证实,并鉴定出相应的分选方法,但人们对它的起源却莫衷一是,干细胞突变、细胞融合、胚胎干细胞残留等都有可能是肿瘤干细胞产生的原因。通过多年对肝癌的研究,笔者提出肝癌干细胞来源的假说:认为干细胞在修复肝炎病毒所致肝损伤的过程中,在病毒与炎症的双重刺激下,干细胞与突变肝细胞之间发生细胞融合、交换,最终产生肝癌干细胞。随着相关研究的不断深入,肿瘤干细胞学说在理论与技术上也面临着诸多质疑与挑战,其中有观点认为,干细胞可能只是被趋化至癌变部位并因其可塑性而表现出恶变表型,但并未在实质上参与肿瘤的发生与发展。     

肝癌干细胞研究进展

肿瘤干细胞学说认为肿瘤是一种干细胞疾病,小部分细胞即肿瘤干细胞在肿瘤中发扮演干细胞的角色,在维持肿瘤发生、发展和耐药过程中发挥着主要作用。肝癌是最常见的肿瘤之一,近几年来有文献报道肝癌中也存在肝癌干细胞,本文就其来源、分离鉴定、细胞信号转导通路等方面做一归纳。      

肿瘤干细胞研究进展

肿瘤是一种干细胞疾病。干细胞的基因突变导致正常的自我更新和分化失衡，干细胞转变成为肿瘤干细胞(TSC)，而后者具有增殖分化形成肿瘤的能力。TSC的存在已在造血系统肿瘤中得到证实，最近亦有在实体瘤中的相关报道。现对TSC及其在各种肿瘤中的研究进展作一综述。     

肺癌干细胞的研究现状

1937年，Jacob和他的同事将患有白血病的小鼠体内的单个未分化白血病细胞输注入正常的小鼠体内，使正常小鼠发生白血病，该实验首次证实了类似于正常的干细胞具备自我更新能力的白血病干细胞，即肿瘤干细胞的存在，从此拉开了研究肿瘤干细胞的序幕。现就肿瘤干细胞的特征及其在肺癌研究中的进展报告如下。[第一段]     

干细胞与肿瘤发生

干细胞具有自我更新及多向分化能力，可以分化成机体组织器官的各种成熟细胞。人们发现许多肿瘤的发生都与成体干细胞有着密切的关系，肿瘤细胞可来源于成体干细胞积累的突变，因为干细胞具有无限增殖能力，在体内可长期存在，这使突变更容易在成体干细胞中发生和积累；肿瘤细胞也可来源于成体干细胞下游祖细胞积累的突变。随着研究深入还发现，肿瘤细胞与成体干细胞之间有着惊人的相似性——相似的生长调控机制和等级现象，由此提出了肿瘤干细胞的概念，并归纳了随机制论和等级理论解释为什么并非每个肿瘤细胞都具有再生肿瘤和转移的能力，许多文献更倾向于等级理论在起作用。目前已经在白血病和一些实体瘤中分离鉴定出肿瘤干细胞，在一些长期培养的肿瘤细胞系中也发现了类似的肿瘤干细胞。这些肿瘤干细胞具有自我更新能力和正常成体干细胞的一些耐药机制，对现有的抗肿瘤治疗不敏感，常导致肿瘤的复发和转移。因此，肿瘤干细胞的根除和检测对于肿瘤的治疗和预后评估都有重要的意义。     

肿瘤干细胞研究进展

干细胞是一类具有自我更新能力和多向分化潜能的原始细胞，干细胞的自我更新调节通路异常与肿瘤形成密切相关。恶性肿瘤的进行性生长、转移和复发与干细胞的基本特性相似，推测在肿瘤组织中存在少数能驱使肿瘤形成与发展的肿瘤干细胞。随着近年来正常干细胞研究的飞速发展，肿瘤干细胞的研究取得了令人鼓舞的成果，急性髓细胞白血病、乳腺癌及脑瘤中的肿瘤干细胞已相继得到分离和鉴定。现对近年来肿瘤干细胞的研究进展作简要综述。     

人肝癌干细胞的富集

目的:从人肝癌细胞株中富集癌干细胞(cancer stem cells,CSCs).方法:将肝癌细胞SMMC-7721接种到裸鼠皮下建立动物模型后,荷瘤鼠随机分成4组,每组5只,每周1次腹腔分别注射环磷酰胺(cyclophosphamide, CTX)0、2、5和10 mg/kg,在肿瘤直径达1.5 cm时获取肿瘤,得到经不同剂量CTX富集的肝癌细胞.比较这些肝癌细胞的侧群(side population, SP)细胞含量、软琼脂克隆形成率、细胞增殖能力及致瘤能力.结果:SP细胞含量、软琼脂克隆形成率、细胞增殖能力及致瘤能力经比较均显示,经CTX(10 mg/kg)富集的肝癌细胞表现最强,且均随着CTX的剂量增加而增长(P<0.05).结论:利用低剂量化疗药能够富集肝癌干细胞,且富集效率与化疗剂量呈正比.     

肝癌干细胞的研究进展

我国是原发性肝癌高发的国家,其发病率、死亡率约占全球的一半以上。尽管目前肝癌的诊断和治疗有了许多新的进展,但是总体疗效仍不满意。近年来的研究表明,肝癌中存在着一群具有干细胞特征、能自我更新、自我无限增殖并具有多向分化潜能的细胞,即肝癌干细胞,这对重新认识肝癌的发生、发展、预后转归以及指导临床治疗将起到极为重要的作用。本文通过复习肝癌干细胞相关文献,就肝癌干细胞起源、分选及相关治疗的研究进展作一综述。     

Cancer stem cells and EMT in carcinoma

The majority of deaths from carcinoma are caused by secondary growths that result from tumour invasion and metastasis. The importance of epithelial-to-mesenchymal transition (EMT) as a driver of invasion and metastasis is increasingly recognised, and recent evidence has highlighted a link between EMT and the cancer stem cells that initiate and maintain tumours and have also been implicated in invasion and metastasis. Here, we review cancer stem cells and their link with EMT, and explore the importance of this link in metastasis and therapeutic resistance of tumours. We also discuss new evidence from our laboratory demonstrating that cancer stem cells display a remarkable phenotypic plasticity that enables them to switch between an epithelial phenotype that drives tumour growth and an EMT phenotype that drives metastasis. As successful therapies must eradicate cancer stem cells in all their guises, the identification of sub-types of cancer stem cells that display therapeutic resistance and phenotypic plasticity has important implications for the future design of therapeutic strategies. The ability to assay the responses of different cancer stem cell phenotypes in vitro holds promise for the rapid development of a new generation of targeted therapies that fulfil this objective.     

Adult stem cells in progression and therapy of hepatocellular carcinoma

Hepatocellular carcinoma is one of the most aggressive solid tumours associated with poor prognosis. Despite its significance, there is only an elemental understanding of the mechanisms that drive disease pathogenesis, and there are just limited therapy options. The medical community is currently experiencing a wave of enthusiasm for clinical trials, in which adult stem/progenitor cells are used for liver regeneration. This is based on promising results in animal models and encouraging reports from some initial clinical studies. On the other hand, several essential precautions are not being fully addressed. Stem cells may contribute to fibrosis or give rise to hepatic cancer stem cells as a source of hepatocellular carcinoma. This review outlines the current state of knowledge in progression of liver disease and highlights the function of adult stem cells in disease and therapy.     

Teratocarcinoma stem cells

Human teratocarcinomas or mixed germ cell tumours are histologically composed of diverse tissues corresponding to somatic and extraembryonic (trophoblastic and yolk sac) like cells, as well as malignant stem cells. In typical teratocarcinomas these stem cells correspond to embryonal carcinoma cells, ie developmentally pluripotent cells equivalent to embryonic cells from the early stages of development. These cells have the capacity to differentiate and give rise to non-proliferating terminally differentiated tissue. Occasionally embryonal carcinoma cells can give rise to more differentiated stem cells which have the phenotype and the restricted developmental potential of choriocarcinoma and yolk sac carcinoma cells, or less commonly to somatic cell malignancies, indistinguishable from typical carcinomas, sarcomas, melanoma or lymphomas. Malignant transformation of benign somatic tissues in teratomas can also give rise to malignant stem cells, which all have a somatic cell phenotype. The biology and the clinical presentation as well as the response to chemotherapy of germ cell tumours depend on the nature of stem cells that form their proliferative compartment and account for the malignancy of these tumours.     

胃癌发生的干细胞机制

研究表明,胃癌发生的部位与胃干细胞定居的部位一致,干细胞可能在胃癌发生的过程中扮演了重要角色.对干细胞与胃干细胞、肿瘤干细胞与胃癌、骨髓干细胞与胃癌之间关系的研究,提示胃癌可能是一种干细胞疾病.     

胃癌发生的干细胞机制

研究表明,胃癌发生的部位与胃干细胞定居的部位一致,干细胞可能在胃癌发生的过程中扮演了重要角色.对干细胞与胃干细胞、肿瘤干细胞与胃癌、骨髓干细胞与胃癌之间关系的研究,提示胃癌可能是一种干细胞疾病.     

Isolation of cancer stem cells from adult glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor and is comprised of a heterogeneous population of cells. It is unclear which cells within the tumor mass are responsible for tumor initiation and maintenance. In this study, we report that brain tumor stem cells can be identified from adult GBMs. These tumor stem cells form neurospheres, possess the capacity for self-renewal, express genes associated with neural stem cells (NSCs), generate daughter cells of different phenotypes from one mother cell, and differentiate into the phenotypically diverse populations of cells similar to those present in the initial GBM. Having a distinguishing feature from normal NSCs, these tumor stem cells can reform spheres even after the induction of differentiation. Furthermore, only these tumor stem cells were able to form tumors and generate both neurons and glial cells after in vivo implantation into nude mice. The identification of tumor stem cells within adult GBM may represent a major step forward in understanding the origin and maintenance of GBM and lead to the identification and testing of new therapeutic targets.     

骨髓间充质干细胞多向分化潜能和微环境关系的研究

目的:深入研究骨髓间充质干细胞(mesenchymal stem cells,MSCs)多向分化的潜能与微环境的关系,从而为促进MSCs向目标组织细胞诱导分化创建新的实验方法。方法:大鼠MSCs进行分离,体外培养、扩增、鉴定。将MSCs向脂肪细胞和胰岛细胞方向诱导分化,并深入研究在不同的微环境下,其分化能力的差别,对照组诱导剂为含有角朊细胞生长因子(KGF)、胰岛素-转铁蛋白-硒(ITS)、尼克酰胺的无血清DMEM/F12培养基,实验组在对照组基础上添加胰腺条件培养液;对诱导的胰岛细胞进行观察、双硫腙染色,并进行葡萄糖刺激实验,测定细胞分泌胰岛素及C-肽功能。结果:培养的MSCs表现为非造血干细胞特性。其可向脂肪细胞,胰岛细胞等不同组织细胞分化。对照组和实验组均可分化为胰岛细胞,但实验组分化而成的胰岛细胞在数量和功能上均高于对照组。结论:MSCs具有多向分化潜能,其分化能力在特定的微环境下更强。     

间充质干细胞基因治疗肿瘤新进展

骨髓间充质干细胞(MSC)是骨髓内除造血干细胞和多功能前祖细胞外另一种成体干细胞,具有很强的自我更新能力、多向分化潜能.该细胞具有明显的趋向肿瘤移动并与肿瘤组织楔合的生长特性.虽然骨髓间充质干细胞有向肿瘤干细胞转化的风险,但其作为一种克隆载体可以转导治疗基因在体内获得长期稳定表达,对肿瘤的靶向治疗有着广阔的前景.     

Sheep,wolf, or werewolf: Cancer stem cells and the epithelial-to-mesenchymal transition

Multiple cancers contain subpopulations that exhibit characteristics of cancer stem cells (CSCs), the ability to self-renew and seed heterogeneous tumors. Recent evidence suggests two potentially overlapping models for these phenotypes: one where stem cells arise from multipotent progenitor cells, and another where they are created via an epithelial to mesenchymal transition. Unraveling this issue is critical, as it underlies phenomena such as metastasis and therapeutic resistance. Therefore, there is intense interest in understanding these two types of CSSs, how they differ from differentiated cancer cells, the mechanisms that drive their phenotypes, and how that knowledge can be incorporated into therapeutics.