CD133与肿瘤干细胞靶向治疗

CD133是肿瘤干细胞的表面标记物,在多种实体肿瘤中都有表达,且与肿瘤的化疗抵抗和放疗抵抗有关.CD133作为一种跨膜糖蛋白,其潜在的肿瘤干细胞靶向治疗的分子靶点作用备受关注,有望为肿瘤治疗提供新希望.     

肿瘤干细胞与恶性肿瘤的靶向治疗

肿瘤是严重危害人类生命健康的重大疾病。在肿瘤研究中,干细胞研究加深了对肿瘤发生、发展的认识,提出了肿瘤来源于干细胞、肿瘤中存在肿瘤干细胞(cancerstemcell)的该学说认为,肿瘤组织中存在极少量瘤细胞,在肿瘤中充当干细胞的角色,具有无限增生的潜能,在启动肿瘤形成和生长中起着决定性的作用,而其余的大多数细胞,经过短暂的分化,最终死亡。因此只有采用靶向消灭肿瘤干细胞的策略,才能从根本上治愈肿瘤。     

靶向肿瘤干细胞治疗策略的研究进展

<正>虽然人类对肿瘤的认识逐渐加深,治疗手段也取得了很大进展,但是恶性肿瘤的治疗效果仍有限。传统治疗初始通常能控制肿瘤生长,取得临床客观缓解,但多数患者最终将经历肿瘤的转移及复发。肿瘤干细胞(cancer stem cells,CSCs)学说认为,肿瘤中的一小部分细胞群体决定着肿瘤的生长及播散,这部分细胞群体称为CSCs。CSCs通过自我更新能力及多向分化潜能确保干细胞池的稳定并生成肿瘤主体细胞维持肿瘤的长期生长。虽然CSCs仅占据肿瘤实体的一小部分,但对传统治疗的高度耐受性使其能够逃避杀伤重新构建肿瘤。因此要想彻底治愈肿瘤,必须清除肿瘤生长、复发及转移的根源——CSCs。本文就靶向作用于CSCs的治疗策略作一综述。     

肿瘤干细胞与相关靶向治疗

目前随着抗肿瘤治疗手段的改进和新药物的出现,大多数肿瘤组织或细胞能够消除,但仍有极少数细胞处于休眠状态,导致肿瘤的复发、转移。其原因可能是在肿瘤组织中存在着极少部分具有干细胞性质的细胞群体,其具有自我更新的能力和多向分化的潜能,称之为肿瘤干细胞(cancer stem cell,CSC),属单克隆起源,是形成肿瘤和肿瘤不断扩大的来源,也是肿瘤细胞对放化疗产生抵抗的原因所在。因此要从真正意义上     

以肿瘤干细胞为靶的免疫治疗

肿瘤干细胞(cancer stem cell,CSC)是肿瘤发生和转移的种子细胞,CSC具有自我更新、增殖和不完全分化的能力。CSC对化疗/放疗的抵抗以及免疫逃逸成为肿瘤复发的根源,要提高肿瘤治愈率必须彻底清除CSC。认识CSC的标记特征和"干性"调节关键分子才能有效和特异地攻击CSC。免疫治疗具有抗原识别的靶向性和时空效应性,是以CSC为靶的治疗的基础;以单克隆抗体和致敏的免疫细胞为主要治疗技术的免疫治疗清除CSC具有可实践性和挑战性。     

肿瘤干细胞的生物学特性与靶向治疗

 肿瘤干细胞（CSC）在肿瘤的发生、复发、转移和耐药中起着十分重要的作用。常规的化疗药物能杀死大部分恶性细胞，但对数量极少的CSC却作用甚微，残存的CSC足以使肿瘤复发和转移。采用针对CSC的靶向治疗，才有可能从根本上治愈肿瘤。深入了解CSC不同于肿瘤组织中其他细胞类型的生物学特性，有助于进一步研究和开展特异性针对CSC的靶向治疗。     

白血病干细胞靶向治疗

研究发现白血病干细胞(LSC)独特的细胞分子生物学特点决定了它是白血病复发的根源.最近研究已经证实,靶向治疗可以根除LSC.     

血液肿瘤靶向治疗和免疫治疗

 引言恶性肿瘤治疗的目的仍然是在不损伤正常组织的前提下 ,长时期根治肿瘤。近年来 ,血液肿瘤治疗的最大进步在于靶向和免疫治疗的基础研究和临床应用。1　靶向治疗肿瘤靶向治疗包括单克隆抗体 (单抗 )、基因和酶抑制等的靶向治疗。借助高度特异的亲肿瘤细胞物质为载体 (如单抗 ) ,发挥特异性导向功能 ,通过抗体依赖细胞介导的细胞毒作用 (ADCC) ,或利用单抗与具有细胞毒作用的物质 (放射性核素、化学药物或毒素等 )结合 ,将细胞毒物质尽量集中在肿瘤细胞部位发挥杀伤作用 ;而基因和酶抑制的靶向治疗则是通过特异性封闭了目的基因的表达或抑制酶的活性而达到抑制肿瘤增殖的目的。1.1　单克隆抗体目前所研制的抗肿瘤靶向药物还是以单抗为主 ,1997年第一个治疗性单抗 (抗CD2 0单抗 ,美罗华 ,Rituximab)问世 ,美罗华对CD2 0 +低度恶性B细胞恶性淋巴瘤治疗效果令人振奋 ,对常规化疗后复发的低度恶性或滤泡型恶性淋巴瘤也有良好效果。使人们对单抗的靶向治疗效果寄予希望。针对CD33+AML细胞的HuM 195 (人源化CD33单抗 )则是另一个比较成功的治疗性单抗。但单独应用单抗的效果仍不理想 ,通过单抗与...     

肿瘤干细胞及肿瘤靶向治疗的研究进展

研究发现引起肿瘤复发或转移的根源是肿瘤中一少部分具有无限增殖能力的肿瘤干细胞,其在体内长期存在并不断自我更新,使肿瘤快速增殖且侵袭、转移能力增加,药物敏感性减弱,成为临床治疗的难题。因此,深入了解肿瘤干细胞进而寻找抑制肿瘤干细胞的方法对临床靶向治疗肿瘤具有重要意义。本文从肿瘤干细胞的发现过程、生物学特性、鉴别及培养方法等方面进行了阐述,根据其特点总结针对肿瘤干细胞治疗肿瘤的方法,并重点综述抗生素治疗肿瘤干细胞的研究进展。     

靶向乳腺癌干细胞免疫治疗的研究进展北大核心CSCD

乳腺癌是一种高侵袭性的恶性肿瘤.近年来,我国乳腺癌的发病人数逐年增加,其高复发率给乳腺癌患者的生存带来了严重威胁.肿瘤干细胞在乳腺癌的发生及进展中扮演了重要角色,是乳腺癌治疗的关键靶点.因此,开发新的靶向乳腺癌干细胞(breast cancer stem cell,BC-SC)的方法对于乳腺癌的治疗至关重要.肿瘤干细胞具有独特的免疫学特性,靶向BCSC的免疫治疗具有巨大的前景.目前已开发的靶向BCSC的免疫疗法包括DC疫苗、CAR-T细胞、免疫检查点抑制剂、溶瘤病毒和单克隆抗体等,为乳腺肿瘤的根除带来了希望.然而,由于缺乏BCSC的特异性标志物,设计有效的BCSC靶向疗法面临着巨大挑战.此外,由于肿瘤的低免疫原性和免疫逃逸特性,免疫疗法在实体肿瘤的治疗中所取得的临床效果仍然有限.全文旨在对靶向BCSC免疫治疗的最新进展和存在问题进行总结与展望,从而为临床和科研工作带来更多新的思路.     

Targeting breast cancer stem cells

The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self‐renewing CSC population that is also capable of differentiating into non‐self‐renewing cell populations that constitute the bulk of the tumor. Although, the CSC hypothesis does not directly address the cell of origin of cancer, it is postulated that tissue‐resident stem or progenitor cells are the most common targets of transformation. Clinically, CSCs are predicted to mediate tumor recurrence after chemo‐ and radiation‐therapy due to the relative inability of these modalities to effectively target CSCs. If this is the case, then CSC must be efficiently targeted to achieve a true cure. Similarities between normal and malignant stem cells, at the levels of cell‐surface proteins, molecular pathways, cell cycle quiescence, and microRNA signaling present challenges in developing CSC‐specific therapeutics. Approaches to targeting CSCs include the development of agents targeting known stem cell regulatory pathways as well as unbiased high‐throughput siRNA or small molecule screening. Based on studies of pathways present in normal stem cells, recent work has identified potential “Achilles heals” of CSC, whereas unbiased screening provides opportunities to identify new pathways utilized by CSC as well as develop potential therapeutic agents. Here, we review both approaches and their potential to effectively target breast CSC.     

Complexity of cancer stem cells

Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy‐based model in which cancer stem cells (CSCs) have the ability both to self‐renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.     

结直肠癌干细胞及靶向治疗研究进展

肿瘤干细胞是一类未分化的原始肿瘤细胞,是肿瘤转移,复发和耐药的根源。研究结直肠癌干细胞及标志物对于寻求针对肿瘤干细胞的治疗措施将是肿瘤治疗研究的新方向,针对性的靶向治疗将成为肿瘤治疗的研究热点。     

Targeting of cancer stem cells by differentiation therapy

Chemoresistance is a hallmark of cancer stem cells (CSCs). To develop novel therapeutic strategies that target CSCs, we established osteosarcoma‐initiating (OSi) cells by introducing the c‐Myc gene into bone marrow stromal cells derived from Ink4a/Arf KO mice. These OSi cells include bipotent committed cells (similar to osteochondral progenitor cells) with a high tumorigenic activity as well as tripotent cells (similar to mesenchymal stem cells) of low tumorigenicity. We recently showed that the tripotent OSi cells are highly resistant to chemotherapeutic agents, and that depolymerization of the actin cytoskeleton in these cells induces their terminal adipocyte differentiation and suppresses their tumorigenicity. We here provide an overview of modulation of actin cytoskeleton dynamics associated with terminal adipocyte differentiation in osteosarcoma as well as discuss the prospects for new therapeutic strategies that target chemoresistant CSCs by inducing their differentiation.     

干细胞标志物在卵巢癌SKOV3细胞侧群细胞中的表达

目的：检测干细胞相关标志物在卵巢癌SKOV3细胞系侧群（side population,SP）细胞和非侧群（Non-SP）细胞中的表达差异,确定卵巢癌干细胞特异性标志物。 方法： Hoechst 33342染色检测SKOV3细胞中SP细胞的比例,流式细胞术检测SKOV3细胞的SP和Non-SP细胞中干细胞标志物CD133、CD117、CD44、ABCG2、ALDH1 的表达情况,荧光定量PCR检测SP和Non-SP细胞中 ABCG2、ALDH2、NANOG、OCT4、SOX2、CD133、CD117 mRNA的表达水平。 结果： SKOV3细胞中SP细胞比例为(1.56±0.35)%。 ALDH1、ABCG2在SP细胞中表达率分别为（87.3±5.76）%、（29.48±4.43）%,在Non-SP的表达率分别为（5.32±0.47）%、（3.01±1.69）%,差异有统计学意义（ P <0.01）;CD44在这两种细胞亚群中的表达率均高于99%（ P >005）;CD133、CD117在这两种细胞亚群中均不表达。 ALDH1、ABCG2、 NANOG、OCT4和SOX2 mRNA在SP细胞中的表达分别是Non-SP细胞的21.03倍（ P =0.001）、3.14倍（ P =0.001）、23.94倍（ P =0.001）、10.73倍（ P =0.009）和21.46倍( P =0001), CD133、CD117 mRNA在两种细胞亚群中均不表达。 结论： 人卵巢癌细胞株SKOV3中存在SP细胞亚群, ALDH1、ABCG2和NANOG、OCT4、SOX2 mRNA可能是卵巢癌干细胞标志物,为诊断及治疗卵巢癌提供了潜在的靶点。     

肿瘤干细胞的研究进展

近年来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,越来越多的证据显示肿瘤与干细胞有着密切的关系,肿瘤可能是干细胞在异常微环境中差异分化的结果,并提出了肿瘤干细胞（tumor stem cell,TSC）的学说。本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,旨在为肿瘤发生发展研究及干细胞在肿瘤治疗方面的应用提供理论依据。     

Targeting cancer stem cells: a new therapy to cure cancer patients

Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. They have been identified in blood, breast, brain, colon, melanoma, pancreatic, prostate, ovarian, lung cancers and so on. It is often considered to be associated with chemo-resistance and radio-resistance that lead to the failure of traditional therapies. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells. Eradicating cancer stem cells, the root of cancer origin and recurrence, has been thought as a promising approach to improve cancer survival or even to cure cancer patients. Understanding the characteristics of cancer stem cells will help to develop novel therapies to eliminate the initiating cancer stem cell, and the relevant patents on the cancer stem cell and cancer therapy by cancer stem cells will be discussed.     

Tumor heterogeneity and cancer stem cell paradigm: Updates in concept,controversies and clinical relevance

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path‐breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage‐tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage‐tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self‐renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non‐CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In‐spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.     

抗肝癌干细胞功能性单克隆抗体的研制

摘 要? 目的：研制抗肝癌干细胞的功能性单克隆抗体,为肝癌干细胞的靶向治疗提供候选抗体药物。方法：从人肝癌组织中分离人肝癌干细胞样细胞（human liver cancer stem-like cells, hLCSLCs）,免疫BALB/c裸鼠,采用脾细胞融合法制备大容量单抗库。应用细胞免疫荧光、无血清成球培养、裸鼠皮下成瘤等方法筛选、鉴定特异识别肝癌干细胞的单克隆抗体。流式细胞仪分选hLCSLCs侧群细胞（hLCSLCs side population cells, hLCSLCs-SP）,无血清悬浮培养法和CCK-8法检测杂交瘤单抗对hLCSLC-SP自我更新和增殖能力的影响。结果：细胞融合后获得2 964株杂交瘤克隆,在能与hLCSLCs反应的237株克隆中,有116株单抗能与hLCSLCs的细胞膜结合,其中的33株杂交瘤单抗只与hLCSLC-SP反应（阳性率为2%~5%）、不与非hLCSLC-SP反应。该33株单抗中有6株能与CD133阳性细胞有不同比例的共染,并且与无血清悬浮培养的成球细胞呈阳性反应(阳性率为3%~26%),明显高于hLCSLCs-SP。裸鼠皮下接种1×104个15D2单抗阳性的hLCSLCs,成瘤率为100%。功能性筛选实验发现,6株单抗中的4株能显著抑制hLCSLC-SP的增殖和成球生长,其抑制率分别为24%~42%和13%~50%。结论：采用自建的大容量单克隆抗体库技术,筛选获得了4株特异性识别hLCSLC-SP的功能性单抗,为肝癌干细胞的抗体靶向治疗奠定了基础。