肿瘤干细胞及其潜在影响实体瘤的治疗

有越来越多的证据表明,多种人类癌症细胞中包含小部分具有干细胞特性的癌细胞,称为肿瘤干细胞.肿瘤干细胞维持肿瘤的生长;可能引发转移.本篇文章的目的是评估肿瘤干细胞存在的证据,及其对现行治疗实体肿瘤的影响.在评估中我们发现肿瘤干细胞具有与正常干细胞相似的两个主要特征,自我更新和分化.肿瘤干细胞的存在与癌症治疗方面具有广阔的临床意义.肿瘤干细胞的靶向治疗,对肿瘤干细胞进行表面标记,在实体瘤中对肿瘤干细胞的鉴别和分离,逆转肿瘤干细胞对放化疗的抵制.临床试验表明肿瘤干细胞能够驱使和维持人类多种类型恶性肿瘤生存.然而,多年的肿瘤干细胞靶向治疗仍然面临多方面困难.     

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。     

肿瘤干细胞和低氧微环境与肿瘤转移的关系

恶性肿瘤迄今仍是一种难以根治的疾病.肿瘤干细胞(cancer stem cell, CSC)理论的提出为肿瘤的彻底治愈带来了希望,我们可以从CSC这一与正常干细胞同样具有自我更新功能的细胞群入手对肿瘤进行治疗.研究表明,CSC周围微环境在肿瘤形成、发展、侵袭、转移过程中有重要作用,尤其是低氧微环境与肿瘤转移密切相关[1].     

肿瘤干细胞和低氧微环境与肿瘤转移的关系

恶性肿瘤迄今仍是一种难以根治的疾病.肿瘤干细胞(cancer stem cell, CSC)理论的提出为肿瘤的彻底治愈带来了希望,我们可以从CSC这一与正常干细胞同样具有自我更新功能的细胞群入手对肿瘤进行治疗.研究表明,CSC周围微环境在肿瘤形成、发展、侵袭、转移过程中有重要作用,尤其是低氧微环境与肿瘤转移密切相关[1].     

盐霉素针对肿瘤干细胞的治疗机制

肿瘤干细胞是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体,它具有自我更新的能力,是形成不同分化程度肿瘤细胞和肿瘤不断扩大的源泉。而现有的治疗肿瘤的方法多是针对一般肿瘤细胞,而非肿瘤干细胞,治疗不彻底,仍会造成肿瘤的复发和转移。因此,开发新的药物杀灭肿瘤干细胞是现今治疗肿瘤的重点。盐霉素由于具有逆转多药耐药、抑制凋亡、调整细胞周期、抑制DNA修复等特点,可应用于肿瘤干细胞的治疗。     

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。     

肿瘤干细胞的研究现状

肿瘤干细胞是近年来肿瘤研究的一个新热点,它具有强大的自我更新和致瘤能力,以及细胞分化潜能。本文介绍了造血系统恶性肿瘤干细胞,乳腺癌干细胞,类神经肿瘤干细胞等其他肿瘤干细胞的研究现状,并对其耐药机制进行阐述。     

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。     

干细胞样SP细胞研究进展

摘要： 干细胞样 SP 细胞是近年来在很多正常组织和恶性肿瘤组织及细胞系中发现的一种具有不同程度分化潜能和自我更新能力的细胞群体。虽然 SP 细胞在总体细胞中所占比例很低, 但这部分具有干细胞特性的细胞在干细胞以及肿瘤干细胞研究方面起着越来越重要的作用。本文综述了 SP 细胞的发现、 生物学特性、 与肿瘤干细胞之间的关系以及 SP 细胞的未来临床应用等。最后对 SP 细胞的发展进行了展望。     

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.     

Can nanomedicines kill cancer stem cells?

Most tumors are heterogeneous and many cancers contain small population of highly tumorigenic and intrinsically drug resistant cancer stem cells (CSCs). Like normal stem cell, CSCs have the ability to self-renew and differentiate to other tumor cell types. They are believed to be a source for drug resistance, tumor recurrence and metastasis. CSCs often overexpress drug efflux transporters, spend most of their time in non-dividing G₀ cell cycle state, and therefore, can escape the conventional chemotherapies. Thus, targeting CSCs is essential for developing novel therapies to prevent cancer relapse and emerging of drug resistance. Nanocarrier-based therapeutic agents (nanomedicines) have been used to achieve longer circulation times, better stability and bioavailability over current therapeutics. Recently, some groups have successfully applied nanomedicines to target CSCs to eliminate the tumor and prevent its recurrence. These approaches include 1) delivery of therapeutic agents (small molecules, siRNA, antibodies) that affect embryonic signaling pathways implicated in self-renewal and differentiation in CSCs, 2) inhibiting drug efflux transporters in an attempt to sensitize CSCs to therapy, 3) targeting metabolism in CSCs through nanoformulated chemicals and field-responsive magnetic nanoparticles and carbon nanotubes, and 4) disruption of multiple pathways in drug resistant cells using combination of chemotherapeutic drugs with amphiphilic Pluronic block copolymers. Despite clear progress of these studies the challenges of targeting CSCs by nanomedicines still exist and leave plenty of room for improvement and development. This review summarizes biological processes that are related to CSCs, overviews the current state of anti-CSCs therapies, and discusses state-of-the-art nanomedicine approaches developed to kill CSCs.     

Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells

Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.     

Increased PD‐L1 expression in breast and colon cancer stem cells

Here we report the expression of programmed cell death ligand 1/2 (PD‐L1/L2) in breast and colon cancer stem cells (CSCs). The stemness of these cells was confirmed by their surface markers. Using flow cytometry analysis we demonstrated that PD‐L1 expression was higher in CSCs of both cancers compared to non‐stem like cancer cells. Consistent with this, detection of cellular PD‐L1 proteins by western blot assay also showed increased PD‐L1 protein in CSCs. In contrast, only trace amounts of PD‐L2 were detected in CSCs of both cancers. Our results suggest that breast and colon cancers may be sensitive to PD1/PD‐L1 immunotherapy and thus warrant further investigations of CSC targeted PD1/PD‐L1 therapy.     

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。     

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.     

Antipsychotic dopamine receptor antagonists,cancer, and cancer stem cells

Cancer is one of the deadliest diseases in the world. Despite extensive studies, treating metastatic cancers remains challenging. Years of research have linked a rare set of cells known as cancer stem cells (CSCs) to drug resistance, leading to the suggestion that eradication of CSCs might be an effective therapeutic strategy. However, few drug candidates are active against CSCs. New drug discovery is often a lengthy process. Drug screening has been advantageous in identifying drug candidates. Current understanding of cancer biology has revealed various clues to target cancer from different points of view. Many studies have found dopamine receptors (DRs) in various cancers. Therefore, DR antagonists have attracted a lot of attention in cancer research. Recently, a group of antipsychotic DR antagonists has been demonstrated to possess remarkable abilities to restrain and sensitize CSCs to existing chemotherapeutics by a process called differentiation approach. In this review, we will describe current aspects of CSC-targeting therapeutics, antipsychotic DR antagonists, and their extraordinary abilities to fight cancer.     

Cancer stem cell-targeted chimeric antigen receptor (CAR)-T cell therapy: Challenges and prospects

Cancer stem cells (CSCs) with their self-renewal ability are accepted as cells which initiate tumors. CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tumor recurrence and resistance to conventional therapies, including radiotherapy and chemotherapy. Chimeric antigen receptor (CAR)-T cells are engineered T cells which express an artificial receptor specific for tumor associated antigens (TAAs) by which they accurately target and kill cancer cells. In recent years, CAR-T cell therapy has shown more efficiency in cancer treatment, particularly regarding blood cancers. The expression of specific markers such as TAAs on CSCs in varied cancer types makes them as potent tools for CAR-T cell therapy. Here we review the CSC markers that have been previously targeted with CAR-T cells, as well as the CSC markers that may be used as possible targets for CAR-T cell therapy in the future. Furthermore, we will detail the most important obstacles against CAR-T cell therapy and suggest solutions.KEY WORDS: Chimeric antigen receptor T cell, Cancer stem cell, Immunotherapy, Tumor associated antigens, Combination therapy, Off-tumor toxicity, Clinical trial, Tumor immunosuppressive microenvironment     

Targeting the Wnt/β-catenin signaling pathway in human cancers

INTRODUCTION: The Wnt/β-catenin signaling pathway plays a pivotal role in the regulation of cell growth, cell development and the differentiation of normal stem cells. Constitutive activation of the Wnt/β-catenin signaling pathway is found in many human cancers, and is thus an attractive target for anti-cancer therapy. Specific inhibitors of this pathway have been keenly researched and developed. AREAS COVERED: This review discusses the potential of inhibiting the Wnt/β-catenin signaling pathway, as a therapeutic approach for cancer, along with an overview of the development of specific inhibitors. EXPERT OPINION: Cancer stem cells (CSCs) play a significant role in the development and recurrence of several cancers, and Wnt/β-catenin signaling is important for the proliferation of CSCs. Inhibition of Wnt/β-catenin signaling is therefore a promising treatment approach. Progress has been made in the development of screening methods to identify Wnt/β-catenin signaling inhibitors. Biomarker-based screening is an effective and promising method for the identification of compounds of interest.     

Rapid phenotyping of cancer stem cells using multichannel nanosensor arrays

Cancer stem cells (CSCs) contribute to multidrug resistance, tumor recurrence and metastasis, making them prime therapeutic targets. Their ability to differentiate and lose stem cell properties makes them challenging to study. Currently, there is no simple assay that can quickly capture and trace the dynamic phenotypic changes on the CSC surface. Here, we report rapid discrimination of breast CSCs from non-CSCs using a nanoparticle-fluorescent-protein based sensor. This nanosensor was employed to discriminate CSCs from non-CSCs, as well as CSCs that had differentiated in vitro in two breast cancer models. Importantly, the sensor platform could also discriminate CSCs from the bulk population of cells in patient-derived xenografts of human breast cancer. Taken together, the results obtained demonstrate the feasibility of using the nanosensor to phenotype CSCs and monitor their fate. Furthermore, this approach provides a novel area for therapeutic interventions against these challenging targets.