Wnt/β-catenin信号转导通路与脑胶质瘤

Wnt/β-catenin信号转导通路是一种在进化中高度保守的信号通路,它参与了胚胎生长、发育、能量代谢和干细胞维持等多种生物学过程的调控.Wnt/β-catenin通路的异常激活与肿瘤的发生密切相关.探讨Wnt/β-catenin信号转导通路与脑胶质瘤细胞增殖、侵袭、凋亡和肿瘤新生血管形成的关系将为脑胶质瘤的治疗提供新的靶点与干预措施.     

Notch信号通路与脑肿瘤

Notch信号通路作为一个对细胞的生长发育具有广泛多样化影响的信号途径,也与肿瘤的发生、发展相关.对于不同的肿瘤或同一肿瘤的不同级别、不同发展阶段Notch信号通路可能具有不同作用.Notch信号在一些脑肿瘤(脑胶质瘤、髓母细胞瘤、神经母细胞瘤、脑膜瘤)中异常表达,且参与这些脑肿瘤的发生、发展.     

血管内皮生长因子和Notch信号通路与肿瘤血管生成

血管内皮生长因子(VEGF)和Notch信号通路是血管发育及肿瘤血管生成的重要机制.阻断VEGF可抑制肿瘤生长和血管生成.Notch能抑制内皮形成尖端细胞,减少血管生成.实验证明,两条通路相互作用,联合阻断VEGF和Notch信号通路可协同抑制肿瘤生长.对VEGF和Notch通路的研究,将为肿瘤临床治疗提供新的方法.     

Notch信号通路在肿瘤干细胞中的研究进展

肿瘤干细胞是一类具有自我更新分化能力,在移植动物宿主中具有致瘤性且对放化疗抵抗的细胞小亚群,是肿瘤复发转移的主要原因。Notch信号通路在进化中高度保守,具有调控细胞增殖、分化和凋亡的功能,且在维持肿瘤干细胞的干细胞特性方面发挥重要作用,在干细胞中与多个信号通路存在交互作用。通过抑制Notch信号通路靶向作用肿瘤干细胞的治疗策略已进入临床试验阶段,具有广阔的发展前景。全文就Notch信号通路在肿瘤干细胞中的作用及其与Wnt、TGF-β、Her-2信号通路的交互作用进行阐述与分析。     

胶质瘤干细胞及相关的信号转导通路

胶质瘤干细胞(glioma stem cells,GSC)是近年来在胶质瘤组织中发现的肿瘤干细胞。GSC具有自我更新和分化的能力,可以通过不断分化产生新的肿瘤;对GSC标志物的鉴定有助于胶质瘤恶性程度的诊断。GSC的起源目前仍不明确,成熟的神经胶质细胞、限制性神经祖细胞以及神经干细胞均可能为GSC的前体。推测如Wnt、Notch、SHH、BMI1、PTEN等信号通路活跃在GSC中,一些新的治疗手段通过作用于GSC的信号转导通路可靶向治疗胶质瘤。深入研究GSC的起源、标志物以及相关信号转导通路,可为胶质瘤治疗提供新的策略。     

Notch信号通路与神经系统肿瘤

Notch信号在神经系统的发育过程中对细胞增殖和分化的调控起关键性的作用。Notch信号通路的失调与神经系统肿瘤关系密切,在神经母细胞瘤,胶质瘤,髓母细胞瘤等神经系统来源的肿瘤中均发现Notch信号通路受体、配体及其下游成分的失调。通过对Notch信号通路的调控可以诱导肿瘤细胞的分化及促进死亡,Notch信号分子可作为神经系统肿瘤基因治疗及新药开发的靶点。     

Notch信号通路与乳腺癌

Notch信号传导通路是影响细胞命运决定的重要通路之一，相邻细胞间通过Notch受体传递信号可以调节包括干细胞在内的多种细胞的分化、增殖和凋亡，影响器官形成和形态发生。Notch信号传导通路中某些分子的基因突变与多种肿瘤的发生发展有关。Notch信号在肿瘤中的作用多样，在不同类型肿瘤中呈现出不同的促癌或抑癌功能。在深入研究Notch信号传导通路的基础上，以其作为靶点设计药物。本文综述了Notch信号通路的组成、其激活方式和主要相关分子以及Notch信号通路在乳腺癌中的作用。     

胶质瘤干细胞的研究新进展

胶质瘤干细胞存在于多种脑胶质瘤组织和细胞系。胶质瘤干细胞具有类似神经干细胞的特性,但在基因表达、分化、动物体内成瘤性、耐药性和耐辐射性等方面又不同于神经干细胞。CD133和nestin作为目前公认的神经干细胞表面标志,被应用于胶质瘤干细胞的分离鉴定。靶向胶质瘤干细胞的树突细胞疫苗的开发和靶向肿瘤干细胞信号传导通路的实验研究为脑胶质瘤的治疗提供了新途径。     

Jagged1/Notch通路与肿瘤血管生成的研究进展

肿瘤的增殖、浸润和转移与肿瘤血管生成(tumor angiogenesis)密切相关,因此抗肿瘤血管生成己经成为肿瘤综合治疗的重要策略。Notch通路在内皮细胞的发育分化、干细胞分化、血管形成及肿瘤发生发展过程中具有重要作用。最近的一系列研究发现,Jagged1作为表达于肿瘤细胞表面的配体之一,可影响Notch信号通路,增强癌细胞VEGF活性,刺激肿瘤新生血管形成从而促进肿瘤生长、侵袭及转移。这一发现为完善肿瘤新生血管与肿瘤生长关系学说提供了新的研究方向。     

Notch信号通路在肿瘤微环境中的调控作用

摘 要：肿瘤细胞与肿瘤微环境（tumor microenvironment，TME）之间通过多种信号通路相互作用，其中Notch信号被认为是重要的信号通路之一。现已证实Notch信号与TME之间的相互作用参与调节肿瘤的血管生成、肿瘤干细胞干性的维持、免疫细胞的浸润和对治疗的抗性。此外，Notch信号还介导许多分子的分泌，影响TME中的细胞功能。大量研究表明，Notch信号在TME中的作用与不同肿瘤中Notch的促癌和抑癌特性有关。该综述讨论了Notch信号在调节TME不同组分之间的相互作用中发挥的重要作用，还从治疗的角度讨论了Notch―TME相互作用的结果。     

Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells

Emerging studies have identified microRNAs (miRNAs) as possible therapeutic tools for the treatment of glioma, the most aggressive brain tumor. Their important targets in this tumor are not well understood. We recently found that the Notch pathway is a target of miRNA-326. Ectopic expression of miRNA-326 in glioma and glioma stem cells induced their apoptosis and reduced their metabolic activity. Computational target gene prediction revealed pyruvate kinase type M2 (PKM2) as another target of miRNA-326. PKM2 has recently been shown to play a key role in cancer cell metabolism. To investigate whether it might be a functionally important target of miR-326, we used RNA interference to knockdown PKM2 expression in glioma cells. Transfection of the established glioma and glioma stem cells with PKM2 siRNA reduced their growth, cellular invasion, metabolic activity, ATP and glutathione levels, and activated AMP-activated protein kinase. The cytotoxic effects exhibited by PKM2 knockdown in glioma and glioma stem cells were not observed in transformed human astrocytes. Western blot analysis of human glioblastoma specimens showed high levels of PKM2 protein, but none was observed in normal brain samples. Strikingly, cells with high levels of PKM2 expressed lower levels of miR-326, suggestive of endogenous regulation of PKM2 by miR-326. Our data suggest PKM2 inhibition as a therapy for glioblastoma, with the potential for minimal toxicity to the brain.     

Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype

Malignant gliomas are the prototype of highly infiltrative tumors and this characteristic is the main factor for the inevitable tumor recurrence and short survival after most aggressive therapies. The aberrant communication between glioma cells and tumor microenvironment represents one of the major factors regulating brain tumor dispersal. Our group has previously reported that the tyrosine kinase receptor Tie2/TEK is expressed in glioma cells and brain tumor stem cells and is associated with the malignant progression of these tumors. In this study, we sought to determine whether the angiopoietin 1 (Ang1)/Tie2 axis regulates crosstalk between glioma cells and endothelial cells. We found that Ang1 enhanced the adhesion of Tie2-expressing glioma and brain tumor stem cells to endothelial cells. Conversely, specific small interfering RNA (siRNA) knockdown of Tie2 expression inhibited the adhesion capability of glioma cells. Tie2 activation induced integrin β1 and N-cadherin upregulation, and neutralizing antibodies against these molecules inhibited the adhesion of Tie2-positive glioma cells to endothelial cells. In 2D and 3D cultures, we observed that Ang1/Tie2 axis activation was related to increased glioma cell invasion, which was inhibited by using Tie2 siRNA. Importantly, intracranial co-implantation of Tie2-positive glioma cells and endothelial cells in a mouse model resulted in diffusely invasive tumors with cell clusters surrounding glomeruloid vessels mimicking a tumoral niche distribution. Collectively, our results provide new information about the Tie2 signaling in glioma cells that regulates the cross-talk between glioma cells and tumor microenvironment, envisioning Tie2 as a multi-compartmental target for glioma therapy.     

The functional role of Notch signaling in human gliomas

Gliomas are among the most devastating adult tumors for which there is currently no cure. The tumors are derived from brain glial tissue and comprise several diverse tumor forms and grades. Recent reports highlight the importance of cancer-initiating cells in the malignancy of gliomas. These cells have been referred to as brain cancer stem cells (bCSC), as they share similarities to normal neural stem cells in the brain. The Notch signaling pathway is involved in cell fate decisions throughout normal development and in stem cell proliferation and maintenance. The role of Notch in cancer is now firmly established, and recent data implicate a role for Notch signaling also in gliomas and bCSC. In this review, we explore the role of the Notch signaling pathway in gliomas with emphasis on its role in normal brain development and its interplay with pathways and processes that are characteristic of malignant gliomas.     

Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells

Background  

Cancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma. Notch signaling, an evolutionarily conserved pathway mediating direct cell-cell interaction, has been shown to regulate neural stem cells (NSCs) and glioma stem cells (GSCs) in normal neurogenesis and pathological carcinogenesis, respectively. However, how Notch signaling regulates the proliferation and differentiation of GSCs has not been well elucidated.     

Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells

Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal and postnatal tissue differentiation. Roles for Notch in carcinogenesis, in the biology of cancer stem cells, tumor angiogenesis and epithelial-to-mesenchymal transition (EMT) have been reported. This mini-review describes the role of Notch signaling deregulation in EMT and tumor aggressiveness. We describe how accumulated evidence suggests that Notch inhibition is an attractive strategy for the treatment of several cancers, at least in part because of its potential to reverse or prevent EMT.     

异甘草素增加人脑胶质瘤干细胞放射敏感性的实验研究

  目的  研究异甘草素对胶质瘤干细胞（glioma stem cells，GSCs）放射敏感性的影响及作用机制。  方法  无血清培养法提取SHG44人脑GSCs。检测异甘草素和X射线联合运用下GSCs活性和干细胞球形成情况。检测Notch1信号通路、NF-κB和cas-pase-3的表达情况。  结果  采用10 μM异甘草素在8 Gy较高剂量X射线存在的情况下，能够抑制GSCs球的数目和直径（P＜0.05）。20 μM异甘草素杀伤GSCs的作用明显，且在4、8 Gy的X射线下联合杀伤GSCs的能力依次增强（P＜00.05）。异甘草素干作用48 h后Notch1的表达下调（P＜00.05）。4 Gy的X射线照射后，分别于6、24 h，异甘草素干预组P-NF-κB表达逐渐增高（P＜00.05），而cleaved caspase-3的表达在X射线照射后的24 h开始升高（P＜00.05）。  结论  异甘草素能够增加GSCs的放射敏感性，抑制Noch1信号通路，上调NF-κB和caspase-3的表达，参与X射线对GSCs的损伤过程。      

Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature

Background Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC.Methods Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice.Results By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control.Conclusion Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies.     

Notch信号通路与白血病干细胞的关系及研究进展

白血病是造血干细胞恶性克隆疾病,多是由染色体畸变诱发,使得造血干细胞（hematopoietic stem cells,HSCs）或更早期的多能祖细胞（multipotent progenitors,MPPs）遗传学发生改变。白血病在恶性肿瘤发病率排名前十位,死亡率高,且多发生在儿童及青年。目前白血病的治疗主要以化疗为主,随着新药的研发和造血干细胞的移植,白血病的缓解率较先前有所提高,但耐药和停药后复发成为治疗的一个难题。目前Notch已经成为公认的与白血病有关的癌基因之一,所以,以Notch为靶向治疗研究可能会给我们提供新的治疗方法。本文重点就Notch与白血病干细胞的关系及治疗进展作一综述。     

miR-129对乳腺癌肿瘤干细胞自我更新能力的调控作用及其机制探讨

目的:探究miR-129在乳腺癌中对肿瘤干细胞自我更新能力的调控作用及其机制。方法:应用免疫组化检测乳腺癌肿瘤干细胞在肿瘤组织与癌旁组织中的数量及其与乳腺癌肿瘤分期的关系,验证miR-129和Numb与乳腺癌肿瘤干细胞之间的相关关系。在体外实验中应用Western Blotting及RT-PCR验证miR-129通过阻断雌激素受体alpha（ER alpha,ESR1）对Notch信号通路的调节作用及其调节的具体机制;应用裸鼠成瘤实验验证miR-129在裸鼠体内水平对乳腺癌肿瘤干细胞的影响。结果:肿瘤组织中乳腺癌肿瘤干细胞的比例高于癌旁组织并与肿瘤分期具有相关性;乳腺癌肿瘤干细胞比例与临床样本中miR-129和Numb的表达水平呈负相关;乳腺癌肿瘤干细胞中miR-129的过表达与Notch信号通路的抑制直接相关,这种作用很可能是miR-129通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来实现的;miR-129在裸鼠体内实验中可以抑制乳腺癌肿瘤干细胞的成瘤。结论:miR-129在乳腺癌组织中可以通过调控Notch信号通路影响乳腺癌肿瘤干细胞自我更新的能力,具体的调节机制可能是通过调控ESR1所引起的Let-7b的表达下调进而导致Numb的释放来最终抑制Notch信号通路的激活。