胶质瘤干细胞及相关的信号转导通路

胶质瘤干细胞(glioma stem cells,GSC)是近年来在胶质瘤组织中发现的肿瘤干细胞。GSC具有自我更新和分化的能力,可以通过不断分化产生新的肿瘤;对GSC标志物的鉴定有助于胶质瘤恶性程度的诊断。GSC的起源目前仍不明确,成熟的神经胶质细胞、限制性神经祖细胞以及神经干细胞均可能为GSC的前体。推测如Wnt、Notch、SHH、BMI1、PTEN等信号通路活跃在GSC中,一些新的治疗手段通过作用于GSC的信号转导通路可靶向治疗胶质瘤。深入研究GSC的起源、标志物以及相关信号转导通路,可为胶质瘤治疗提供新的策略。     

肿瘤干细胞与滑膜肉瘤相关研究进展

20世纪50年代Makino等[1]通过肿瘤细胞自体移植实验发现肿瘤组织中极少数细胞具有干细胞特性能诱发新的肿瘤组织,首次提出肿瘤干细胞（cancerstem cells,CSCs）理论.该理论认为,肿瘤干细胞作为一类特殊的干细胞,具有自我更新能力和分化潜能,以及高致瘤性和耐药性的特点,可以通过分化为肿瘤细胞而产生肿瘤,即认为肿瘤干细胞是肿瘤启动、增殖生长、转移复发的根源.     

肿瘤干细胞与肿瘤的诊断、转归和预后的关系

肿瘤干细胞(cancer stem cells,CSCs)是近年来干细胞研究和肿瘤研究的热点之一,它具有强大的自我更新和致瘤能力以及不断分化的潜能。目前研究发现肿瘤治疗后易复发、预后差、具有强耐药性与肿瘤中存在肿瘤干细胞有密切的关系。且肿瘤干细胞学说认为,肿瘤很可能是肿瘤干细胞产生的,并且已有学者和专家在造血系统肿瘤和多种实体瘤中分离并鉴定出肿瘤干细胞。对肿瘤干细胞、肿瘤干细胞与肿瘤的发生、发展、诊断、治疗及预后之间的关系作一综述。     

肿瘤干细胞与肿瘤的诊断、转归和预后的关系

肿瘤干细胞（cancerstemcells,CSCs）是近年来干细胞研究和肿瘤研究的热点之一,它具有强大的自我更新和致瘤能力以及不断分化的潜能。目前研究发现肿瘤治疗后易复发、预后差、具有强耐药性与肿瘤中存在肿瘤干细胞有密切的关系。且肿瘤干细胞学说认为,肿瘤很可能是肿瘤干细胞产生的,并且已有学者和专家在造血系统肿瘤和多种实体瘤中分离并鉴定出肿瘤干细胞。对肿瘤干细胞、肿瘤干细胞与肿瘤的发生、发展、诊断、治疗及预后之间的关系作一综述。     

肿瘤干细胞的研究进展

肿瘤干细胞是存在于肿瘤中的一小部分具有干细胞性质的细胞群,具有高度的致瘤性和耐药性。同正常干细胞一样,肿瘤干细胞具有无限的自我更新和多向分化的潜能,使肿瘤在体内不断扩大或形成新的肿瘤,导致肿瘤复发和转移。肿瘤干细胞的研究有助于认识和理解肿瘤发生发展的机制,指导肿瘤的临床治疗。     

肿瘤干细胞的研究进展

肿瘤干细胞是存在于肿瘤中的一小部分具有干细胞性质的细胞群,具有高度的致瘤性和耐药性。同正常干细胞一样,肿瘤干细胞具有无限的自我更新和多向分化的潜能,使肿瘤在体内不断扩大或形成新的肿瘤,导致肿瘤复发和转移。肿瘤干细胞的研究有助于认识和理解肿瘤发生发展的机制,指导肿瘤的临床治疗。     

肿瘤干细胞与microRNA的研究进展

肿瘤干细胞是肿瘤的起源性细胞, 具有高度的致瘤性和耐药性。微小RNA(microRNA或miRNA)是由21~25个核苷酸组成的内源性非编码单链RNA, 是基因表达调控因子, 参与许多生物功能的调节。最近的研究发现, microRNA参与肿瘤干细胞的分化、自我更新等生物学特性的调控。肿瘤干细胞和microRNAs可以作为肿瘤研究的一个新的切入点。本文就近年来的研究进展做简要综述。      

乙醛脱氢酶在肿瘤干细胞鉴定中的作用

摘 要：肿瘤干细胞被认为是肿瘤复发和转移的根源,其鉴定尤为重要。当前肿瘤干细胞鉴定的主要方法有利用干细胞表面标志鉴定、细胞增殖和分化能力的鉴定、动物体内致瘤性鉴定、化疗耐药性的鉴定、放疗抵抗性的鉴定等。乙醛脱氢酶是细胞质中调节乙醛代谢的一种重要酶类,其在肿瘤干细胞中显示出很高的活性,可作为肿瘤干细胞鉴定的标志物。研究乙醛脱氢酶在肿瘤干细胞鉴定中的作用将有利于肿瘤的诊断、治疗和预后评估。     

口腔颌面部恶性肿瘤干细胞标志物用于靶向治疗的研究进展

口腔颌面部恶性肿瘤包括口腔鳞状细胞癌(OSCC)、唾液腺恶性肿瘤、颌面部皮肤癌以及骨肉瘤等在内的一系列恶性肿瘤,预后一般较差。近年来,一些研究发现口腔癌及其他恶性肿瘤中仅有一小部分肿瘤细胞有致瘤性,绝大多数肿瘤细胞没有或仅有有限的增殖能力,小部分肿瘤细胞具有与干细胞相似的自我更新、增殖、分化等干性特征,并将具有致瘤性和类似干细胞特性的这类肿瘤细胞称为肿瘤干细胞(CSC)。其可能与口腔癌的发生、转移和复发等有着密切联系,并产生放化疗抗性,导致预后不良。基于上述研究,新的理念认为针对CSC的肿瘤治疗有助于提高肿瘤根治的可能性。本文将对口腔癌CSC相关标志物及其可能的相应靶向治疗的研究进展进行综述。     

乳腺癌肿瘤标志物新的研究进展

目前乳腺癌已成为危害女性健康的第一大恶性肿瘤, 且发病率呈逐年递增趋势, 其早期诊断、治疗及预后成为当下研究的热点。乳腺癌肿瘤标志物对于其早期诊断、个体化治疗及预后均具有重要的临床实践指导意义。分子生物学的不断发展, 为乳腺癌肿瘤标志物的基础与临床研究奠定了良好的基础。近年来, 乳腺癌的诊断治疗手段逐渐增多, 肿瘤标志物的应用也不断受到青睐, 经典的肿瘤标志物已不足以更好的指导临床实践, 因此不断有新的肿瘤标志物出现。为了解乳腺肿瘤标志物在乳腺癌诊治中的重要作用及其相关最新研究, 本文结合国内外最新研究报道, 对乳腺肿瘤标志物新的研究进展做一简要综述。      

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.     

靶向肿瘤干细胞治疗肿瘤

具有独特的分子表达、表面标志物、干性相关信号通路和代谢模式等方面特征的肿瘤干细胞（cancer stem cell, CSC） 因其具有高致瘤、高转移、高治疗抵抗能力,可能是多种类型恶性肿瘤生长、转移、治疗抵抗的关键因素,也是肿瘤发生和复发的 重要根源。正常干细胞在产生了第一个致癌突变之后将逐步发展成为癌前干细胞和CSC,随后在突变和微环境的共同作用下进 一步积累突变增加异质性,并与CSC可塑性转变交织在一起推动肿瘤的发生和进展,促进肿瘤的复发、转移及治疗抵抗。为了更 好地治疗肿瘤,现已研发了多种类型的靶向CSC的治疗策略,包括靶向CSC的细胞表面标志物、信号转导途径、微环境、代谢模式 等,以及促CSC分化、靶向CSC的免疫治疗等其他策略。多个靶向CSC治疗肿瘤的新药在临床试验中已经展现出良好的治疗效 果,然而,也有一些抗肿瘤新药的失败为未来研发提供了值得注意的教训。未来肿瘤治疗中,特异地靶向患者肿瘤中所有异质性 的CSC,并同时清除癌前干细胞和子代肿瘤细胞,将会更好地抑制肿瘤生长、转移和复发,从而为治愈肿瘤带来新的希望。     

Cancer stem cell niche: the place to be

Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies.     

4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance,proliferation and metastasis

Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors.     

Nanomedicine strategies for sustained,controlled, and targeted treatment of cancer stem cells of the digestive system

Cancer stem cells (CSCs) constitute a small proportion of the cancer cells that have self-renewal capacity and tumor-initiating ability. They have been identified in a variety of tumors, including tumors of the digestive system. CSCs exhibit some unique characteristics, which are responsible for cancer metastasis and recurrence. Consequently, the development of effective therapeutic strategies against CSCs plays a key role in increasing the efficacy of cancer therapy. Several potential approaches to target CSCs of the digestive system have been explored, including targeting CSC surface markers and signaling pathways, inducing the differentiation of CSCs, altering the tumor microenvironment or niche, and inhibiting ATP-driven efflux transporters. However, conventional therapies may not successfully eradicate CSCs owing to various problems, including poor solubility, stability, rapid clearance, poor cellular uptake, and unacceptable cytotoxicity. Nanomedicine strategies, which include drug, gene, targeted, and combinational delivery, could solve these problems and significantly improve the therapeutic index. This review briefly summarizes the ongoing development of strategies and nanomedicine-based therapies against CSCs of the digestive system.     

胃癌干细胞研究进展

肿瘤干细胞(CSC)是一群具有自我更新能力和多向分化潜能的肿瘤细胞,许多研究已证实在多种实体瘤中存在CSC.虽然CSC在肿瘤细胞总数中只占很小比例,但在肿瘤的起源、发展、转移及复发等方面均有重要的作用.胃癌CSC的研究尚处于探索阶段,仍未发现胃癌CSC特异性标记物,但对其存在和来源均开展了一系列的研究.     

Molecular identification and targeting of colorectal cancer stem cells

Tumor initiating or cancer stem cells (CSCs) are suggested to be responsible for tumor initiation and growth. Moreover, therapy resistance and minimal residual disease are thought to result from selective resistance of CSCs. Isolation of CSCs from colon carcinomas can be accomplished by selection of a subpopulation of tumor cells based on expression of one or multiple cell surface markers associated with cancer stemness, like CD133, CD44, CD24, CD29, CD166 and Lgr5. Identification of colon CSCs will lead to a better rational for new therapies that aim to target this fraction specifically. In this review, we analyze known markers used for selection of colon CSCs and their potential function in CSC biology. Moreover, we discuss potential targeting strategies for eradicating CSCs specifically in order to develop more effective therapeutic strategies as well as to address more fundamental questions like the actual role of CSCs in tumor growth.     

Ovarian cancer stem cells: Working towards the root of stemness

Despite medical advances made over the past decade, ovarian cancer remains one of the more lethal gynecologic cancers in the United States. While current therapeutic strategies are relatively effective, there is a high incidence of recurrent chemoresistant disease. This has been attributed, in part, to a regenerative tumor cell sub-population that has acquired stem cell properties which allows these cells to escape standard chemotherapeutics and drive recurrent disease. To date, a number of laboratories have identified these cancer stem cell (CSC) sub-populations in ovarian cancer cell lines, tumors or ascites and the collective findings suggest ovarian CSCs are likely to be as heterogeneous as the disease itself. Moreover, the multiple ovarian histophenotypes and possible sites of disease origin together with the potential for differential hierarchal contributions of multiple CSCs populations represent significant challenges to the identification, functional characterization and therapeutic targeting of ovarian CSC. This review will highlight the markers and methodology currently used to identify and isolate these cells. We will discuss some of the underlying ovarian CSC biology, the signaling pathways implicated in their survival, replication and differentiation and potential therapeutic targeting strategies.     

Urothelial carcinoma: Stem cells on the edge

Tumors are heterogeneous collections of cells with highly variable abilities to survive, grow, and metastasize. This variability likely stems from epigenetic and genetic influences, either stochastic or hardwired by cell type-specific lineage programs. That differentiation underlies tumor cell heterogeneity was elegantly demonstrated in hematopoietic tumors, in which rare primitive cells (cancer stem cells (CSCs)) resembling normal hematopoietic stem cells are ultimately responsible for tumor growth and viability. Because of the compelling clinical implications CSCs pose—across the entire spectrum of cancers—investigators applied the CSC model to cancers arising in tissues with crudely understood differentiation programs. Instead of relying on differentiation, these studies used empirically selected markers and statistical arguments to identify CSCs. The empirical approach has stimulated important questions about “stemness” in cancer cells as well as the validity and stoichiometry of CSC assays. The recent identification of urothelial differentiation programs in urothelial carcinomas (UroCas) supports the idea that solid epithelial cancers (carcinomas) develop and differentiate analogously to normal epithelia and provides new insights about the spatial localization and molecular makeup of carcinoma CSCs. Importantly, CSCs from invasive UroCas (UroCSCs) appear well situated to exchange important signals with adjacent stroma, to escape immune surveillance, and to survive cytotoxic therapy. These signals have potential roles in treatment resistance and many participate in druggable cellular pathways. In this review, we discuss the implications of these findings in understanding CSCs and in better understanding how UroCas form, progress, and should be treated.     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs - allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.