上皮间质转化与肿瘤干细胞在化疗耐药中作用的研究进展

肿瘤的复发、转移以及获得性耐药的高度关联是导致90%以上肿瘤患者治疗失败的最主要原因。化疗是治疗恶性肿瘤最有效且应用广泛的治疗手段,但化疗耐药性的产生是影响肿瘤的临床疗效的主要障碍。肿瘤干细胞(cancer stem cells,CSCs)是肿瘤的起源,与肿瘤的复发、侵袭和转移密切相关,而且具有多药耐药(对目前绝大多数化疗药物不敏感),抵抗放化疗和长期静寂的特点,是导致获得性耐药的重要原因。上皮间质转化(epithelial-mesenchymal transition,EMT)是上皮细胞向间充质细胞分化的过程,可使肿瘤细胞具有干细胞的特征,从而促进CSCs的产生,在肿瘤的侵袭转移发挥着重要的作用。本文旨在综述CSCs和EMT在化疗耐药发生中的作用的研究进展,以期为肿瘤的临床治疗提供指导。     

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。     

肿瘤干细胞的研究进展

肿瘤干细胞（cancerstemcells,CSCs）是肿瘤组织中具有无限增殖潜能的极少量干细胞样癌细胞亚群,肿瘤的复发、抗辐射、转移以及耐药等特征都可能与肿瘤干细胞有关,肿瘤治疗的关键应是针对CSCs,以其为治疗靶点,即针对干细胞的治疗既要杀灭肿瘤干细胞又要保护正常干细胞。     

肿瘤干细胞miRNA及miRNA作为肿瘤标志物的研究和临床应用进展

肿瘤干细胞(CSCs)理论为肿瘤的研究开辟了一个新的方向,CSCs学说认为肿瘤细胞具有异质性,肿瘤中存在干细胞样细胞,该群细胞是一种增殖失控、可形成肿瘤的细胞,只占肿瘤细胞很少部分,具有干细胞特性,是形成不同分化程度肿瘤细胞和肿瘤增长、复发及转移的根源。微小核糖核酸(miRNA)是广泛存在的非编码小RNA,调节着人类1/3的基因,越来越多的证据显示miRNA在肿瘤的发生发展中起着重要的作用,作为重要的转录后调控因子,广泛参与肿瘤相关基因调控的生物程序,使不同类型的肿瘤表现出特异的miRNA表达谱。近年来,CSCs的miRNA研究日益成为热点,已经发现多种CSCs中存在特异性表达的miRNA,对CSCs的生物学行为有了更进一步的认识。有研究发现肿瘤患者血浆中表达某些特异的miRNA,这些miRNA可以作为肿瘤的标志物对患者的病情及预后进行预测和判断。本文就近来CSCs中miRNA研究进展及miRNA作为肿瘤标志物研究进展进行综述。     

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。     

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。     

肿瘤分子靶向药物耐药性研究进展

目的：综述肿瘤分子靶向药物的作用靶点、耐药机制和逆转措施。方法：应用Pubmed和CNKI期刊全文数据库检索系统,以“肿瘤”、“耐药性”、“靶向药物”和“逆转耐药”为关键词进行检索。纳入标准：①靶向药物的分子靶点;②靶向耐药的机制;③逆转靶向药物的耐药性,共筛选出相关文献32篇。结果：靶向药物的分子靶点以细胞膜受体和细胞内激酶为主,其耐药机制主要包括细胞信号转导、基因突变、肿瘤干细胞、肿瘤微环境、肿瘤细胞代谢和上皮-间质转化等。个体化用药、联合用药、改善肿瘤微环境以及研发新药等措施有望逆转靶向耐药。结论：靶向药物的分子靶点多样,耐药机制复杂,应该积极采取措施加以预防和逆转。     

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.     

肿瘤干细胞靶向治疗

多种肿瘤中都存在肿瘤干细胞(cancer stem cell,CSC),这部分细胞具有自我更新能力和分化潜能,是肿瘤生长、增殖和转移的根源。此外,肿瘤干细胞具有正常干细胞的自我保护特性,如有效的DNA修复、高表达多药耐药型膜转运蛋白以及处于相对静止状态及拥有特定的微环境,使其能够逃逸现有的肿瘤治疗手段,导致肿瘤复发。针对这些保护机制,并利用肿瘤干细胞与正常干细胞的之间的差异进行靶向治疗,可能达到根治肿瘤的疗效。     

白血病多药耐药研究进展

近年来肿瘤药物治疗效果多不理想,主要是由于肿瘤细胞发生了多药耐药.即肿瘤细胞接触一种化疗药物并产生耐药性,同时对其他多种结构和作用机制不同的化疗药物亦产生耐药性.目前,这方面的研究已经成为了肿瘤研究领域的热点.已知的多药耐药机制包括P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)、肺相关蛋白(LRP)的增多、乳腺癌耐药蛋白;拓扑异构酶II(Topo-II)活力降低;谷胱甘肽-S-转移酶以及还原型谷胱甘肽(GST)升高;肿瘤某些生化特征的改变:膜离子通道、蛋白激酶(PKC).     

F-box proteins in cancer stemness: An emerging prognostic and therapeutic target

Cancer is a complex heterogenic disease with significant therapeutic challenges. The presence of cancer stem cells (CSCs) in cancer tissue orchestrates tumor growth, progression, and metastasis, the tumor heterogeneity, disease relapse, and therapeutic resistance. Hence, it is imperative to explore how progenitor or cancer-initiating cells acquire stemness features and reprogram different biological mechanisms to maintain their sustained oncogenicity. Interestingly, deregulation of F-box proteins (FBPs) is crucial for cancer stemness features, including drug resistance and disease relapse. In this review, we highlight recent updates on the clinical significance of targeting FBPs in cancer therapy, with emphasis on eliminating CSCs and associated therapeutic challenges. Moreover, we also discuss novel strategies for the selective elimination of CSCs by targeting FBPs.     

Targeting cancer stem cells

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell–niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.     

Targeting cancer stem cells

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell-niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.     

Recent trends in cancer drug resistance reversal strategies using nanoparticles

INTRODUCTION: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc. AREAS COVERED: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors. EXPERT OPINION: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.     

Functionalised nanomaterials for eradication of CSCs,a promising approach for overcoming tumour heterogeneity

Today, intratumoural heterogeneity has been recognised as one of the main causes of cancer treatment failure and drug resistance development through which multiple mechanisms are simultaneously involved. From the broad diversity of cells presented in tumour microenvironment, owing to their proliferative potential and longevity, cancer stem cells (CSCs), are the main cell subpopulation involved in tumour development, propagation, metastatic dissemination and induction of intratumoural heterogeneity. Accordingly, selective targeting and eradication of CSCs may represent a promising approach for cancer therapy and evading drug resistance development. Nanotechnology is an attractive outgrowing field in medicine due to its promising capabilities in solving several obstacles associated with conventional chemotherapy agents including poor solubility, lack of selectivity and high systemic toxicity. Accordingly, multiple types of nanocarriers have been successfully developed for improving selective delivery and reducing non-selective toxicities of CSC-specific chemotherapy agents. In Current review, we mostly focus on examining the role of CSCs in development of intratumoral heterogeneity and introducing recently developed nano delivery systems for more efficient targeting and eradication of them.     

Metastatic cancer stem cells: new molecular targets for cancer therapy

The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge.     

Targeting cancer stem cells with natural products

The cancer stem cell (CSC) hypothesis presents a fundamentally different paradigm for cancer treatment. CSCs reflect a small fraction of tumor initiating cells capable of sustained self-renewal and differentiation to form the heterogeneous tumor bulk. In order to cure cancer, it is necessary to eliminate cancer stem cells in addition to differentiated cancer cells to decrease metastasis, reduce recurrence, and improve patient survival. In this article, we review cancer stem cell signaling pathways, including Wnt, Hedgehog, and Notch, as well as interactions of CSCs with the tumor microenvironment. We also review methods to isolate CSCs and demonstrate therapeutic efficacy of natural products to modulate these signaling pathways for eliminating CSCs.     

肿瘤干细胞的治疗耐受机制研究进展

肿瘤的发病率和死亡率位居各类疾病之首,肿瘤的复发和转移是目前肿瘤治疗失败的主要原因,肿瘤治疗的失败又与肿瘤干细胞有着密切的关系。肿瘤干细胞的耐药机制一般包括以下几个方面：高表达的ABC转运蛋白介导化疗药物外排;乙醛脱氢酶的高表达与肿瘤的发病率和预后差显著相关;高效的DNA损伤修复能力;促存活通路的激活能力。笔者综合介绍肿瘤干细胞几种主要的治疗耐受机制,以期为开发新型抗肿瘤药物以及临床合理用药提供理论依据。     

Approaches for targeting cancer stem cells drug resistance

ABSTRACT

Introduction: Several reports have suggested that a population of undifferentiated cells known as cancer stem cells (CSCs), is responsible for cancer formation and maintenance. In the last decade, the presence of CSCs in solid cancers have been reported.

Areas covered: This review summarizes the main approaches for targeting CSCs drug resistance. It is indeed known that CSCs may contribute to resistance to conventional chemotherapy, radiotherapy and targeted agents. Among the mechanisms by which CSCs escape anticancer therapies, removal of therapeutic agents by drug efflux pumps, enhanced DNA damage repair, activation of mitogenic/anti-apoptotic pathways; the main features of CSCs, stemness and EMT, are involved, as well as the capability to evade immune response.

Expert opinion: Different approaches are suitable to target CSCs mediated drug resistance. Some of them are currently under clinical evaluation in different cancer types. A better understanding of CSC biology, as well as more accurate study design, may maximize the therapeutic effects of these agents. In this respect, it is important to establish: (i) which molecules should be targeted; (ii) what drug combinations may be suitable; (iii) which patient settings will CSC targeting offer the highest clinical benefit; and (iv) how to integrate therapeutic approaches targeting CSCs with standard cancer therapy.     

Recent trends in cancer drug resistance reversal strategies using nanoparticles

Introduction: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc.

Areas covered: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors.

Expert opinion: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.