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1、精品文档，仅供学习与交流，如有侵权请联系网站删除肿瘤干细胞的发育调控研究进展摘要：肿瘤中存在肿瘤干细胞。肿瘤干细胞数目极少，却对肿瘤发生、转移起决定性的作用。肿瘤干细胞是一种特殊类型的干细胞，具备高度增殖能力与自我更新能力，可以多向分化为包括肿瘤细胞在内的各种细胞的子细胞，其结果是维持肿瘤干细胞数目稳定并产生肿瘤。本文介绍了肿瘤干细胞的历史、特征以及与成体干细胞的关系，最后对肿瘤干细胞理论在肿瘤临床的意义进行了初步的阐述。关键词：肿瘤干细胞、发育、调控前言: 干细胞是存在于动物和人的一种特殊功能细胞，具有多种分化能力和自我更新能力。干细胞生物学特性包括：(1)全能性或多功能性，干细胞具有分为多
2、种类型细胞的潜能；(2)自我更新能力，干细胞一旦形成，在机体终生都具有自我更新能力，通过不均一分裂进行自我更新和产生分化祖细胞，维持机体组织器官的稳定性。(3)高度增殖能力，对于维持机体正常功能有着重要的作用。肿瘤干细胞(tumor stem cells,TSC)表现为一种特殊类型的干细胞，具备高度增殖能力与自我更新能力，也具备多向分化的潜能。TSC增殖过程中，通过不均一分裂，一个TSC分裂形成一个新的TSC和另一个可最终分化为包括肿瘤细胞在内的各种细胞的子细胞，其结果是维持TSC数目稳定并产生肿瘤。1肿瘤干细胞简介定义 肿瘤如同人体其他组织，也是由具有不同增殖潜能的异质细胞组成，这些细胞的很
3、小一部分能通过移植产生肿瘤，这一小部分细胞被称为TSC。它有着干细胞的属性即自我更新和分化能力。有学者将其定义为：能分化出不同表型的非致瘤性肿瘤细胞，而且也能自我克隆产生子代致瘤性细胞的肿瘤细胞。细胞起源 人体各种组织都存在干细胞，人们根据干细胞分化潜能的不同将干细胞分为：(1)全能干细胞，如胚胎干细胞，具有全能性，可分化发育成机体任何一部分组织器官的能力。(2)多能干细胞，为成人组织干细胞，包括神经干细胞、血液干细胞、骨髓间充质干细胞、表皮干细胞等。能产生出几种不同类型的细胞。(3)单能干细胞，如肝干细胞。 TSC因为在各种致瘤因素的作用下，在基因水平失去对其生长的正常调控，而表现出无限增殖
4、、转移、异质性等特点。随着对肿瘤发病机制认识的深入，人们发现干细胞与TSC有很多极为相似的特征：(1)都具有无限增殖和分化的特点；(2)存在相似的调节自我更新的信号传导途径；(3)都具有不同表型，异质性；(4)都具有端粒酶活性；都能转移到各种不同的组织且有相似的归巢和转移途径。当然，TSC还具有不同于干细胞的特点：(1)自我更新信号转导途径的负反馈机制已被破坏；(2)缺乏分化成熟能力；(3)倾向于累积复制的错误，而干细胞能够防止复制错误的发展等。从TSC和干细胞的异同点不难看出，TSC可能起源于相应正常干细胞的突变。1根据干细胞理论，肿瘤干细胞起源于干细胞，在增殖过程中必然也存在异常的分化现象
5、。肿瘤干细胞在肿瘤的发生发展中起着关键性作用，它与肿瘤的转移、抗药性的产生以及治疗后的复发有密切关系。Skipper曾将一个L1210白血病干细胞注入小鼠体内，即可产生致死量的肿瘤细胞，这说明肿瘤组织中存在一种能自我更新和增殖产生肿瘤群体的细胞肿瘤干细胞。2人的肿瘤也同样存在着肿瘤干细胞。Muhammad等从乳腺癌中分离鉴定出一类表型特异的细胞群，即ESA+CD44+CD24-/LowLin-,将这类细胞称为成瘤细胞，发现这类细胞在NOD/SCID鼠中可持续地形成肿瘤。肿瘤干细胞的成功分离证明了肿瘤干细胞的存在，同时找到肿瘤恶变的源泉，为药物治疗明确了靶细胞。肿瘤干细胞中抑癌基因的研究概况和功
6、能研究 临床治疗方面 TSC理论可以解释临床上肿瘤对放射治疗与化疗药物治疗不敏感的原因。TSC理论认为，肿瘤一开始就有转移能力，只要TSC到达一个新的区域，转移将不可避免。所以，肿瘤治疗的焦点是杀伤TSC。针对TSC治疗肿瘤已经取得一定的进展：在80%前列腺癌中表达的特有标记前列腺干细胞抗原，是前列腺癌治疗很好的靶点。使用分子芯片技术，可分析TSC与他们相应成体干细胞基因表达特征的不同。利用这种差异，可能会出现既直接针对TSC，又能保护成体干细胞的治疗手段；自体造血干细胞移植中，通过TSC的特征标记，可以去除污染的TSC。3TSC理论对肿瘤诊断与预后判断的影响 慢性粒细胞白血病中肿瘤细胞的CD
7、38阳性率大于20%的患者，其病情往往处于进展期;而CD38阴性的患者预后较好。 恶性程度高的成神经管细胞瘤与胶质母细胞瘤较恶性程度较低的星形细胞瘤含TSC的比例要高一些。Clarke指出，极度恶性的乳腺癌，其TSC的比例可达到肿瘤细胞总数的25%。前列腺早期干细胞突变形成的肿瘤会表达一些神经内分泌标志，象嗜铬粒蛋白A(CgA)，但不表达特异性前列腺抗原(PSA) ;源于分化晚期的前列腺干细胞产生的肿瘤细胞表达PSA，而不是CgA。以此类推，源于分化中期干细胞的前列腺癌会同时表达CgA和PSA。通过对根据CSC生物学特性以及相关信号通路的深入研究,针对CSC细胞的调控机制,寻找特异性靶向CSC
8、的药物,为治疗癌症提供理论基础和新途径。上述调控肿瘤生长。增殖的信号通路如Wnt。Notch。VEGFR。CDC2。NF-B以及PTEN等都在肿瘤干细胞的自我更新中发挥重要的作用,因此利用相关抑制药物选择性的靶向这些异常通路,是治疗癌症的可行手段。相关研究报道,axin(-catenin的抑制因子)抑制异常激活的Wnt信号通路,可以使慢性粒细胞白血病的CSC增殖力降低。Notch通路-分泌酶(-secretase)抑制剂GSI218能降低CD133+ 的细胞比率。环王巴明(Hedgehog信号通路受体SMO的天然抑制剂)可使胶质瘤球的形成数目明显下降。虽然目前发现的大部分CSC标记在NSC中也
9、存在,但随着更多CSC特异标记物的发现,CSC标记有望成为治疗靶点。以高表达于急性髓性白血病干细胞中的黏附分子CD44为靶点,Jin等发现, H90(抗CD44 的单克隆抗体)能有效靶向白血病干细胞,降低了白血病干细胞的自我更新和转移能力。4诱导CSC分化也是治疗癌症的一种方法,在利用全反式维甲酸治疗急性早幼粒白血病患者中,大约90%患者获得完全缓解,超过70%的患者获得治愈,全反式维甲酸可能诱导了白血病干细胞的分化。骨形成蛋白(BMP)能诱导神经前体细胞分化成星形胶质细胞,在恶性胶质瘤中,BMP能促进CD133+ 脑肿瘤干细胞的分化,并降低其致瘤能力。微环境对肿瘤干细胞的自我更新也起着重要的
10、作用。研究表明,播散于骨髓的细胞角蛋白阳性的乳腺癌细胞,在原发灶去除后并不复发,说明干细胞的激活有可能依赖于微环境,提示可以通过改变干细胞的微环境,达到诱导其凋亡或死亡的目的。在神经系统肿瘤中, CSC存在于微血管丰富的微环境中, 扰乱这种微环境可能靶向肿瘤干细胞。用Erlotinib (选择性的EGFR 和ERBB2 酪氨酸激酶抑制剂) 或Bevacizumab (抗VEGF的单克隆抗体) 处理后, 肿瘤微环境中的微血管的密度下降, 肿瘤干细胞的数目也明显降低, 但没有影响到肿瘤中大部分细胞的增殖和凋亡, 提示其选择性地作用于肿瘤干细胞。5Stem-cell ruling riles res
11、earchersClinics that offer unproven stem-cell treatments often end up playing cat and mouse with health regulators, no matter which country they operate in. In Italy, however, one such treatment now has official sanction. The countrys health minister, Renato Balduzzi, has decreed that a controversia
12、l stem-cell treatment can continue in 32 terminally ill patients, mostly children even though the stem cells involved are not manufactured according to Italys legal safety standards.The unexpected decision on 21 March has horrified scientists, who consider the treatment to be dangerous because it ha
13、s never been rigorously tested. In the opinion of stem-cell researcher Elena Cattaneo of the University of Milan: “It is alchemy”.6Defining the mode of tumour growth by clonal analysisRecent studies using the isolation of a subpopulation of tumour cells followed by their transplantation into immunod
14、eficient mice provide evidence that certain tumours1, 2, including squamous skin tumours3, 4, 5, contain cells with high clonogenic potential that have been referred to as cancer stem cells (CSCs). Until now, CSC properties have only been investigated by transplantation assays, and their existence i
15、n unperturbed tumour growth is unproven. Here we make use of clonal analysis of squamous skin tumours using genetic lineage tracing to unravel the mode of tumour growth in vivo in its native environment. To this end, we used a genetic labelling strategy that allows individual tumour cells to be mark
16、ed and traced over time at different stages of tumour progression. Surprisingly, we found that the majority of labelled tumour cells in benign papilloma have only limited proliferative potential, whereas a fraction has the capacity to persist long term, giving rise to progeny that occupy a significa
17、nt part of the tumour. 7As well as confirming the presence of two distinct proliferative cell compartments within the papilloma, mirroring the composition, hierarchy and fate behaviour of normal tissue, quantitative analysis of clonal fate data indicates that the more persistent population has stem-
18、cell-like characteristics and cycles twice per day, whereas the second represents a slower cycling transient population that gives rise to terminally differentiated tumour cells. Such behaviour is shown to be consistent with double-labelling experiments and detailed clonal fate characteristics. By c
19、ontrast, measurements of clone size and proliferative potential in invasive squamous cell carcinoma show a different pattern of behaviour, consistent with geometric expansion of a single CSC population with limited potential for terminal differentiation. This study presents the first experimental ev
20、idence for the existence of CSCs during unperturbed solid tumour growth.3A restricted cell population propagates glioblastoma growth after chemotherapyGlioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year1. This poor prognosis is due to t
21、herapeutic resistance and tumour recurrence after surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is admi
22、nistered to transiently arrest tumour growth. A nestin-TK-IRES-GFP (Nes-TK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a t
23、umour re-growth cell hierarchy originating with the Nes-TK-GFP transgene subpopulation. 8Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset
24、 of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.9Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Aden
25、omasThe concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted great interest but remains controversial. Studying mouse models, we provide direct, functional evidence for the presence of stem cell activity within primary intestinal adenom
26、as, a precursor to intestinal cancer. By “lineage retracing” using the multicolor Cre-reporter R26R-Confetti, we demonstrate that the crypt stem cell marker Lgr5 (leucine-rich repeatcontaining heterotrimeric guanine nucleotidebinding proteincoupled receptor 5) also marks a subpopulation of adenoma c
27、ells that fuel the growth of established intestinal adenomas. These Lgr5+ cells, which represent about 5 to 10% of the cells in the adenomas, generate additional Lgr5+ cells as well as all other adenoma cell types. The Lgr5+ cells are intermingled with Paneth cells near the adenoma base, a pattern r
28、eminiscent of the architecture of the normal crypt niche.10结语目前，在血液肿瘤、乳腺癌、脑肿瘤及前列腺癌中恶性肿瘤干细胞已被发现并分离。但是，各种TSC的鉴定与分离、TSC特征以及TSC与成体干细胞的确切关系，迫切需要通过一些严谨而富有想象力的实验进行探索。TSC理论是肿瘤基础与临床理论上的突破，必将对肿瘤发生、发展的了解，以及肿瘤的临床诊断、治疗都带来深远的影响。然目前实体瘤干细胞的研究仍存在一些问题如CSC所占肿瘤细胞总数很少且同种肿瘤中CSC比率变化相当大0.1% 30%不等,给CSC的鉴定和分选带来困难,大多数肿瘤干细胞特异性
29、标记仍不清楚,与正常干细胞有许多共性,缺乏有效的标记物去鉴别,同时肿瘤干细胞自我更新的机制。调节机理与小分子RNA间的关系还有待进一步研究。但在对肿瘤干细胞的研究不断深入中,我们逐渐对肿瘤干细胞的形成。分化。转移等多方面有了较为全面深刻的认识,由此开发出针对肿瘤干细胞的特异药物或诊断试剂将对肿瘤的预防,诊断和治疗及预后评估产生深远影响,为肿瘤患者带来福音。1References: 1.Metcalfe, C. and F.J. de Sauvage, A tumor-specific stem cell. Nat Genet, 2013. 45(1): p. 7-9. 2.Spath, C.,
30、 et al., Inverse Relationship between Tumor Proliferation Markers and Connexin Expression in a Malignant Cardiac Tumor Originating from Mesenchymal Stem Cell Engineered Tissue in a Rat in vivo Model. Front Pharmacol, 2013. 4: p. 42. 3.Theurich, S., et al., Brentuximab vedotin combined with donor lym
31、phocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustained clinical remission. J Clin Oncol, 2013. 31(5): p. e59-63. 4.Liu, L.N., et al., Comparison of drug and cell-based delivery: engineered adult mesenchymal ste
32、m cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models. Stem Cells Transl Med, 2013. 2(5): p. 362-75. 5.Borghese, C., et al., Gefitinib inhibits the cross-talk between mesenchymal stem cells and prostate cancer cells leading to tumor cell prolif
33、eration and inhibition of docetaxel activity. J Cell Biochem, 2013. 114(5): p. 1135-44. 6.Bianchi, G., et al., Close interactions between mesenchymal stem cells and neuroblastoma cell lines lead to tumor growth inhibition. PLoS One, 2012. 7(10): p. e48654. 7.Gill, S. and D.L. Porter, Reduced-intensi
34、ty hematopoietic stem cell transplants for malignancies: harnessing the graft-versus-tumor effect. Annu Rev Med, 2013. 64: p. 101-17. 8.Hernanda, P.Y., et al., Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma. Carcinogenesis, 2013. 9.Fessler, E., et al.
35、, Cancer stem cell dynamics in tumor progression and metastasis: Is the microenvironment to blame? Cancer Lett, 2012.10.Gemei, M., et al., CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo. Cancer, 2013. 119(4): p. 729-38.References: 1.Me
36、tcalfe, C. and F.J. de Sauvage, A tumor-specific stem cell. Nat Genet, 2013. 45(1): p. 7-9. 2.Theurich, S., et al., Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustai
37、ned clinical remission. J Clin Oncol, 2013. 31(5): p. e59-63. 3.Fessler, E., et al., Cancer stem cell dynamics in tumor progression and metastasis: Is the microenvironment to blame? Cancer Lett, 2012. 4.Gemei, M., et al., CD66c is a novel marker for colorectal cancer stem cell isolation, and its sil
38、encing halts tumor growth in vivo. Cancer, 2013. 119(4): p. 729-38. 5.Bianchi, G., et al., Close interactions between mesenchymal stem cells and neuroblastoma cell lines lead to tumor growth inhibition. PLoS One, 2012. 7(10): p. e48654. 6.Liu, L.N., et al., Comparison of drug and cell-based delivery
39、: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models. Stem Cells Transl Med, 2013. 2(5): p. 362-75. 7.Borghese, C., et al., Gefitinib inhibits the cross-talk between mesenchymal stem cells and prostate cancer
40、cells leading to tumor cell proliferation and inhibition of docetaxel activity. J Cell Biochem, 2013. 114(5): p. 1135-44. 8.Spath, C., et al., Inverse Relationship between Tumor Proliferation Markers and Connexin Expression in a Malignant Cardiac Tumor Originating from Mesenchymal Stem Cell Engineer
41、ed Tissue in a Rat in vivo Model. Front Pharmacol, 2013. 4: p. 42. 9.Gill, S. and D.L. Porter, Reduced-intensity hematopoietic stem cell transplants for malignancies: harnessing the graft-versus-tumor effect. Annu Rev Med, 2013. 64: p. 101-17.10.Hernanda, P.Y., et al., Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma. Carcinogenesis, 2013.【精品文档】第 6 页