肺癌干细胞

现有研究表明,在肺癌中与干细胞功能相关的Wnt、Notch和Hedgehog信号通路被异常激活,它们与肺癌干细胞的高致瘤性、高转移性、耐药性等特性密切相关.多项研究显示肺癌干细胞群高度表达肿瘤耐药蛋白并且对放化疗明显耐受.因此,如何靶向治疗肺癌干细胞,最终根治肺癌,正逐渐成为肿瘤靶向治疗研究中的热点.     

肿瘤干细胞疫苗的研究进展

目前已知的绝大多数癌症治疗方法如化疗、放疗、免疫靶向治疗等主要以肿瘤细胞为靶目标,但很多肿瘤并不能被完全治愈且治疗后伴随很多并发症。一群高度耐药的肿瘤细胞能够使肿瘤重新聚集并转移到新的部位,使肿瘤继续发生发展。如果可以基于它们的表型或功能特征来鉴定具有干细胞样特征的癌细胞,从而找到肿瘤干细胞特异性抗原制成干细胞疫苗,进而激活机体内特异的免疫应答,以达到靶向清除肿瘤干细胞的目的,就能一定程度上控制肿瘤的复发及转移,杀灭肿瘤干细胞甚至可以消除肿瘤对放化疗的拮抗性及耐药性。因此肿瘤干细胞疫苗即靶向肿瘤干细胞的主动免疫疗法的研究与发展对恶性难治性肿瘤的治疗有着重要意义,本篇综述将对近年来肿瘤干细胞及其疫苗的发现、发展与研究结果进行概述。     

乳腺癌干细胞研究现状

肿瘤干细胞理论认为肿瘤可能是由肿瘤干细胞和其所处微环境产生,而肿瘤干细胞由正常干细胞突变而来.乳腺癌干细胞是第一个在实体瘤中被鉴定的肿瘤干细胞,人们采用多种策略成功分离出乳腺癌干细胞,对其生物学行为的认识正逐渐深入.乳腺癌干细胞的自我更新、分化等特性受到微环境和许多信号转导通路的调控.如何靶向治疗乳腺癌干细胞,最终根治乳腺癌,正逐渐成为肿瘤靶向治疗研究的一个热点.     

卵巢癌肿瘤干细胞的研究进展

卵巢癌肿瘤干细胞是从卵巢癌组织及癌性腹腔积液中分离出的一小群具有自我更新和多向分化潜能的细胞,与卵巢癌的高复发率、强耐药性密切相关.因此治疗晚期卵巢癌的关键在于研究以肿瘤干细胞为靶向的治疗方法.随着对卵巢癌肿瘤干细胞的成功分离鉴定,为卵巢癌的基因靶向治疗提供了可能.     

Id1在人肺癌细胞系A549肿瘤细胞球中的表达

目的:探讨Id1在人肺癌细胞系A549肿瘤细胞球中的表达情况,为肺癌干细胞的基因靶向治疗提供理论依据。方法:应用干细胞无血清培养技术培养A549细胞肿瘤细胞球,采用克隆形成实验检测肺癌肿瘤球细胞增殖能力,流式细胞术检测ABCG2在肺癌肿瘤球细胞中的表达情况,Western blotting检测Id1在肺癌肿瘤球细胞中的表达情况。结果:与贴壁细胞相比,人肺癌细胞系A549肿瘤细胞球细胞具有较强的克隆能力,且高表达ABCG2,符合肺癌干细胞的特点,Id1在人肺癌细胞系A549肿瘤细胞球细胞中高表达。结论:Id1可能成为靶向肺癌干细胞肺癌治疗的靶点。     

靶向肿瘤干细胞天然药物的研究进展

摘 要：在肿瘤的发生、转移及复发过程中,肿瘤干细胞的自我更新和增殖分化能力发挥着关键作用。了解调控肿瘤干细胞自我更新的分子机制对研发靶向肿瘤干细胞的抗癌药物具有深远意义。天然活性化合物在肿瘤治疗中备受关注,越来越多的研究证实其可作用于肿瘤干细胞。文章综述了近年靶向肿瘤干细胞的热点天然药物,并对其抑制肿瘤干细胞的机制作一简单介绍。     

肿瘤干细胞的研究进展

肿瘤干细胞(cancer stem cell)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.近年来,越来越多的学者认为肿瘤干细胞的残存是恶性肿瘤复发的根源.随着研究的深入,肿瘤干细胞的靶向治疗为恶性肿瘤的治疗带来了新的希望.     

间质干细胞与肿瘤转移

间质干细胞(MSC)能够向炎症和肿瘤部位趋化,参与肿瘤微环境的组成,对肿瘤的生长和转移起重要作用.对间质干细胞在肿瘤生长与转移中的作用及机制研究将为肿瘤发生及肿瘤靶向治疗提供新的思路.     

肿瘤干细胞的调控机制研究进展

肿瘤干细胞是一群未分化、具有自我更新、多系分化潜能的细胞.现有的研究表明肿瘤干细胞的自我更新、分化、转移、致瘤性受到Wnt、Notch、Hedgehog、CXCR4-SDF-1轴、PTEN等多种信号传导通路的调控.而肿瘤干细胞与间充质干细胞分别构成肿瘤的上皮部分与间质部分,它们之间可能也存在着相互调控.深入研究肿瘤干细胞的调控机制,对于开发以肿瘤干细胞为靶点的新型靶向治疗药物,最终根除肿瘤具有重要意义.     

胰腺癌干细胞靶向治疗研究进展

摘 要：胰腺癌干细胞在胰腺癌的发生发展过程中起着很关键的作用。最近不断有报道证实针对肿瘤干细胞的治疗可以明显减弱肿瘤干细胞的信号传导。因此胰腺癌干细胞靶向治疗药物可以明显改善胰腺癌患者的预后。现对胰腺癌干细胞靶向治疗的进展作一综述。     

Intracellular signals of lung cancer cells as possible therapeutic targets

In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment; they have produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the development of lung cancers, a number of oncogenes are not covered by these advanced therapies. For the treatment of lung cancers, which is a group of heterogeneous diseases, persistent effort in developing individual therapies based on the respective causal genes is important. In addition, for the development of a novel therapy, identification of the lung epithelial stem cells and the origin cells of lung cancer, and understanding about candidate cancer stem cells in lung cancer tissues, their intracellular signaling pathways, and the mechanism of dysregulation of the pathways in cancer cells are extremely important. However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well‐known phenomenon. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies on origin and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies.     

Lung cancer stem cells: Tumor biology and clinical implications

The concept of cancer stem cells (CSC) has drawn great attention from researchers in both molecular and clinical fields as has brought a new perspective to the way we manage cancer. CSC have several characteristics that are shared by the properties of normal stem cells, such as differentiation, self-renewal and homeostatic control. However, CSC have the capacity to both divide and expand the CSC pool and to differentiate into heterogeneous non-tumorigenic cancer cells. Even more, CSC have an inherent high resistance to chemotherapeutic agents that leads to recurrence and poor long-term survival, especially in lung cancer patients. CSC-targeting agents are now undergoing in vitro and in vivo studies, some of which have provided promising results for further clinical studies setting. In this article we review the concept of CSC from the perspective of tumor biology, including the origin of CSC and its biomarkers. As lung cancer is the leading cause of cancer-related deaths worldwide, we focus on the properties and clinical implications of lung CSC.     

ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Molecular targeting therapeutics, such as EGFR tyrosine kinase inhibitors (TKIs), are important treatment strategies for lung cancer. Currently, the major challenge confronting targeted cancer therapies is the development of resistance. Cancer stem cells (CSCs) represent a rare population of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance and spreading. Resistance to conventional chemotherapeutic drugs is a common characteristic of CSCs. However, the issue of whether CSCs contribute to EGFR TKI resistance in lung cancer is yet to be established. In the current study, we explored the association of ALDH1A1 expression with EGFR TKI resistance in lung cancer stem cells. ALDH1A1-positive lung cancer cells displayed resistance to gefitinib, compared to ALDH1A1-negative lung cancer cells. Moreover, PC9/gef cells (gefitinib-resistant lung cancer cells) presented a higher proportion of ALDH1A1-positive cells, compared to PC9 cells (gefitinib-sensitive lung cancer cells). Clinical sample studies were consistent with results from cell culture model systems showing that lung cancer cells with resistance to EGFR TKI and chemotherapy drugs contain significantly increased proportions of ALDH1A1-positive cells. These findings collectively suggest that ALDH1A1 positivity in cancer stem cells confers resistance to EGFR TKI in lung cancer.     

Cancer stem cells in solid tumors

According to the cancer progression model, several events are required for the progression from normal epithelium to carcinoma. Due to their extended life span, stem cells would represent the most likely target for the accumulation of these genetic events but this has not been formally proven for most of solid cancers. Even more importantly, cancer stem cells seem to harbor mechanisms protecting them from standard cytotoxic therapy. While cancer stem cells have been demonstrated to be responsible for therapy resistance in glioblastoma and pancreatic cancer, further evidence now points to similar mechanisms in colon cancer stem cells. Therefore, it appears reasonable to conclude that there is sufficient evidence now for the existence of cancer stem cells in several epithelial tumors and that these cancer stem cells pose a significant threat via their resistance to standard therapies. Accumulating evidence suggests, however, that novel approaches targeting cancer stem cells are capable of overcoming these resistance mechanisms. To further foster our understanding of in vivo cancer stem cell biology, novel imaging modalities in conjunction with clinically most relevant cancer stem cell models need to be developed and utilized. These studies will then pave the way to better elucidate the underlying regulatory mechanisms of cancer stem cells and develop platforms for targeted theragnostics, which may eventually help improving the prognosis of our patients suffering from these deadly diseases.     

Lung cancer stem cells: Progress and prospects

Epithelial stem cells are critical for tissue generation during development and for repair following injury. In both gestational and postnatal stages, the highly branched and compartmentalized organization of the lung is maintained by multiple, resident stem/progenitor cell populations that are responsible for the homeostatic maintenance and injury repair of pulmonary epithelium. Though lung epithelial injury in the absence of oncogenic mutation is more commonly expressed as chronic lung disease, lung cancer is the most common form of death worldwide and poses a highly significant risk to human health. Cancer is defined by the cell of origin, responsible for initiating the disease. The Cancer Stem Cell Hypothesis proposes that cancer stem cells, identified by stem-like properties of self-renewal and generation of differentiated progeny, are responsible for propagating growth and spread of the disease. In lung cancer, it is hypothesized that cancer stem cells derive from several possible cell sources. The stem cell-like resistance to injury and proliferative potentials of bronchioalveolar stem cells (BASCs) and alveolar epithelial type II cells (AEC2), as well as cells that express the cancer stem cell marker glycoprotein prominin-1 (CD133) or markers for side populations make them potential reservoirs of lung cancer stem cells. The abnormal activation of pathways that normally regulate embryonic lung development, as well as adult tissue maintenance and injury repair, including the Wnt, Hedgehog (Hh) and Notch pathways, has also been identified in lung tumor cells. It is postulated that therapies for lung cancer that specifically target stem cell signaling pathways utilized by lung cancer stem cells could be beneficial in combating this disease.     

Do stem-like cells play a role in drug resistance of sarcomas?

Stem cells are defined by their unique characteristics, which include their abilities to self-renew and differentiate. Normal somatic stem cells have been isolated from various tissues such as bone marrow, adipose tissue, mammary glands and the nervous system. They are considered naturally resistant to chemotherapeutic agents because they express high levels of membrane transporter molecules, detoxifying enzymes and DNA repair proteins. Several recent studies have identified the presence of side populations in various cancer tissues, the so-called ‘cancer stem cells’, which are defined as the counterparts of stem cells in tumor tissues. These cancer stem cells possess stem-like properties, such as self-renewal and differentiation abilities, as well as playing a role in tumor initiation. Most sarcomas, which are thought to originate from mesenchymal stem cells, are highly malignant and approximately 30–40% of them show local and/or distant relapse (metastasis), even in the case of relatively chemosensitive tumors such as osteosarcomas and Ewing sarcomas. Several studies have suggested the presence of stem-like cell populations in sarcomas, based on their tumorigenicity and drug resistance. This review explores the issues of drug resistance of cancer stem cells in sarcomas and the possibilities of targeting cancer stem cells for the future treatment of sarcomas.     

侧群细胞与肺癌肿瘤干细胞

侧群(side population,SP)细胞是一小群能够将染料Hoechst 33342排出从而在流式细胞图上呈现Hoechst 33342低染的细胞,研究者已在多种肿瘤组织和细胞系中检测出了SP细胞并验证这些SP细胞具有强干细胞活性。现有试验结果证实多种肺癌组织和肺癌肿瘤细胞系中也存在具有类干细胞特性的SP细胞,这些SP细胞的鉴别与分离对于肺癌肿瘤干细胞的研究有何意义?本文将整合现有研究资料就这一问题进行阶段性综述。     

CD133作为肺癌干细胞标记物的应用及其局限性

肺癌是临床上最常见的恶性肿瘤之一,尚缺乏预后较为理想的治疗方案。肿瘤干细胞学说认为肺癌干细胞是肺癌发生、发展、转移、复发、耐受放化疗以及肺癌细胞具有侵袭性的主要原因。近年来越来越多的机构利用CD133糖基化表位来鉴定、分离、提纯肺癌干细胞。然而,随着研究的深入,CD133作为肺癌干细胞标记物逐渐受到质疑。本文对近年来利用CD133作为肺癌干细胞表面标记物的应用及其局限性做一综述。     

Therapy‐induced enrichment of putative lung cancer stem‐like cells

Tumour drug resistance is a major issue in the management of lung cancer patients as almost all lung tumours are either intrinsically resistant or quickly develop acquired resistance to chemotherapeutic drugs. Cancer drug resistance has recently been linked, at least in part, to the existence of cancer stem‐like cells (CSLCs), a small sub‐population of cells within the tumour that possess stem‐like properties. CSLCs are often isolated by fluorescence activated cell sorting (FACS) according to the expression of certain stem‐like cell membrane markers. Conflicting results regarding the specificity of particular stem cell surface markers for isolating CSLCs have, however, been recently reported. Therefore, alternative strategies enabling the identification and study of CSLCs should be considered, particularly in tumour types where appropriate stem cell markers are not well established and validated, like in lung cancer. In this article, we review data indicating therapy‐selection as a valid approach for putative lung CSLCs enrichment. We believe that this strategy would be determinant for correctly assessing and characterising the sub‐populations of CSLCs that are able to survive chemo or radiotherapy regimens and, at the same time, also have the ability to recapitulate and sustain tumour growth. Using therapy‐induced enrichment of CSLCs may, therefore, prove to be an extremely useful method for studying CSLCs and provide new clues regarding potential therapeutic targets for their efficient elimination, which will undoubtedly play a decisive role in improving lung cancer patients' survival.