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.     

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。     

Preclinical development of cancer stem cell drugs

Background: Despite recent progress in cancer treatment, the current cancer chemotherapy can mainly produce remission but often fails to cure cancer due to the existence of cancer stem cells. The emerging cancer stem cell hypothesis offers new insight into the failure of current cancer drugs and suggests new approaches for improved understanding of cancer biology and cancer drug development. Objective: In this review, we discuss the concept of cancer stem cells, origin of cancer stem cells and different approaches for isolating or enriching cancer stem cells. We also review the resistance of cancer stem cells to standard chemotherapy and radiation therapy and potential mechanisms for the resistance. Finally, based on the current knowledge on cancer stem cells, we discuss potential approaches for developing new drugs that target cancer stem cells and propose new methods for evaluation of cancer stem cell drugs. Conclusion: Improved cancer treatment is likely to be achieved by a combination of drugs that kill both replicating cancer cells and more quiescent cancer stem cells.     

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit.

Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy.

Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.     

Mesenchymal stem cells: a new trend for cell therapy

Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.     

乳腺癌干细胞VEGF表达的实验研究

目的探讨乳腺癌干细胞血管内皮生长因子（Vascular endothelial growth factor,VEGF）的表达及意义。方法应用流式细胞分选技术从乳腺癌细胞株MCF-7细胞分离乳腺癌干细胞和非干细胞,采用Northern blot技术测定干细胞与非干细胞VEGF表达情况。结果与乳腺癌非干细胞相比,乳腺癌干细胞VEGF表达水平明显增强。结论乳腺癌干细胞可通过高表达VEGF增强转移能力,是乳腺癌转移的关键因素之一。     

肿瘤干细胞的研究进展

随着对肿瘤研究的不断深入,以及对干细胞了解的日益加深,越来越多的证据提示肿瘤中某些细胞具有干细胞特性,并提出了肿瘤干细胞的学说,认为肿瘤的生长、转移以及耐药等均于肿瘤干细胞的关系密切.该文综述了肿瘤干细胞的发现、特点,以及在肿瘤的诊断、治疗和预后判断中的作用.     

MUC1 plays an essential role in tumor immunity of colorectal cancer stem cell vaccine

Increasing knowledge of colorectal cancer stem cells (CCSCs) and tumor microenvironment improves our understanding of cellular mechanisms involved in the immunity against colorectal cancer (CRC). Tumor associated antigens were evaluated via RNA-seq and bioinformatics analysis, evoking promising targets for tumor immunotherapy. MUC1 has been demonstrated to participate in the maintenance, tumorigenicity, glycosylation and metastasis of CCSCs, which may provide a new priority for CSC vaccination. In the present study, the vaccination with CCSCs with high expression of MUC1 was evaluated in a murine model for the vaccine’s immunogenicity and protective efficacy against CRC. CD133⁺ CCSCs were isolated from SW620 cell line using a magnetic-activated cell sorting system, and shMUC1 was further used to knock down the expression of MUC1 in CD133⁺ CCSCs. Mice were subcutaneously immunized with the cell lysates of CCSCs and shMUC1 CCSCs, followed by a challenge with SW620 cells at ten days after final vaccination. The results indicated CCSC vaccine significantly reduced the tumor growth via a target killing of CCSCs as evidenced by a decrease of CD133⁺ cells and ALDH⁺ cells in tumors. Moreover, CCSC vaccine resulted in the elevated NK cytotoxicity, production of perforin, granzyme B, IFN-γ, memory B cells, and anti-MUC1 antibodies. Of note, MUC1 knockdown partly impaired the anti-tumor efficacy of CCSC vaccine. Importantly, the CCSC vaccine has no toxic damage to organs. Overall, CCSC vaccine could serve as a potent and safe vaccine for CRC treatment, and MUC1 might play an essential role in CCSC vaccine.     

Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach

Introduction: Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies.

Areas covered: This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics.

Expert opinion: The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.     

Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemotherapeutic drugs

Aim:

Cancer stem cells have the capacity to initiate and sustain tumor growth. In this study, we established a CD44⁺ colorectal cancer stem cell line with particular emphasis on its self-renewal capacity, enhanced tumor initiation and drug resistance.

Methods:

Fresh colon cancer and paired normal colon tissues were collected from 13 patients who had not received chemotherapy or radiotherapy prior to surgery. Among the 6 single-cell derived clones, only the P6C cell line was cultured for more than 20 passages in serial culture and formed holoclones with high efficiency, and then the stemness gene expression, colony formation, tumorigenicity and drug sensitivities of the P6C cell line were examined.

Results:

Stemness proteins, including c-Myc, Oct3/4, Nanog, Lgr5, and SOX2, were highly expressed in the P6C cell line. Oct3/4-positive P6C cells mostly generated holoclones through symmetric division, while a small number of P6C cells generated meroclones through asymmetric division. P6C cells stably expressed CD44 and possessed a high capacity to form tumor spheres. A single cell-derived sphere was capable of generating xenograft tumors in nude mice. Compared to SW480 and HCT116 colorectal cancer cells, P6C cells were highly resistant to Camptothecin and 5-fluorouracil, the commonly used chemotherapeutic agents to treat colorectal cancers.

Conclusion:

We established a colorectal cancer stem cell line P6C with a high tumorigenic capacity and the characteristics of normal stem cells. It will benefit the mechanistic studies on cancer stem cells and the development of drugs that specifically target the cancer stem cells.     

细胞集落刺激因子诱导肺癌干细胞分化的临床应用

目的诱导肺癌干细胞进入分裂期以提高对化疗药物的敏感度。方法未手术晚期肺腺癌患者115例随机分为诱导化疗组(试验组)和常规化疗组(对照组)。两组均予以长春瑞滨+顺铂(NP)方案化疗;试验组化疗期间加用重组人粒细胞集落刺激因子(rhG-CSF)诱导肺癌干细胞分化。化疗2个周期后2周比较两组的疗效。结果试验组近期有效率明显高于对照组(61.8%vs.41.5%)(P<0.05)。结论通过诱导肺癌干细胞向相应的成熟细胞分化使其对化疗敏感,可以提高治疗效果。     

肿瘤干细胞的耐药性及其治疗策略

随着对肿瘤研究的不断深入,以及对干细胞了解的日益加深,越来越多的证据表明肿瘤中某些细胞具有干细胞特性,由此提出了肿瘤干细胞学说。这一学说,不仅认为肿瘤的生长、转移与肿瘤干细胞的关系密切,而且传统的化疗方法不能根治肿瘤的原因可能也与肿瘤干细胞耐药有关。已有研究表明, ABC转运体能够保护肿瘤干细胞免受药物的毒性作用,因此更深入的理解肿瘤干细胞耐药机制对我们找到行之有效的肿瘤治疗方法以及新的治疗靶点有十分重要的意义。     

乳腺癌靶向治疗的新策略

目前,乳腺癌的常规治疗手段如化疗、放疗等存在严重的全身副作用,为此,开展乳腺癌的靶向治疗研究具有重大意义。本文综述了乳腺癌靶向治疗的3个研究领域:抗体介导的靶向、微载体介导的靶向、乳腺癌干细胞靶向,并阐述这些治疗策略的基本研究思路,分析这些新的治疗策略面临的一些问题,从而提出解决这些问题的相关见解。     

抗前列腺干细胞抗原单克隆抗体的制备及初步鉴定

目的　制备抗前列腺干细胞抗原 (PSCA)单克隆抗体 (McAb) ,并对其特性进行鉴定。方法　应用PC 3细胞免疫BALB/c小鼠 ,按常规方法融合并经间接ELISA方法筛选 ,制备稳定的抗PSCAMcAb ,并对McAb的亚型、组织特异性进行鉴定。结果　制备出抗PSCA单克隆抗体 ,免疫扩散鉴定为IgG1亚类 ,ELISA法测定其腹水效价为 5× 1 0 -5。组织学检查与前列腺癌组织呈阳性反应 ,与其他肿瘤组织均呈阴性反应 ,和人体正常组织细胞无一出现阳性反应。结论　初步制备出一株抗PSCA的单克隆抗体细胞株 ,能特异性识别前列腺癌组织 ,对前列腺癌的诊断和治疗提供有用的工具。     

间质干细胞与肿瘤的关系研究进展

间质干细胞(mesenchymal stem cells,MSCs)是来源于中胚层的一类具有高度自我更新能力和多向分化潜能的非造血干细胞,具有很好的组织迁移能力和肿瘤靶向性。MSCs用于抗肿瘤治疗已经开展了广泛的研究,MSCs可以作为细胞载体发挥抗肿瘤作用,同时通过促肿瘤血管生成、免疫抑制、分化为肿瘤相关成纤维细胞等方式促进肿瘤的恶性行为。该文对近年来该领域的研究进展进行简要综述。     

肺癌血管生成的新理解

肺癌是全世界最常见的恶性肿瘤之一.近年来,抑制肿瘤血管生成的分子靶向治疗为肺癌提供了新的治疗手段.许多研究不仅使人们对肿瘤血管生成有了新的理解,还提出了新的治疗靶点和方法.本文总结该类别系列药物的开发,并指出其可能对临床治疗的影响.     

肿瘤干细胞耐药机制研究进展

肿瘤是一种干细胞疾病,治疗肿瘤面临的主要挑战之一是肿瘤对传统治疗产生了耐药性,研究证明耐药性的产生与肿瘤干细胞(cancer stem cells,CSCs)的生物学特性密切相关。鉴定各种肿瘤中的CSCs以及维持其特性所必需的微环境和生物学进程对治疗肿瘤复发至关重要。CSCs周围局部微环境(niche)的改变能影响其生物学行为,而多种与发育相关的信号通路的激活,DNA修复能力的增强以及ABC转运蛋白介导的药物外排等是导致临床耐药的主要原因。该文就近年来CSCs与耐药的相关研究进展作一综述。