干细胞的异常分化与肿瘤发生

干细胞是一类具有自我更新和多向分化潜能的细胞群体。越来越多的研究表明,干细胞异常分化可导致肿瘤。并且在肿瘤组织中存在部分细胞,它们具有干细胞的多种特性,被称为肿瘤干细胞(cancer stem cell,CSC)。肿瘤干细胞理论的提出,为肿瘤的治疗与研究提供了新的方向。本文综述了正常干细胞异常分化、肿瘤干细胞的存在和特性、肿瘤干细胞靶向治疗的前景及所面临的问题等方面的研究进展。     

干细胞、肿瘤干细胞与肿瘤

干细胞是一种具有自我更新、无限增殖和多向分化能力的细胞.而多数肿瘤是由不同增殖潜能的不均一性细胞构成.随着对干细胞的研究不断深入,使人们对肿瘤的发生机制重新进行了审视,并在造血系统、脑、肺、乳腺等部位肿瘤中发现极少量的具有与干细胞非常类似生物学特性的细胞,称之为肿瘤干细胞,它们很可能是肿瘤细胞的起源.肿瘤干细胞的提出.使得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.所以研究肿瘤干细胞的起源及其与肿瘤的发生关系,成为当前研究和治疗肿瘤领域的新热点.本文就肿瘤干细胞的存在证据、干细胞与肿瘤干细胞的异同点及它们与肿瘤发生之间的关系作简要的综述.     

长非编码RNA HOTAIR调控胃癌细胞SGC-7901来源肿瘤干细胞样细胞

肿瘤干细胞样细胞具有自我更新、无限增殖和多向分化能力,且受到长非编码RNA（long non-coding RNAs, lncRNAs）的调控。长非编码RNA HOTAIR在人胃癌细胞中表达升高,且具有调控功能。但目前对其在胃癌干细胞样细胞中的功能尚无研究。本研究的目的是探讨胃癌肿瘤干细胞中HOTAIR对肿瘤恶性行为的调控作用。本研究采用无血清培养基在补充细胞因子条件下培养SGC-7901细胞,获得悬浮生长的肿瘤干细胞样细胞微球,检测微球细胞的表面特征因子CD44、CD24及HOTAIR的表达量变化;并通过CCK-8、流式细胞分析及ELISA等技术探讨了HOTAIR对肿瘤干细胞样细胞功能调控作用。结果表明,无血清培养基中获得的肿瘤干细胞样细胞具有自我更新能力,其可连续传代细胞微球的比率为4.75%±0.76%;RT-qPCR检测显示,相对于SGC-7901细胞,肿瘤干细胞样细胞中的HOTAIR表达量明显升高;通过慢病毒干扰技术发现,HOTAIR干扰抑制了HLA-G蛋白分泌、促进肿瘤干细胞样细胞的细胞周期推进、细胞增殖和自我更新能力维持。本研究提示,胃癌细胞系SGC-7901中的肿瘤干细胞样细胞中HOTAIR表达量升高,并可能通过促进肿瘤干细胞样细胞干性调控肿瘤恶性行为。     

综述: 肿瘤干细胞微环境与靶向干预策略

肿瘤干细胞具有自我更新和可塑性的潜能,能够维持肿瘤生长和异质性的能力．肿瘤干细胞是肿瘤产生、转移、耐药和复发的根源,肿瘤干细胞学说逐渐被肿瘤研究者所接受,因此,对肿瘤干细胞的深入理解有重大的科学和临床意义．肿瘤干细胞的微环境是肿瘤微环境的组成部分,包括细胞-细胞接触、分泌型因子等．肿瘤非干细胞和肿瘤干细胞本身都可以作为肿瘤干细胞的微环境．肿瘤干细胞的微环境可以维持肿瘤干细胞的可塑性,保护肿瘤干细胞免受免疫系统攻击,也可以促进其转移．肿瘤干细胞对其微环境的塑造、肿瘤干细胞的微环境对肿瘤干细胞自我更新的影响,以及针对肿瘤干细胞微环境的靶向干预等问题,已成为肿瘤干细胞研究的前沿问题．本文就肿瘤干细胞的发现、自我更新维持机制、肿瘤干细胞的微环境,及其肿瘤干细胞及微环境的干预策略等研究进展进行了综述．     

肿瘤干细胞微环境与靶向干预策略

肿瘤干细胞具有自我更新和可塑性的潜能,能够维持肿瘤生长和异质性的能力.肿瘤干细胞是肿瘤产生、转移、耐药和复发的根源,肿瘤干细胞学说逐渐被肿瘤研究者所接受,因此,对肿瘤干细胞的深入理解有重大的科学和临床意义.肿瘤干细胞的微环境是肿瘤微环境的组成部分,包括细胞-细胞接触、分泌型因子等.肿瘤非干细胞和肿瘤干细胞本身都可以作为肿瘤干细胞的微环境.肿瘤干细胞的微环境可以维持肿瘤干细胞的可塑性,保护肿瘤干细胞免受免疫系统攻击,也可以促进其转移.肿瘤干细胞对其微环境的塑造、肿瘤干细胞的微环境对肿瘤干细胞自我更新的影响,以及针对肿瘤干细胞微环境的靶向干预等问题,已成为肿瘤干细胞研究的前沿问题.本文就肿瘤干细胞的发现、自我更新维持机制、肿瘤干细胞的微环境,及其肿瘤干细胞及微环境的干预策略等研究进展进行了综述.     

肿瘤干细胞放射抗拒的相关研究进展

为了解肿瘤干细胞在放射抗拒中的作用及其相关机制的研究进展。应用pubmed和CNKI数据库检索系统,以"肿瘤干细胞"、"放射抗拒"、"细胞凋亡"等为关键词,检索相关文献。收入标准为:肿瘤干细胞与放射抗拒之间的关系。根据相关标准分析相关文献。肿瘤干细胞是导致放射治疗失败的主要细胞,其放射抗拒机制包括细胞存活和凋亡相关信号转导通路的异常激活、肿瘤微环境对肿瘤干细胞的保护作用、肿瘤干细胞放射损伤的自我修复和大多数的肿瘤干细胞处于静止期。肿瘤干细胞是导致放疗失败的主要因素之一,对于放射抗拒的研究有助于展开针对肿瘤干细胞的靶向治疗,提高放射治疗的敏感性。     

肿瘤干细胞

干细胞和肿瘤细胞在生物学特性和传导调控途径及机制等诸多方面有着极其相似的生物学行为,从而将干细胞理论应用于肿瘤学研究领域产生肿瘤干细胞理论。近年来研究认为,肿瘤干细胞是决定肿瘤发生发展及转归的一群主要细胞群体,该细胞群体很有可能起源于干细胞的突变。该文介绍干细胞、肿瘤细胞和肿瘤干细胞之间的相互作用及其关系。     

肿瘤干细胞起源及其生物学特性

肿瘤干细胞与正常成体干细胞在自我更新与增殖分化能力、表型标记和强耐药性等诸多方面存在着相类似的生物学特征,所以肿瘤干细胞被推测为肿瘤发生的细胞起源。基于肿瘤干细胞与正常干细胞之间的相似性质和肿瘤发生的分子机制,科学家建立了一系列从肿瘤组织或肿瘤细胞系分离肿瘤干细胞的实验方法和研究肿瘤干细胞起源的动物实验模型。现就目前在肿瘤干细胞起源和生物学特性领域的研究作概括阐述。     

肿瘤干细胞生长相关的信号转导通路

肿瘤干细胞是肿瘤中存在的一小群具有自我更新和分化潜能的细胞,也是存在于肿瘤 组织中具有干细胞样能力的肿瘤细胞亚群,在肿瘤的发生、发展中起着非常重要的作用.近年来发现,肿瘤干细胞的生长调控与Wnt、Notch、Hedgehog等多种信号转导通 路有关.本文简要综述了肿瘤干细胞生长相关信号转导通路的研究进展,旨在为肿瘤干细胞研究和临床应用提供理论依据.     

针对肿瘤干细胞的抗体靶向治疗——靶向部分信号通路及细胞表面标志分子

肿瘤干细胞是指肿瘤细胞群体中的未分化细胞,能够自我更新及无限增殖;通常具有正常干细胞样的多潜能性,可以分化产生异质性的肿瘤细胞及组织,对于传统的化疗药物具有耐药性。肿瘤干细胞与正常干细胞有一定的差异,如某些信号通路异常活化、细胞表面表达特异的分子等。针对肿瘤干细胞的这些特性,科学家们提出新的肿瘤治疗策略,即通过设计特异的抗体药物靶向信号通路或者细胞表面分子等,从根源上杀死肿瘤起始细胞,从而达到彻底治愈恶性肿瘤的目的。该文介绍了针对不同信号通路(如Notch和Wnt)或肿瘤细胞表面标志分子(如Ep CAM和CD44等)的抗体药物,并且探讨了抗体药物的优点以及面临的问题。     

肺癌中piR-932的表达及其生物学行为机制研究

目的研究肺癌干细胞中piR-932的表达,以期为肺癌的治疗提供参考。方法应用piRNA芯片检测肺癌于细胞中piRNAs的表达,应用基因芯片检测肺癌干细胞中基因表达的差异,并检测表达下调的基因之一——Latexin的甲基化程度。结果经诱导至EMT的肺癌干细胞中,piR-932的表达明显增高,而Latexin的表达显著下降,并且Latexin启动子区域CpG岛发生了明显的甲基化。结论piR-932可能通过促进Latexin的甲基化而正渊节肺癌干细胞的EMT过程,它可作为肺癌治疗的一个潜在靶点。     

Regulation of self-renewal in normal and cancer stem cells

Mutations can confer a selective advantage on specific cells, enabling them to go through the multistep process that leads to malignant transformation. The cancer stem cell hypothesis postulates that only a small pool of low-cycling stem-like cells is necessary and sufficient to originate and develop the disease. Normal and cancer stem cells share important functional similarities such as 'self-renewal' and differentiation potential. However, normal and cancer stem cells have different biological behaviours, mainly because of a profound deregulation of self-renewal capability in cancer stem cells. Differences in mode of division, cell-cycle properties, replicative potential and handling of DNA damage, in addition to the activation/inactivation of cancer-specific molecular pathways confer on cancer stem cells a malignant phenotype. In the last decade, much effort has been devoted to unravel the complex dynamics underlying cancer stem cell-specific characteristics. However, further studies are required to identify cancer stem cell-specific markers and targets that can help to confirm the cancer stem cell hypothesis and develop novel cancer stem cell-based therapeutic approaches.     

Cancer initiating cells or cancer stem cells in the gastrointestinal tract and liver

It has been suggested that cancer stem cells population within the solid tumor with indefinite proliferation potential drives the growth and metastasis of cancer. In literature, these malignant stem cells also named Cancer initiating cells. Cancer stem cells exhibit low rate of division and proliferation in their niche that help them to avoid chemotherapy and radiation. Epithelial cancers are believed to originate from transformation of tissue stem cells. Bone marrow-derived cells, which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy in the gastrointestinal tract. Pancreatic cancer is one of most common cause of cancer-related death. Pancreatic cancer stem cells have been characterized recently through serial transplantation of human pancreatic cancer cells. The phenotype of Pancreatic cancer stem cells has been defined as CD24(+)CD44(+)CD326 (ESA)(+). CD133 antigen has been also suggested as a potential marker for cancer stem cell in gastrointestinal tract but recently there is also debate in this regard. More recently, other cancer stem cells in gastrointestinal tract, such as colon cancer stem cells, liver cancer stem cells, have been also characterized in their phenotype. These advances clearly will bring the new strategy in cancer treatment and control in the gastrointestinal tract. In this review, the author will discuss the current status and progress about cancer stem cell research in gastrointestinal tract and liver.     

Mathematical model for the cancer stem cell hypothesis

Recent research on the origin of brain cancer has implicated a subpopulation of self-renewing brain cancer stem cells for malignant tumour growth. Various genes that regulate self-renewal in normal stem cells are also found in cancer stem cells. This implies that cancers can occur because of mutations in normal stem cells and early progenitor cells. A predictive mathematical model based on the cell compartment method is presented here to pose and validate non-intuitive scenarios proposed through the neural cancer stem cell hypothesis. The growths of abnormal (stem and early progenitor) cells from their normal counterparts are ascribed with separate mutation probabilities. Stem cell mutations are found to be more significant for the development of cancer than a similar mutation in the early progenitor cells. The model also predicts that, as previously hypothesized, repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.     

Chemotherapy not only enriches but also induces cancer stem cells

Cancer stem cells are regarded as the hurdle of cancer therapy at least partially due to their intrinsic resistance to therapy. To this end, chemotherapy is widely used for enrichment of cancer stem cells. In contrast to the dogma, we hypothesized that besides enrichment, cancer stem cells could also be induced by chemotherapy in those regions without sufficient drug delivery. Due to the imbalance of the angiogenesis and insufficient blood supply in certain regions of the tumor mass, chemotherapy delivery is compromised in these regions. The insufficient drug delivery in turn transforms the bulk cancer cells to stem cells rather than kill them through NFkappaB-HIF, NFkappaB-Wnt and other signals. Detection of the induction of cancer stem cells from the chemotherapy treated non-stem cancer cells would shed light on our hypothesis, which in turn would broad our understanding of clinical cancer chemotherapy.     

Stem cells and brain cancer

An increasing body of research is showing that cancers might contain their own stem cells. In fact, cancer cells, like stem cells, can proliferate indefinitely through a deregulated cellular self-renewal capacity. This raises the possibility that some features of tumor cells may be due to cancer stem cells. Stem cell-like cancer cells were isolated from several solid tumors. Now, evidence has shown that brain cancers, such as glioblastomas, medulloblastomas and astrocytomas, also contain cells that may be multipotent neural stem cell-like cells. In this review, we discuss the results of these studies, along with the molecular pathways that could be involved in cancer stem cell physiopathology.     

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases (DNMT) 1, DNMT3A and DNMT3B via 5-Azacytidine (Aza) and 5-Aza-2’-deoxycytidine (Aza-dC) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza-dC, and of their apoptotic- and differentiation-inducing effects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their “malignant memory”.     

转录因子SOX2 对胃癌干细胞自我更新、增殖和迁移的影响

目的:检测SOX2在胃癌组织中的表达,探讨SOX2对胃癌干细胞自我更新、增殖和转移能力的影响。方法:采用免疫组化检测SOX2在胃癌及癌旁组织中的表达情况。通过肿瘤球形成实验富集、分离胃癌干细胞。构建SOX2过表达慢病毒并感染胃癌干细胞中,通过实时定量PCR和western bolt检测感染慢病毒后胃癌干细胞中SOX2表达情况。分别利用肿瘤球形成实验检测SOX2对胃癌肿瘤干细胞自我更新能力的影响,CCK-8实验检测SOX2对胃癌干细胞增殖能力的影响,流式细胞术分析SOX2对胃癌干细胞的细胞周期的影响,Transwell实验检测SOX2对胃癌干细胞转移能力的影响。结果:SOX2在胃癌组织中表达显著低于癌旁组织。肿瘤球形成实验能够有效富集胃癌细胞SGC-7901和BGC-823的干细胞。慢病毒载体感染能够显著增强SOX2在胃癌干细胞中的表达。过表达SOX2能够抑制胃癌干细胞的自我更新、增殖和侵袭能力。结论:SOX2在胃癌中发挥抑癌基因的功能,其机制可能通过抑制肿瘤干细胞的自我更新、增殖和侵袭转移能力而抑制胃癌的发生发展。     

Therapeutic implications of cancer stem cells

Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. In addition, dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. This new model for cancer will have significant ramifications for the way we study and treat cancer. In addition, through targeting the cancer stem cell and its dysregulated self-renewal, our therapies for treating cancer are likely to improve.     

Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D₃, are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.