肝癌组织中侧群细胞的检测及初步分析

随着对肿瘤研究的不断深入及对干细胞了解的日益加深,越来越多的研究证实,一些肿瘤组织中存在肿瘤干细胞.由于没有特异性的表面标记分子,迄今为止尚无成熟的肝癌干细胞的分离与鉴定技术,从而导致对肝癌干细胞的研究举步维艰.侧群(SP)细胞有着和组织特异的肿瘤干细胞几乎相同的功能和分子特点,快速的Hoechst 33342染料排斥特性可以应用到多种肿瘤干细胞的分离和纯化中,为肿瘤干细胞研究提供了更为便利的途径.本研究采用Hoechst 33342染色法从肝癌患者的肝癌组织中分离、培养肝癌SP细胞,并对其进行初步分析,为进一步研究其生物学特性奠定基础.     

结肠癌干细胞标志分子及其功能研究现状

结肠癌干细胞是一小部分存在于结肠癌中具有自我更新、无限增殖和多项分化潜能的肿瘤干细胞,它与结肠癌的复发、转移和治疗耐受有着密切的联系.通过结肠癌细胞表面表达的标志分子如CD133、CD44、CD29、ALDH1和Wnt等从结肠癌中分离得到少部分具有干细胞特性的结肠癌细胞即结肠癌干细胞,以这部分肿瘤干细胞作为肿瘤治疗靶点将为肿瘤治疗带来新的治疗方向.此文就标志分子在结肠癌干细胞筛选及生物学中的功能研究作一回顾,并探讨其作为肿瘤干细胞治疗靶点的可能性.     

肿瘤干细胞的研究进展

如何解决恶性肿瘤的复发和转移问题仍是当前肿瘤治疗中的一大难题.一种新的理论--肿瘤干细胞学说认为,在肿瘤组织中存在着少数具有干细胞性质的细胞群体,这些细胞具有自我更新能力和多向分化潜能,被称为肿瘤干细胞(cancer stem cells,CSCs);CSCs可能是导致恶性肿瘤复发和转移的根本原因.本文就CSCs分离纯化和鉴定的方法和多药耐药机制的研究进展情况进行综述.     

结肠癌干细胞表面标志物、特性及致病机制的研究概况

全球范围内结肠癌肿瘤发病位列第3位.随着分子生物学研究不断进步,人们发现肿瘤细胞中存在着一小部分特殊的细胞亚群,即肿瘤干细胞.肿瘤干细胞通过不断自我更新和分化使肿瘤具有持续生长、远处转移和复发的能力.研究表明,传统的放化疗无法彻底消除肿瘤干细胞,通过特异性细胞表面标志精确地将肿瘤干细胞从大量肿瘤细胞和正常健康细胞中分离,为精确靶向治疗提供了基础.充分认识和利用结肠癌干细胞的自我更新和分化机制,应用分子生物技术阻断其稳态调控,将成为靶向治疗结肠癌的新契机.     

肝癌干细胞的调控机制及靶向治疗的研究进展

随着肿瘤干细胞(cancer stem cells,CSCs)在人类许多实体肿瘤中得到证实,肝癌被认为很可能也是一种干细胞疾病.肝癌中是否存在肝癌干细胞(liver cancer stem cells,LCSCs)一直是近来研究热点.CSCs学说认为,肿瘤的发生、发展、转移、复发与耐药均与CSCs有密切关系.因此,确认并分离鉴定LCSCs对于早期预防及早期诊断、有效治疗及改善预后有着极为重要的作用.本文就LCSCs的来源、表面标志、信号转导与调控、治疗策略等方面的相关研究作一综述.     

未来肝癌治疗的新靶点-肝癌干细胞

肿瘤起源于干细胞的假说正在各种人类肿瘤中得到证实,肿瘤不单是一种基因病,而且是一种干细胞病.基因突变作用于干细胞,干细胞突变成为肿瘤干细胞,这是肿瘤发生、再生、转移和复发的关键.最新研究表明,肝细胞型肝癌可能是由肝干细胞未分化或分化不全引起的.对于肝癌细胞的研究我们知道肝细胞型肝癌中的细胞具有干细胞特性,如永生性,可移植性以及对治疗手段的抵抗性.但至今为止,确切的肝癌干细胞的标志物没有找到,而且没有分离出肝癌干细胞.     

侧群细胞与消化系恶性肿瘤干细胞研究

侧群(side population,SP)细胞是利用Hoechst33342染料和流式细胞术进行造血干/祖细胞分离时发现的一群特殊细胞,既有干细胞样自我更新和多向分化潜能,而且具有独特的SP表型标志,为干细胞研究提供了新的方向。侧群细胞在正常组织和恶性肿瘤细胞中均有表达,且其有与肿瘤干细胞相似的生物学特性。近年来在消化系肿瘤干细胞的研究中发现侧群细胞对于分选鉴定肿瘤干细胞意义重大。本文就侧群细胞与消化系肿瘤干细胞的关系进行研究。     

肺癌干细胞研究进展

肿瘤干细胞具有自我更新和分化潜能,是肿瘤转移、复发的根源.研究已证实肺癌干细胞的存在,但其分离和鉴定还存在一些争议.本文对肺癌干细胞学说、肺癌干细胞与肿瘤耐药、分子调控机制、治疗策略等进行综述,为肺癌的治疗提供新的策略.     

肝癌干细胞的研究进展

肿瘤干细胞已经被证实存在于一些肿瘤组织中,而肝癌干细胞是否存在仍未得到确切的结果.通过实验,研究人员对于肝癌干细胞的来源提出了两个假说:成熟肝细胞的去分化与肝干细胞的"成熟受阻".目前后者是较为公认的肝癌形成途径.同时,为了得到肝癌干细胞存在的直接证据,研究人员一直致力于其表面标志物的研究,希望通过得到理想的标志物来鉴定分选出肝癌干细胞.SP细胞与肝癌干细胞的研究也是目前研究的热点.因此,肝癌干细胞的研究将会对肝癌的诊断和治疗产生重大的意义.     

肿瘤干细胞与消化道肿瘤的研究进展

研究者发现肿瘤干细胞(CSC)在肿瘤的发生、发展、复发及转移过程中发挥着重要作用.CSC是存在于肿瘤组织中具有干细胞样能力的肿瘤细胞亚群,一个CSC能够产生整个肿瘤组织的(处于不同分化阶段的)所有肿瘤细胞[1].CSC概念的提出为研究肿瘤细胞的生物学特性提供了新思路,并为肿瘤的临床治疗提供了新靶点,目前已逐渐成为肿瘤防治研究的新的热点.     

The biology of cancer stem cells and its clinical implication in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor with limited treatment options in its advanced state. The molecular mechanisms underlying HCC remain unclear because of the complexity of its multi-step development process. Cancer stem cells (CSCs) are defined as a small population of cells within a tumor that possess the capability for self-renewal and the generation of heterogeneous lineages of cancer cells. To date, there have been two theories concerning the mechanism of carcinogenesis, i.e., the stochastic (clonal evolution) model and the hierarchical (cancer stem cell-driven) model. The concept of the CSC has been established over the past decade, and the roles of CSCs in the carcinogenic processes of various cancers, including HCC, have been emphasized. Previous experimental and clinical evidence indicated the existence of liver CSCs; however, the potential mechanistic links between liver CSCs and the development of HCC in humans are not fully understood. Although definitive cell surface markers for liver CSCs have not yet been found, several putative markers have been identified, which allow the prospective isolation of CSCs from HCC. The identification and characterization of CSCs in HCC is essential for a better understanding of tumor initiation or progression in relation to signaling pathways. These markers could be used along with clinical parameters for the prediction of chemoresistance, radioresistance, metastasis and survival and may represent potential targets for the development of new molecular therapies against HCC. This review describes the current evidence for the existence and function of liver CSCs and discuss the clinical implications of CSCs in patients demonstrating resistance to conventional anti-cancer therapies, as well as clinical outcomes. Such data may provide a future perspective for targeted therapy in HCC.     

The tumor stem cell concept—Implications for endocrine tumors?

The cancer stem cell hypothesis has recently evolved from an increasing body of evidence suggesting that in some cancers a small population of tumor cells with stem cell-like properties represents a critical component that dictates the malignant behavior of a given tumor. These observations challenge classical cancer biology and its theory, that tumor growth is mainly based on genomic alterations followed by modulation of cell cycle pathways, which finally result in uncontrolled clonal proliferation. Over the last few years, much progress in the field of tumor stem cells has been achieved in non-endocrine malignancies. In this review, we summarize the existing evidence regarding the tumor stem cell concept for tumor pathophysiology in general and highlight current models that have the potential to further impact research on endocrine tumors.     

Immunotherapy targeting colon cancer stem cells

In the last 10 years, cancer stem cells have interested the scientific community because this small tumorigenic population is also associated with tumor progression in human patients and specific targeting of cancer stem cells could be a strategy to eradicate cancers currently resistant to conventional therapy. Clinical studies have recently demonstrated that adding immune therapy to chemotherapy has survival benefits in comparison with chemotherapy alone that can sensitize tumors to immune cell-mediated killing (e.g., increasing sensitivity of tumor cells to subsequent cytotoxicity by T cells via upregulation of death receptors DR5 and Fas). However, loss of MHC molecules is often observed in cancer cells, rendering tumor cells resistant to CD8 T-cell-mediated cytotoxicity. For this reason, we review the role of other T-cell subsets, such as γδ T and NK cells that are able to efficiently recognize and kill tumor cells and that could be used in passive or active immunotherapy in cancer stem cell eradication.     

Chemopreventive drugs:Mechanisms via inhibition of cancer stem cells in colorectal cancer

Recent epidemiological studies,basic research and clinical trials on colorectal cancer(CRC)prevention have helped identify candidates for effective chemopreventive drugs.However,because of the conflicting results of clinical trials or side effects,the effective use of chemopreventive drugs has not been generalized,except for patients with a high-risk for developing hereditary CRC.Advances in genetic and molecular technologies have highlighted the greater complexity of carcinogenesis,especially the heterogeneity of tumors.We need to target cells and processes that are critical to carcinogenesis for chemoprevention and treatment of advanced cancer.Recent research has shown that intestinal stem cells may serve an important role in tumor initiation and formation of cancer stem cells.Moreover,studies have shown that the tumor microenvironment may play additional roles in dedifferentiation,to enable tumor cells to take on stem cell features and promote the formation of tumorigenic stem cells.Therefore,early tumorigenic changes of stem cells and signals for dedifferentiation may be good targets for chemoprevention.In this review,I focus on cancer stem cells in colorectal carcinogenesis and the effect of major chemopreventive drugs on stem cell-related pathways.     

Glioblastoma and stem cells

This review presents compelling evidence that human glioblastoma is a heterogenous tumor composed from tumor cells and small portion of cancer stem cells - tumor-initiating cells, which have a high tumorigenic potential and a low proliferation rate. Glioma cancer stem cells are phenotypically similar to the normal stem cells, they express CD133 gene and other genes characteristic of neural stem cells and posses the self-renewal potential. Cancer stem cells derived from glioblastoma are capable recapitulate original polyclonal tumors when xenografted to nude mice. They are chemoresistant and radioresistant and therefore responsible for tumor progression and recurrence after conventional glioblastoma therapy. Cancer stem cells contribute to glioma radioresistance by an increase of DNA repair capacity through preferential activation of the DNA damage response checkpoints. Potential therapies that modulate or target cancer stem cells are also reviewed. Mesenchymal stem cells and/or neural stem cells were shown to target brain tumors therefore these cells are considered as an effective delivery system to target and disseminate therapeutic agents to brain tumors. Stem cell-based gene therapies for glioblastoma were shown in experiments to be effective way to target brain tumors. Effects of bone morphogenetic protein (BMP4) on glioma cancer stem cells are also reviewed. BMP4 reduces effectively proliferation of CD133 positive cells in vitro and the tumor growth in vivo. BMP4 may act as a key inhibitory regulator of cancer initiation and therefore may be used in combined stem cell-based therapy as a non-cytotoxic therapeutic agent. Key words: Glioblastoma, cancer stem cells, CD113 marker, chemoresistance, radio-resistance, rat glioma models, vascular niche, mesenchymal stem cells, stem cell-based gene therapy, BMP4.     

CD20 positive cells are undetectable in the majority of multiple myeloma cell lines and are not associated with a cancer stem cell phenotype

Although new therapies have doubled the survival of multiple myeloma patients, this remains an incurable disease. It has been postulated that the so-called myeloma cancer stem cells would be responsible for tumor initiation and relapse but their unequivocal identification remains unclear. Here, we investigated in a panel of myeloma cell lines the presence of CD20(+) cells harboring a stem-cell phenotype. Thus, only a small population of CD20(dim+) cells (0.3%) in the RPMI-8226 cell line was found. CD20(dim+) RPMI-8226 cells expressed the plasma cell markers CD38 and CD138 and were CD19(-)CD27(-). Additionally, CD20(dim+) RPMI-8226 cells did not exhibit stem-cell markers as shown by gene expression profiling and the aldehyde dehydrogenase assay. Furthermore, we demonstrated that CD20(dim+) RPMI-8226 cells are not essential for CB17-SCID mice engraftment and show lower self-renewal potential than the CD20(-) RPMI-8226 cells. These results do not support CD20 expression for the identification of myeloma cancer stem cells.     

Stem cells in tumor angiogenesis

Contribution from diverse tissue-specific stem cell types is required to create the cell populations necessary for the activation of angiogenesis and neovascular growth in cancer. Bone marrow (BM)-derived circulating endothelial progenitors (EPCs) that would differentiate to bona fide endothelial cells (ECs) were previously believed to be necessary for tumor angiogenesis. However, numerous recent studies demonstrate that EPCs are not needed for tumor angiogenesis and indicate EPCs to be artifactual rather than physiological. It is evident that tumor infiltrating hematopoietic cells produced by BM-residing hematopoietic stem cells (HSCs) may contribute to tumor angiogenesis in a paracrine manner by stimulating ECs or by remodeling the extracellular matrix. Therefore, identification of the various hematopoietic cell subpopulations that are critical for tumor angiogenesis and better understanding of their proangiogenic functions and mechanisms of action have potential therapeutic significance. Stem and progenitor cell subsets for also other vascular or perivascular cell types such as pericytes or mesenchymal/stromal cells may provide critical contributions to the growing neovasculature. Furthermore, we hypothesize that the existence of a yet undiscovered—and largely unsearched—tissue-specific adult vascular endothelial stem cell (VESC) would provide completely novel targeted approaches to block pathological angiogenesis and cancer growth. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".     

干细胞、肿瘤干细胞与肿瘤发生

肿瘤干细胞是肿瘤研究的一个新热点,指出肿瘤可能是由肿瘤干细胞产生,肿瘤干细胞则由正常干细胞恶变形成.正常干细胞的特有性状,使其较成体细胞更易成为肿瘤发生的靶细胞.干细胞可能经基因突变、异常不对称分裂和细胞融合转化为肿瘤干细胞.利用不同的蛋白标志物或荧光探针,通过流式细胞仪分选是发现肿瘤干细胞的主要方法.已证实的肿瘤干细胞皆具有强大的自我更新和增殖能力,以及细胞分化潜能.针对肿瘤干细胞的检测和杀伤,可能为肿瘤早期诊断和治疗带来希望.     

A distinct "side population" of cells with high drug efflux capacity in human tumor cells

A subset of stem cells, termed the "side population" (SP), has been identified in several tissues in mammalian species. These cells maintain a high efflux capability for antimitotic drugs. We have investigated whether functionally equivalent stem cells also may be detected in human cancers. We initially examined primary tumor cells from 23 patients with neuroblastoma and cell lines derived from a range of other tumors. A distinct SP was found in neuroblastoma cells from 15 of 23 patients (65%). The SP was capable of sustained expansion ex vivo and showed evidence for asymmetric division, generating both SP and non-SP progeny. These cells also expressed high levels of ABCG2 and ABCA3 transporter genes and had a greater capacity to expel cytotoxic drugs, such as mitoxantrone, resulting in better survival. A SP also was detected in breast cancer, lung cancer, and glioblastoma cell lines, suggesting that this phenotype defines a class of cancer stem cells with inherently high resistance to chemotherapeutic agents that should be targeted during the treatment of malignant disease.