肿瘤干细胞靶向治疗研究进展

<正>肿瘤干细胞(cancer stem cell,CSC)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。现有治疗肿瘤的方法主要是针对肿瘤组织内的大多数细胞,而不是肿瘤干细胞。即使99.99%的肿瘤细胞被杀死,但只要有0.01%的肿瘤干细胞存在,仍然会造成肿瘤的复     

肿瘤干细胞与肿瘤耐药

肿瘤细胞对化疗药物耐药是肿瘤治疗的主要障碍,肿瘤干细胞(CSC)是造成肿瘤耐药的最根本原因,故肿瘤治疗的关键应以CSC为治疗靶点。CSC概念的提出为癌症靶向治疗的研究带来了新的思路,提供了选择性杀伤CSC的靶向分子疗法,即新的药物应有选择的杀伤CSC而不损伤正常的干细胞,克服肿瘤耐药、防止治疗后的复发与转移,达到真正的治愈肿瘤。     

药物靶向、分子靶向、激素靶向及干细胞靶向与骨质疏松症的治疗

背景：骨质疏松症引起的骨折及其他并发症严重影响中老年人生活质量。 目的：探讨靶向疗法治疗骨质疏松的进展,以促进其临床应用。 方法：由第一作者应用计算机检索PubMed、中国期刊全文数据库(CNKI)中1997-05/2011-12相关文献。在标题、摘要、关键词中以“targeted therapy,bone target,stem cell,osteoporosis,treatment”或“靶向治疗,骨靶向,干细胞,骨质疏松,治疗”为检索词进行检索。选择文章内容与靶向疗法治疗骨质疏松有关者,同一领域则选择近期发表在权威杂志上的文章。 结果与结论：初检得到148篇文献,根据纳入标准选择38篇文献进行综述。靶向治疗骨质疏松已成为骨质疏松治疗中的研究热点。目前研究领域涉及药物靶向、分子靶向、激素靶向、受体靶向及干细胞靶向治疗等,其中药物、分子及激素靶向疗法为目前常用的治疗方法,常用药物有四环素、双膦酸盐类、Denosumab等。但目前靶向治疗骨质疏松尚未完全成熟,所导致的临床不良反应限制其应用进展,仍有许多问题有待解决。     

肿瘤干细胞——肿瘤治疗的新靶点

肿瘤干细胞(cancer stem cell,CSC)是肿瘤组织中具有无限增殖潜能的极少量干细胞特征的细胞亚群,具有自我更新和多向分化能力.CSC是肿瘤增殖的源泉,目前常规放、化疗很难将其杀灭,使得CSC难以根除,肿瘤多次复发.由此看来,能否杀灭CSC是根治肿瘤的关键.通过阻止(或抑制)CSC信号通路,改变CSC生长的微环境,诱导其分化,开展针对CSC表面标志、CSC特定基因以及miRNA为基础的分子靶向治疗,将成为治疗肿瘤的新方法.     

肝癌干细胞的分子标记与靶向治疗

肿瘤干细胞假说认为只有很小一部分细胞具有引起肿瘤发生、维持肿瘤生长、保持肿瘤异质性的能力,这样的细胞叫肿瘤干细胞（cancer stem cell,CSC）。     

靶向肿瘤干细胞的免疫疗法

由于肿瘤干细胞(TSCs)与肿瘤的发生﹑发展﹑转移﹑复发和耐药等有着密切关系,是肿瘤的根源细胞,意味着治愈肿瘤的关键途径可能在于根除TSCs。因传统的手术﹑化疗和放疗等对肿瘤治疗的方法无法杀死TSCs,容易导致肿瘤转移和复发,而靶向TSCs的免疫疗法已确定能杀伤TSCs,如靶向TSCs的表面抗原﹑T细胞靶向TSCs的应用和分化疗法等。     

基于纳米材料与纳米技术的肿瘤靶向治疗

结合多学科的力量、特别是借助新技术的发展对肿瘤进行有效治疗,是目前肿瘤治疗研究方面的一个重要趋势。本文在肿瘤靶向治疗的定义和对主要几类方法说明的基础上,重点介绍和分析纳米材料和纳米技术的被动靶向、场致靶向和分子靶向等方面的最新研究进展,并讨论存在的一些问题和今后可能的努力方向。     

靶向药物内照射治疗肿瘤的现状与未来

本文从发展内照射治疗药物的必要性出发，提出了分子核医学靶向治疗中值得关注的３类靶向抑癌药物，即用放射性核素标记的抗肿瘤抗体，可与肿瘤受体相结合的生物活性肽，以及原癌基因的反义寡核苷酸。结合这３类药物的发展过程，着重阐述了它们的治疗机理和优点；同时也分析了存在的问题及今后发展的趋势     

基于靶向肿瘤干细胞的抗肿瘤策略研究进展

肿瘤干细胞（cancer stem cells,CSC）是肿瘤组织中数量较少的侧群细胞,但在肿瘤的发生、发展、复发和转移等病理过程中起着关键作用。强大的自我更新、增殖和失活凋亡机制的能力使得CSC对放疗和化疗具有较强的耐受性,并可诱导肿瘤的复发和转移。肿瘤的复发和转移是导致患者死亡的主要原因,因此,基于靶向CSC的抗肿瘤策略的研究是十分必要的。本文就CSC靶点和基于CSC靶点设计的抗肿瘤策略的最新研究进展作简要综述。     

靶向药物治疗肿瘤降低死亡率

靶向治疗和靶向药物是近年来肿瘤治疗的新理念和新措施。日前在亚特兰大召开的美国临床肿瘤学会年会上,又有多个靶向药物的研究成果在大会上公布,表明了人类攻克癌症又向前迈进了一大步。     

Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM

Background

Adoptive transfer of tumor infiltrating or circulating lymphocytes transduced with tumor antigen receptors has been examined in various clinical trials to treat human cancers. The tumor antigens targeted by transferred lymphocytes affects the efficacy of this therapeutic approach. Because cancer stem cells (CSCs) play an important role in tumor growth and metastasis, we hypothesized that adoptive transfer of T cells targeting a CSC antigen could result in dramatic anti-tumor effects.

Results

An EpCAM-specific chimeric antigen receptor (CAR) was constructed to transduce human peripheral blood lymphocytes (PBLs) and thereby enable them to target the CSC marker EpCAM. To investigate the therapeutic capabilities of PBLs expressing EpCAM-specific CARs, we used two different tumor models, PC3, the human prostate cancer cell line, which has low expression levels of EpCAM, and PC3M, a highly metastatic clone of PC3 that has high expression levels of EpCAM. We demonstrate that CAR-expressing PBLs can kill PC3M tumor cells in vitro and in vivo. Despite the low expression of EpCAM on PC3 cells, CAR-expressing PBLs significantly inhibited tumor growth and prolonged mouse survival in a PC3 metastasis model, probably by targeting the highly proliferative and metastatic population of cancer cells.

Conclusions

Our data demonstrate that PBLs expressing with EpCAM-specific CARs have significant anti-tumor activity against prostate cancer. Therefore, the adoptive transfer of T cells targeting EpCAM could have great potential as a cancer treatment.     

Successful therapy must eradicate cancer stem cells

Despite significant improvements in cancer therapy, tumor recurrence is frequent and can be due to a variety of mechanisms, including the evolution of resistance and tumor progression. Cancer stem cells have been postulated to maintain tumor growth similar to normal stem cells maintaining tissue homeostasis. Recently, the existence of these malignant stem cells has been proven for hematological as well as some solid tumors. Tumor stem cells are not targeted by standard therapy and might be responsible for treatment failure and tumor recurrence in many patients. We designed a simple mathematical model to demonstrate the importance of eliminating tumor stem cells. We explored different therapeutic scenarios to illustrate the properties required from novel therapeutic agents for successful tumor treatment. We show that successful therapy must eradicate tumor stem cells.     

Co-delivery of thioridazine and doxorubicin using polymeric micelles for targeting both cancer cells and cancer stem cells

In this study, thioridazine (THZ), which was reported to kill cancer stem cells, was used in a combination therapy with doxorubicin (DOX) to eradicate both cancer cells and DOX-resistant cancer stem cells to mitigate the reoccurrence of the disease. Both THZ and DOX were loaded into micelles with sizes below 100 nm, narrow size distribution and high drug content. The micelles were self-assembled from a mixture of acid-functionalized poly(carbonate) and poly(ethylene glycol) diblock copolymer (PEG-PAC) and urea-functionalized poly(carbonate) (PUC) and PEG diblock copolymer (PEG-PUC). The drug-loaded mixed micelles (MM) were used to target both cancer cells and stem cells via co-delivery. Cancer stem cells were sorted by a side population assay from BT-474 and MCF-7 human breast cancer cell lines, and identified by CD44+/CD24− phenotype. The cytotoxicity of various formulations was evaluated on the sorted cancer stem cells (side population SP cells), sorted non-stem-like cancer cells (non-side population NSP cells) and unsorted cancer cells. Antitumor activity was also evaluated on BT-474 xenografts in nude mice. As compared with NSP cells, DOX suppressed SP cell growth less effectively, while THZ and THZ-MM were more effective in the inhibition of SP cells. A stronger inhibitory effect was observed on SP cells with the co-delivery of free DOX and THZ or DOX-MM and THZ-MM as compared to free DOX or DOX-MM. THZ and THZ-MM were capable of lowering the population of SP cells in unsorted cells. In the BT-474 xenografts, the co-delivery of DOX-MM and THZ-MM produced the strongest antitumor efficacy, and both THZ and THZ-MM showed strong activity against cancer stem cells. This combination therapy may provide a promising strategy for breast cancer treatment by targeting both cancer cells and cancer stem cells.     

Embryonic stem cells and gene targeting

The development of gene targeting technology, the exchange of an endogenous allele of a target gene for a mutated copy via homologous recombination, and the application of this technique to murine embryonic stem cells has made it possible to alter the germ-line of mice in a predetermined way. Gene targeting has enabled researchers to generate mouse strains with defined mutations in their genome allowing the analysis of gene function in vivo. This review presents the essential tools and methodologies used for gene targeting that have been developed over the past decade. Special emphasis has been laid on the available embryonic stem cell lines and the importance of the genetic background. Also, the state-of-the art of gene targeting approaches in species other than mice will be discussed.     

肿瘤干细胞与胶质瘤细胞起源

经过过去20年的努力,癌基因和抑癌基因在神经胶质瘤形成及发展中的核心地位已达共识.然而,在生命科学研究突飞猛进、肿瘤诊断与治疗手段日新月异的今天,我们尚未确立这些核心分子在胶质瘤中作用的靶标,因此,胶质瘤的细胞起源-这一决定着人类最终克服胶质瘤的根本问题再度引起人类的关注.     

Potential gene therapy strategies for cancer stem cells

To be maximally effective, therapy of cancer must be directed against both the resting stem cells and the proliferating cells of the cancer. The cell populations of both normal and cancer tissues consist of resting stem cells, proliferating transit-amplifying cells, terminally differentiating cells and dying (apoptotic) cells. The difference between normal tissue renewal and growth of cancers is that some of the transit-amplifying cells in the cancer population do not mature into terminally differentiating cells, but instead continue to proliferate and do not die (maturation arrest). Because of this the number of cancer cells increase, whereas the cell population of normal tissues remains a relatively constant. Conventional radiation treatment and chemotherapy kill the actively proliferating transit- amplifying cells of the cancer. Differentiation therapy, using specific targeted inhibitors of activation, effectively induces differentiation of the proliferating transit-amplifying cancer cells. However, even if the proliferating cancer cells are completely inhibited or eliminated, the cancer stem cells may restore the transit-amplifying population, so that clinical remission is usually temporary. The hypothesis presented in this paper is that successful cancer therapy must be directed against both the resting stem cells and the proliferating cells of the cancer. This may be possible if specific stem cell signals are inhibited using gene therapy, while at the same time attacking proliferating cells by conventional radiation treatment or chemotherapy. With advances in approaches using specific inhibitory RNA, such combination therapy may now be possible, but critical problems in delivering the inhibitory effect specifically to the cancer stem cells have yet to be worked out.     

Non-viral delivery of RNA interference targeting cancer cells in cancer gene therapy

RNA interference (RNAi) is a collection of small RNA-directed mechanisms that result in sequence-specific inhibition of gene expression. RNAi delivery has demonstrated promising efficacy in the treatment of genetic disorders in cancer. Although viral vectors are currently the most efficient systems for gene therapy, potent immunogenicity, mutagenesis, and the biohazards of viral vectors remain their major risks. Various non-viral delivery vectors have been developed to provide a safer approach for gene delivery, including polymers, peptides, liposomes, and nanoparticles. However, some concerns and challenges of these non-viral gene delivery approaches remain to be overcome. In this review, we summarize the recent progress in the development of non-viral systems delivering RNAi and the currently available preclinical and clinical data, and discuss the challenges and future directions in cancer therapy.     

几种值得深入研究的肿瘤相关干(祖)细胞

越来越多证据表明,肿瘤是一类多因素致病、多步骤发生、异质性演进的遗传性疾病,是特殊的"难愈性创伤",并与慢性炎性过程密切相关.肿瘤还被认为属于分化异常性干细胞疾病[1].不仅肿瘤的发生与干细胞(stem cells)和(或)祖细胞(progenitor cells)密切相关,而且多种具有干细胞或祖细胞特性的细胞也参与肿瘤的生长和演进[2-3].存在于肿瘤内并参与肿瘤发生发展的干(祖)细胞可统称为肿瘤相关干(祖)细胞(tumor associated stem/progenitor cells).这些细胞包括来源于骨髓经血液进入肿瘤组织的一些干(祖)细胞和肿瘤组织固有的肿瘤干细胞(cancer stem cells)及其衍生的干细胞样细胞.深入研究肿瘤相关干(祖)细胞的病理生物学特性和作用,对于进一步揭示肿瘤发病机制、寻找防治新方法,具有重要意义.