调控癌干细胞凋亡的外来因素

背景：目前收集的证据表明癌干细胞或肿瘤原始细胞是肿瘤形成和进展的关键驱动程序,这些细胞的高抵抗特性使常规治疗模式被阻碍。迄今为止,只有少量的研究发表癌干细胞死亡定向凋亡疗法的潜能。 目的：综述癌干细胞调节其凋亡的外来因素。 方法：由第一作者采用电子检索的方式在PubMed数据及万方数据库中检索1990年1月至2011年12月有关肿瘤干细胞和干细胞凋亡的研究。英文检索词为“cancer stem  cells,apoptosis,extrinsic factors”,中文关键词为“癌干细胞,凋亡,外来因素”。计算机初检得到120篇文献,阅读标题和摘要进行初筛,排除与研究目的相关性差及内容陈旧、重复的文献70篇,纳入50篇符合标准的文献进行综述。 结果与结论：癌干细胞理论在癌症的研究中有重要意义。它不仅在理解恶性肿瘤行为上有重要突破,而且有能力发展新的治疗方法。调节癌干细胞凋亡的外在因素包括微环境提供的外源性因子如分泌存活因子,黏附介导的凋亡抵抗和缺氧条件。潜在调节癌干细胞肿瘤微环境是非常关键的研究领域,并且这领域仍然进一步研究。通过各种已成型的各种机制解释癌干细胞的调控将一定会成为未来的研究趋势。     

肿瘤干细胞的研究现状

传统理论认为肿瘤生长是所有肿瘤细胞一起增殖的结果,因而治疗方法主要是针对肿瘤组织内的大多数细胞,常有复发和转移,使治疗失败。肿瘤干细胞的提出,可靶向性杀伤肿瘤干细胞从而使根治肿瘤和防止肿瘤复发和转移成为可能,且先前诸多关于肿瘤发生发展机制、细胞信号途径等研究成果可能需要重新评价,对传统的肿瘤治疗方式提出了巨大挑战。就肿瘤干细胞的起源、存在证据、肿瘤干细胞与正常干细胞之间关系、临床意义及展望综述如下。     

A novel stem cell associated marker identified by monoclonal antibody HESC5:3 differentiates between neoplastic lesions in follicular thyroid neoplasms

Follicular thyroid lesions are the bane of cytopathology. Differentiation between adenoma and carcinoma is impossible, and often these neoplasms are indistinguishable even from uninodular goitre. In other cancers as well, a theory of stem cells as the origin of cancer has been discussed in thyroid carcinogenesis. We aimed to examine a novel stem cell associated marker identified by monoclonal antibody HESC5:3 in follicular lesions in an attempt to find a marker for differential diagnosis in thyroid cytopathology. HESC5:3 was raised against and is specific for undifferentiated human embryonic stem cells. The epitope of this novel antibody is to be defined. Immunohistochemical expression of HESC5:3 was examined in clinical material comprised of follicular neoplasms (83 adenomas, 43 carcinomas) and non‐neoplastic lesions (41 goitrous, 22 hyperplastic, 23 normal tissue specimens). Staining differed significantly between neoplastic and non‐neoplastic lesions. Nuclear staining was increased in non‐neoplastic cells, whereas in neoplastic cells expression was mainly cytoplasmic. There was no difference between benign and malignant lesions, suggesting a role in early tumourigenesis. In conclusion, the HESC5:3 epitope may be of benefit as a neoplasia marker in distinguishing between uninodular goitre and neoplasia. Characterization of the epitope would increase the interest in this promising new stem cell associated marker.     

Stem cells and solid cancers

Recently, there have been significant advances in our knowledge of stem cells found in tissues that can develop solid tumours. In particular, novel stem cell markers have been identified for the first time identifying multipotential cells: a required characteristic of a stem cell. The scarcity of cancer stem cells has been questioned. Current dogma states that they are rare, but novel research has suggested that this may not be the case. Here, we review the latest literature on stem cells, particularly cancer stem cells within solid tumours. We discuss current thinking on how stem cells develop into cancer stem cells and how they protect themselves from doing so and do they express unique markers that can be used to detect stem cells. We attempt to put into perspective these latest advances in stem cell biology and their potential for cancer therapy. Stuart A. C. McDonald, Trevor A. Graham and Stefanie Schier contributed equally to this work.     

衰老可导致间充质干细胞氧化损伤修复能力降低

背景：DNA损伤及损伤后的应答异常会导致基因组不稳定,基因组不稳定是肿瘤形成的重要因素之一。在细胞衰老过程中,衰老细胞基因组稳定性下降,对于端粒、端粒酶的研究以及对于原癌基因和抑癌基因的研究,表明细胞衰老和肿瘤有密切的联系。 目的：以氧化损伤为模型,探索DNA损伤应答异常是衰老细胞基因组不稳定性的直接原因。 方法：培养骨髓间充质干细胞,流式细胞术进行检测鉴定。衰老相关β-半乳糖苷酶检测细胞衰老情况,BrdU掺入实验检测细胞增殖情况。建立体外培养人间充质干细胞衰老模型,通过CCK-8法检测细胞存活情况, DCFH-DA荧光探针检测细胞内活性氧,单细胞凝胶电泳观察细胞DNA损伤情况。 结果与结论：人间充质干细胞经长期培养发生衰老,培养40代以后,衰老相关β-半乳糖苷酶染色阳性细胞明显增多,BrdU掺入能力显著下降,提示间充质干细胞长期培养后发生衰老。生存曲线结果显示H₂O₂作用下,年轻间充质干细胞存活率明显高于衰老间充质干细胞;活性氧及单细胞凝胶电泳结果显示,H₂O₂处理后衰老间充质干细胞DNA损伤更严重,修复时间更长,说明衰老间充质干细胞比年轻间充质干细胞对H₂O₂损伤更为敏感。     

Stem cells and cancer: an intimate relationship

Tumour-wide 'omics' approaches have long held sway as the approach to identifying useful therapeutic targets. This view is changing with the realization that many, if not all, cancers contain a minority population of self-renewing stem cells, the cancer stem cells, which are entirely responsible for sustaining the tumour as well as giving rise to proliferating but progressively differentiating cells that are responsible for much of the cellular heterogeneity that is so familiar to histopathologists. Moreover, although many tumours probably have their origins in normal stem cells, persuasive evidence from the haematopoietic system suggests that genetic alterations in more committed progenitor cells can reactivate the self-renewal machinery, resulting in a further source of cancer stem cells. Thus, the bulk of the tumour is not the problem, and so the identification of cancer stem cells and the factors that regulate their behaviour are likely to have an enormous bearing on the way that we treat neoplastic disease in the future.     

肺癌干细胞与肺癌的发生

背景：肺癌具有高度异质性,能够抵抗化疗药物治疗,5年生存率小于15%,目前难以确定肺癌的异质性和耐药性的发病基础。肿瘤干细胞模型近年来吸引了相当多的关注,通过这种模型可以解释各种肿瘤的异质性、耐药性、休眠、复发和转移的机制。 目的：通过综述各类肺癌的组织学类型和肿瘤生长部位的特征,概括肺癌干细胞与各种肺癌发生的关系,从而为消灭肺癌干细胞攻克肺癌提供理论依据。 方法：以英文检索词为“lung cancer,cancer stem cell,lung cancer stem cell,lung cancer occur,tumor heterogeneity, drug resistance,gene mutation,signal pathways”由第一作者检索 1990至2014年Sciencedirect/PubMed 数据库,查阅近年肺癌干细胞对肺癌发生的影响的相关文献,最终保留48篇文献。 结果与结论：肿瘤干细胞模型近年来吸引了相当多的关注,通过这种模型可以解释各种肿瘤的异质性、耐药性、休眠、复发和转移。肺癌干细胞被认为是一类异质的细胞群,多种信号通路可以有针对性的有效的消除他们,从而有助于增强治疗效果。目前多学科通力合作,正在进行肺癌干细胞表征和靶定,这将给肺癌治疗领域带来显著的治疗受益。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

干细胞移植与神经修复

背景：随着生命科学发展,利用干细胞来源的组织工程技术,有可能使受损的神经组织恢复再生能力。 目的：针对较为重要的几种干细胞在神经系统修复中的临床应用做一综述,以期阐明各自适用范围和临床效度,为临床医师按需选择提供参考。 方法：应用计算机检索PubMed 数据库中1998至2011年期间的关于干细胞移植在神经修复方面研究的文章,检索词为“Stem cells, Transplantation, Nerve repair”,限定语种为“English”。同时,检索万方数据库中2006至2011年期间的相关文章,检索词为“干细胞,移植,神经修复”,限定语种为中文。 结果与结论：初次检索得到288篇文章,选择与移植干细胞的来源、分化、特征及其在神经修复方面相关的文章,包括基础研究和临床研究,观察对象无论为人或动物,均进行审校。根据纳入标准,在排除重复和个案报道类文章之后,重点选择32篇文章进行综述。说明干细胞移植为神经系统疾病的治疗提供了一条新途径,使传统认为的不可修复、不可再生的神经组织的结构修复和功能重建成为可能。干细胞移植是一个全新的领域,还有许多问题亟待解决。     

间充质干细胞对肝癌细胞增殖、侵袭及生物学行为的影响

背景：研究者们正尝试应用各种方法研究肝癌的发生机制、干预措施等,间充质干细胞因其具有低免疫原性及趋瘤性等特点,成为肿瘤研究热门的工具细胞。目前间充质干细胞已经开始应用于肝癌的研究中。 目的：综述近年来间充质干细胞运用于肝癌基础与临床的研究进展。 方法：第一作者应用计算机检索2004年1月至2013年1月PubMed数据库、中国期刊全文数据库有关间充质干细胞、经修饰的间充质干细胞对肝癌细胞影响效应及其作用机制的文章,英文检索词“mesenchymal stem cell,liver cancer,tumor”,中文检索词“间充质干细胞,肝癌,肿瘤”。排除重复性研究,47篇文献符合纳入标准。 结果与结论：干细胞运用于肝癌的研究报道较少,目前的研究结果显示,间充质干细胞对肝癌细胞增殖、侵袭等生物学行为有一定影响,然而因各实验室使用的细胞株种类、实验条件、动物模型、干细胞输注途径等诸多因素的不同,实验结果也不一致。学者们主要针对Wnt途径、肿瘤坏死因子相关凋亡诱导配体途径等机制进行了一系列的研究。间充质干细胞对包括肝癌在内的肿瘤细胞具有趋向性是公认的,利用这一特性,已经有学者将治疗基因、药物等导入或修饰间充质干细胞用于干预肝癌的发展,并取得了进展,为肝癌的细胞治疗提供了新的途径。但目前对间充质干细胞的体内安全性研究及临床实验报道较少,存在安全隐患,需要进一步研究探索。     

Small intestinal stem cell identity is maintained with functional Paneth cells in heterotopically grafted epithelium onto the colon

To develop stem cell therapy for small intestinal (SI) diseases, it is essential to determine whether SI stem cells in culture retain their tissue regeneration capabilities. By using a heterotopic transplantation approach, we show that cultured murine SI epithelial organoids are able to reconstitute self-renewing epithelia in the colon. When stably integrated, the SI-derived grafts show many features unique only to the SI but distinct from the colonic epithelium. Our study provides evidence that cultured adult SI stem cells could be a source for cell therapy of intestinal diseases, maintaining their identity along the gastrointestinal tract through an epithelium-intrinsic mechanism.     

Expression of the adult intestinal stem cell marker Lgr5 in the metastatic cascade of colorectal cancer

The recently advanced cancer stem cell model postulates that progression and metastasis of cancer are mainly driven by tumor cells with stem cell properties. Intestinal cancer stem cells are difficult to study due to the lack of reliable markers, but expression of the Wnt target gene Lgr5 is promising to define at least stem cell like cells in intestinal and colorectal cancer. The aim of this study was to find a possible link of stem cell like cancer cells to the metastatic process of colorectal cancer. To this end, we evaluated immunohistochemical Lgr5 expression in 31 distant metastases and in primary tumor compartments with relevance for metastasizing, comprising 89 colorectal carcinomas. Lgr5 expression was seen in 51.6% of distant metastases. 12.9%, 14.8% and 26.7% of primary tumors with histologically confirmed tumor buds, angioinvasion and perineural infiltrates, respectively, showed evidence of Lgr5 expression in these tumor compartments. However, distant metastases, which were derived from carcinomas with such Lgr5 positive tumor compartments, showed 6- to 11.5-fold higher median value of Lgr5 expression compared to those metastases derived from tumors without Lgr5 expressing cells in these compartments. These differences between the metastases were statistically significant, if being related to tumor buds (all tumors; p = 0.047) and to vascular infiltrates (stage IV tumors; p = 0.007). In conclusion, our results point to rare evidence of Lgr5 positive stem cell like cells in the metastatic cascade of colorectal cancer, but these few cells might be biologically powerful in the metastatic process of cancer subsets. Clonal analysis is necessary to proof this hypothesis.     

Breast Cancer Stem Cells-Research Opportunities Utilizing Mathematical Modeling

There is increasing evidence for the “cancer stem cell hypothesis” which holds that cancers originate in tissue stem cells or progenitor cells. As a result of this, cancers are driven by a cellular subcomponent that retains stem cell properties. Among these properties are self-renewal and multi-lineage differentiation. The biological processes which account for stem cell properties are currently being elucidated. Cancer stem cells maintain many of the same characteristics of their normal counterparts. The combination of biological research with mathematical modeling may provide for a greater understanding of the complex picture of breast cancer stem cells and assist cancer biologists and clinical oncologists in designing and testing novel therapeutic strategies.     

肝癌干细胞分离及其细胞生物学特性

背景：正常干细胞和肿瘤干细胞在基因表达和依赖的细胞信号通路上应该存在不同,如何发现能选择性杀伤肿瘤干细胞的治疗手段是一个仍然需要大量研究的课题。 目的：分离人肝癌细胞系肿瘤干细胞MHCC97,分析其细胞生物学特性。 方法：采用流式细胞技术在人高转移肝癌细胞系MHCC97中筛选肿瘤干细胞,分离正常人肝脏干细胞CD133^-CD34^- MHCC97和人肝癌细胞系肿瘤干细胞CD133⁺CD34⁺ MHCC97,分别检测其表型、生长曲线、细胞周期和多系分化能力。 结果与结论：人肝癌细胞系CD133⁺CD34⁺ MHCC97肿瘤干细胞的表型为CD133⁺CD34⁺ ,人肝癌细胞系CD133⁺CD34⁺ MHCC97具有与CD133^-CD34^- MHCC97相似的细胞曲线和生长周期,可以向上皮和内皮细胞分化,并表达相应特异性的分子标志。提示人肝癌细胞系中CD133⁺CD34⁺MHCC97细胞具有肿瘤干细胞的特性,可以向内皮和上皮细胞分化,同时具有肿瘤干细胞的生物学特性,是肿瘤复发转移的根源,也是临床治疗的靶点。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

The Limbal Epithelial Progenitors in the Limbal Niche Environment

Limbal epithelial progenitors are stem cells located in limbal palisades of vogt. In this review, we present the audience with recent evidence that limbal epithelial progenitors may be a powerful stem cell resource for the cure of human corneal stem cell deficiency. Further understanding of their mechanism may shed lights to the future successful application of stem cell therapy not only to the eye tissue, but also to the other tissues in the human body.     

间质干细胞、肿瘤干细胞和肿瘤

近来研究认为肿瘤来源于干细胞,提出了肿瘤中存在极少量肿瘤干细胞(CSC)的新学说.问质干细胞(MSC)作为间质细胞的来源,与肿瘤的关系尤为密切.本文就间质干细胞,肿瘤干细胞和肿瘤的发生,发展作一综述.     

肿瘤干细胞与卵巢癌

卵巢肿瘤干细胞（OCSCs)是存在于卵巢癌组织中的一类具有自我更新和多向分化潜能的细胞,表面共表达CD44和CD117分子标记。虽然其起源不是很确定,但目前倾向于认为卵巢表面上皮细胞来源于OCSCs。研究OCSCs自我更新机制和表观遗传学的改变,可为肿瘤发生的机制及新药的开发提供很好的基础     

Fibroblast growth factors as regulators of stem cell self-renewal and aging

Organ and tissue dysfunction which is readily observable during aging results from a loss of cellular homeostasis and reduced stem cell self-renewal. Over the past 10 years, studies have been aimed at delineating growth factors that will sustain and promote the self-renewal potential of stem cells and support the expansion of primitive stem cells in vitro and in vivo. Recently, strong evidence is emerging indicating that fibroblast growth factors (FGFs) play a crucial role in stem cell maintenance. FGFs belong to a family of polypeptide growth factors that are involved in multiple functions including cell proliferation, differentiation, survival and motility. In this review, we discuss the regulatory role of FGFs on hematopoietic stem cells (HSCs), neural stem cells (NSCs) and embryonic stem (ES) cells in maintaining stem cell self-renewal. These findings are useful and important to further our knowledge in stem cell biology and for therapeutic approaches.     

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.