Wnt信号通路与肿瘤干细胞耐药

肿瘤细胞对化疗药物产生交叉耐药性,是造成肿瘤患者化疗失败的主要原因之一。肿瘤细胞具有异质性,即在同一肿瘤细胞中存在不同基因型或亚型的细胞。在化疗过程中,药物杀死对药物敏感的肿瘤细胞,而有一部分肿瘤细胞则表现出较强的耐药性,不能被化疗药物杀伤。肿瘤干细胞(Cancer stem cells,CSCs)的发现,为肿瘤耐药现象的研究提供了新的思路。CSCs是指肿瘤中具有自我更新能力并能产生异质性肿瘤细胞的细胞,其具有自我更新,多向分化,DNA修复以及耐药等特征。Wnt信号通路是调控肿瘤干细胞自我更新和分化的关键信号途径,该通路的激活在多种肿瘤的发生、发展和耐药过程中发挥重要作用。对Wnt信号通路的研究有助于揭示肿瘤干细胞耐药的机制,并有望成为治疗恶性肿瘤的一个新靶点。该综述重点阐述了Wnt信号通路在肿瘤干细胞介导的耐药过程中的研究进展。     

消化系常见肿瘤miRNA与细胞凋亡调控

微小 RNA(microRNA,miRNA)是一类在转录后水平调节基因表达的长20～24nt的非编码RNA,具有调节细胞凋亡和增殖等作用,参与调控多种生理和病理过程,其与肿瘤的关系备受关注,近年来越来越多的研究表明miRNA表达异常与消化系常见肿瘤(结肠癌、直肠癌和肝癌)的发生、发展、预后和治疗等密切相关。本文拟阐述miRNA与消化系常见肿瘤细胞凋亡的相关性,探讨miRNA诱导消化系常见肿瘤细胞凋亡的通路和调控环路,旨在揭示miRNA可否作为消化系常见肿瘤早期诊断及预后的生物标志物和治疗的新靶点。     

宫颈癌干细胞相关研究进展

宫颈癌是威胁全球女性健康的主要恶性肿瘤之一.近年,随着宫颈癌筛查的开展、早期诊断及不断改良的治疗方案,早期宫颈癌死亡率呈下降趋势,但宫颈癌的复发与转移,对放化疗敏感度不高,严重影响了患者的预后.肿瘤干细胞(CSCs)是肿瘤中一小部分具有肿瘤起源、自我更新能力及异质性的细胞.肿瘤干细胞的这些特性认为与肿瘤的维持生长、复发及远处转移有关,并且对于常规的放化疗普遍耐受.目前的研究不仅证实了肿瘤干细胞的存在,并且探索其异于正常细胞的机制,发现了肿瘤干细胞相关标志物.而新兴的肿瘤干细胞靶向免疫治疗对于宫颈癌治疗来说既是机遇也是挑战.本文就宫颈癌干细胞相关研究进展及肿瘤干细胞免疫治疗进行系统分析及综述.     

肿瘤干细胞的来源、标志物以及在毒理学研究中的应用

肿瘤干细胞(CSCs)是一类具有自我更新能力并且可以产生异质性肿瘤的细胞,是目前肿瘤研究的热点,在肿瘤的发生、发展和转移的机制探讨,肿瘤的评估、早期诊断和预后以及抗肿瘤药物的筛选方面展现了良好的应用前景。本文综述了CSCs来源的几种形式,归纳了常见恶性肿瘤中的标志物,概括了CSCs在毒理学研究中的应用,最后展望了CSCs研究的发展方向。     

头颈部癌中BMI1表达与肿瘤干细胞的研究进展

头颈部癌中晚期患者治疗仍不尽如意,其主要死亡原因是肿瘤的复发和转移。肿瘤干细胞(CSCs)能够维持肿瘤的转移、复发、抵抗放化疗。BMI1重要的功能即CSCs的生物标志物,所以对于这一标志物的研究使我们更好理解CSCs在头颈部癌的作用机制。     

肿瘤干细胞理论及肿瘤干细胞分离和鉴定研究进展

肿瘤是当今社会对人类健康和生命危害最大的疾病之一,即使在人类医学科技迅速发展的今天,对于肿瘤的治疗仍是一大难题,其根本原因是对肿瘤的发生、发展、转移和复发的机制尚不清楚。近些年来,研究人员通过对肿瘤细胞表面标志物、增殖能力和致瘤能力等的深入研究,提出了肿瘤干细胞理论,即肿瘤中存在着少数具有无限自我更新能力和异种免疫缺陷动物致瘤能力的干细胞样肿瘤细胞,它们在肿瘤的发生、生长和转移等生物学过程中起着决定性的作用,该理论的提出给肿瘤治疗提供了新的思路和策略。本文将对肿瘤干细胞理论的形成和发展过程,肿瘤干细胞的特性以及肿瘤干细胞的分离和鉴定最新研究进展进行综述。     

肿瘤干细胞与microRNA的关系

肿瘤干细胞是肿瘤组织中具有自我更新和多项分化潜能,可形成新的肿瘤细胞,具有放化疗抵抗性。MircoRNA是一类长约21~25个核苷酸组成的内源性非编码单链RNA分子。在细胞中起到转录后调控作用。研究表明MircoRNA同样参与肿瘤干细胞的自我更新过程,其与肿瘤干细胞的关系,成为肿瘤干细胞研究的一个重要方面。     

卵巢癌肿瘤干细胞标记物研究的新进展

卵巢癌是女性生殖系统一种常见的恶性肿瘤,一般在治疗的初始阶段患者能够获得较好的疗效,但在治疗后期,部分患者会复发,这与卵巢癌干细胞之间有着密切的联系。肿瘤干细胞在肿瘤组织中数量稀少,对常规化疗耐药,能够形成新的肿瘤细胞,是导致肿瘤复发的根源之一。近年来,人们针对卵巢癌干细胞的鉴定与分离开展了大量的研究,分析了该类细胞特征性的标志物。目前已被证实的卵巢癌干细胞标志物主要有CD133、乙醛脱氢酶、CD44、CD117、CD24等。本文旨在对这些卵巢癌干细胞的标志物的相关研究及其在卵巢癌的诊断与治疗中的作用进行综述。     

成球培养法富集胰腺癌肿瘤干细胞的研究

目的 研究成球培养法培养胰腺癌肿瘤干细胞的可行性。方法 通过细胞成球培养体系富集胰腺癌肿瘤干细胞并进行培养,流式细胞术检测分析干细胞的表型特征。结果 光镜下,成球培养细胞形态发生明显变化,细胞由贴壁时的多边形变成圆形,并形成肿瘤细胞微球。流式细胞仪检测发现,与普通细胞培养相比,成球培养体系富集的胰腺癌肿瘤干细胞干性相关基因CD24、CD44共表达水平明显升高。结论 利用成球培养法能够富集得到CD24、CD44高表达的胰腺癌肿瘤干细胞。     

miRNA在肝细胞癌患者预后中的应用

越来越多的证据证实miRNA（microRNA）通过上调癌基因或抑制抑癌基因的表达,参与肿瘤的发生、侵袭转移、血管形成和凋亡的过程,从而影响肿瘤患者的预后。肝细胞癌（HCC）是常见且侵袭性较强的恶性肿瘤之一,起病隐匿,发展迅速,恶性程度高,预后极差。究其关键原因是缺乏预测预后的高敏感度及高特异度的分子标志物。而目前研究发现,单个或联合多个miRNA在HCC中的异常表达可预测患者的预后。     

Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells

Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.     

Cancer stem cell-targeted therapeutics and delivery strategies

Introduction: Cancer initiating or stem cells (CSCs) are a small population of cells in the tumor mass, which have been reported to be present in different types of cancers. CSCs usually reside within the tumor and are responsible for reoccurrence of cancer. The imprecise, inaccessible nature and increased efflux of conventional therapeutic drugs make these cells resistant to drugs. We discuss the specific markers for identification of these cells, role of CSCs in chemotherapy resistance and use of different therapeutic means to target them, including elucidation of specific cell markers, exploitation of different signaling pathways and use of nanotechnology.

Area covered: This review covers cancer stem cell signaling which are used by these cells to maintain their quiescence, stemness and resistant phenotype, distinct cell surface markers, contribution of these cells in drug resistance, inevitability to cure cancer and use of nanotechnology to overcome this hurdle.

Expert opinion: Cancer stem cells are the main culprit of our failure to cure cancer. In order to cure cancer along with other cells types in cancer, cancer stem cells need to be targeted in the tumor bed. Nanotechnology solutions can facilitate clinical translation of the therapeutics along with other emerging technologies to cure cancer.     

Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice

It is now believed that cancer stem cells (CSCs) that are resistant to chemotherapy due to their undifferentiated nature drive tumor growth, metastasis and relapse, so development of drugs that induce differentiation of CSCs should have a profound impact on cancer eradication. In this study, we screened medicines that are already in clinical use for drugs that induce differentiation of CSCs. We used MDA-MB-231, a human breast cancer cell line that contains cancer stem cell-like cells. We found that acetaminophen, an anti-inflammatory, antipyretic and analgesic drug, induces differentiation of MDA-MB-231 cells. Differentiation was assessed by observing alterations in cell shape and expression of differentiated and undifferentiated cell markers, a decrease in cell invasion activity and an increase in susceptibility to anti-tumor drugs. This increased susceptibility seems to involve suppression of expression of multidrug efflux pumps. We also suggest that this induction of differentiation is mediated by inhibition of a Wnt/β-catenin canonical signaling pathway. Treatment of MDA-MB-231 cells with acetaminophen in vitro resulted in the loss of their tumorigenic ability in nude mice. Furthermore, administration of acetaminophen inhibited the growth of tumor xenografts of MDA-MB-231 cells in both the presence and absence of simultaneous administration of doxorubicine, a typical anti-tumor drug for breast cancer. Analysis with various acetaminophen derivatives revealed that o-acetamidophenol has a similar differentiation-inducing activity and a similar inhibitory effect on tumor xenograft growth. These results suggest that acetaminophen may be beneficial for breast cancer chemotherapy by inducing the differentiation of CSCs.     

肿瘤干细胞的生物学特性及临床意义的研究进展

研究表明肿瘤干细胞（cancer stem cells,CSC）起源于正常干细胞（stem cells,SC）的基因突变,SC的DNA受到损伤或处于与肿瘤相关的微环境是其发生基因突变,进而转化为CSC的主要原因。CSC可与肿瘤细胞相互转化,且与肿瘤细胞相比,其增殖和转移的速度更快,恶性程度更高,对化疗和放疗的耐受性更强。不同肿瘤的CSC生物学标记并不完全相同,即使是同一类肿瘤,因细胞系不同,生物学标记也有差异。CSC的生物学标记物也可以用于CSC的诊断、肿瘤的预后判断和治疗。因此,探索CSC的生物学标记和调控因子,并将其作为肿瘤的治疗靶标,开发相关的药物,将是未来CSC和肿瘤研究的重点。本文主要对肿瘤干细胞的起源、生物学特性及其临床意义进行了综述。     

Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer

Introduction: Epithelial-to-mesenchymal transition (EMT) is a pathological phenomenon of cancer that confers tumor cells with increased cell motility, invasive and metastatic abilities with the acquisition of ‘cancer stem-like cell’ (CSC) phenotype. EMT endows tumor cells with intrinsic/acquired resistant phenotype at achievable doses of anticancer drugs and leads to tumor recurrence and progression. Besides the complex network of signaling pathways, microRNAs (miRNAs) are being evolved as a new player in the induction and regulation of EMT.

Areas covered: In this review article, the author has searched the PubMed and Google Scholar electronic databases for original research and review articles to gather current information on the association of EMT-induced CSCs with therapeutic resistance, tumor growth and metastasis, which are believed to be regulated by certain miRNAs.

Expert opinion: This review outlines not only the perspective on selective targeting of EMT-induced CSCs through altered expression of novel miRNAs and/or the use of conventional drugs that affect the levels of critical miRNAs but also the strategies on overcoming the drug resistance by interfering with EMT and modulating its associated pathways in CSCs that can be considered as potential therapeutic approaches toward eradicating the tumor recurrence and metastasis.     

Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway

Cancer stem cells (CSCs) are considered as the initiators of the carcinogenic process and are therefore emerging targets for innovative anticancer therapies. In order to evaluate the anticancer chemopreventive activity of flavagline derivatives, we used the pluripotent teratocarcinomal cell as a model of Oct4-expressing cancer stem-like cell and determined the underlying cellular and molecular mechanisms induced by a synthetic flavagline. We precisely investigated the effects of the flavagline derivative FL3 on the human embryonal carcinoma (EC) cell line NT2/D1 and compared the responses to those of a normal more restrictive pluripotent stem cell line (i.e. BJ fibroblast cell line). FL3 selectively inhibited the proliferation of NT2/D1 cells by inducing G₁ phase cell cycle arrest in a dose-dependent manner. Moreover, FL3 treatment specifically triggered apoptosis in association with an induction of the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and caspase-3 activation followed by a drastic downregulation of the master regulator of stemness Oct4. Forced inhibition of p38 MAPK activity by the specific pharmacological inhibitor SB203580 or by p38 MAPK gene knockdown using small-interfering RNA (siRNA) counteracted the effects of FL3, demonstrating that its chemopreventive action is related to growth inhibition and a p38-dependent caspase-3-dependent induction of apoptosis in Oct4-expressing CSCs. This study also shows that FL3 selectively kills poorly differentiated and highly aggressive carcinomal cells, but has little effect on normal stem-like cells. Thus FL3 offers great promise for cancer treatment since it is able to target the carcinogenic process without affecting normal cells.     

Role of microRNAs in maintaining cancer stem cells

Increasing evidence sustains that the establishment and maintenance of many, if not all, human cancers are due to cancer stem cells (CSCs), tumor cells with stem cell properties, such as the capacity to self-renew or generate progenitor and differentiated cells. CSCs seem to play a major role in tumor metastasis and drug resistance, but albeit the potential clinical importance, their regulation at the molecular level is not clear. Recent studies have highlighted several miRNAs to be differentially expressed in normal and cancer stem cells and established their role in targeting genes and pathways supporting cancer stemness properties. This review focuses on the last advances on the role of microRNAs in the regulation of stem cell properties and cancer stem cells in different tumors.     

CD133 as a target for colon cancer

INTRODUCTION: Recent evidence based on cancer stem cell (CSC) models, is boosting the progress of translational research and providing relevant clinical implications in many tumour types, including colorectal cancer. The current failure of standard therapies is attributed to a small fraction of the primary cell population with stem-like characteristics, such as self-renewal and differentiation. Identification of CSCs is based on two different criteria of selection: stemness-selective conditions and direct isolation based on putative stem cell markers expression. CD133, a transmembrane glycoprotein, was associated with tumor-initiating cells derived from several histological variants of tumors, including colon. AREAS COVERED: In this review the current understandings about CD133 as putative marker of tumour-initiating cells in colorectal cancer (CRC) is described. The focus of the discussion is on the need for additional markers to better identify the cell population able to recapitulate the parental tumor in immunocompromised mice. EXPERT OPINION: Identification and characterization of CSCs represents a relevant issue to define innovative therapeutic approaches, overcoming the emergence of cancer cell clones capable of evading standard therapy.