低氧诱导因子与铁代谢紊乱促肿瘤发展研究进展

肿瘤是威胁人类生命健康的严重疾病。低氧诱导因子（HIF）及铁代谢紊乱与肿瘤发展密切相关。铁是人体必需的微量元素,其含量受铁代谢相关蛋白调控。一般缺铁上调HIF表达,而HIF通过调控铁代谢相关蛋白以改变机体各部位铁含量。铁代谢紊乱和HIF上调促进肿瘤细胞增殖、迁移、侵袭及能量代谢异常,促进肿瘤血管生长,抑制肿瘤免疫微环境,从而促进肿瘤的发生与发展。联合使用铁离子螯合剂和HIF抑制剂能够显著增强其抗肿瘤作用,靶向铁代谢与HIF途径可能为肿瘤的研究与治疗提供新思路。     

低氧诱导因子1α在神经干细胞缺氧、复氧损伤的作用

取出生在24h内的Wistar大鼠,无菌条件下分离海马组织,制成细胞悬液,转入培养瓶中培养。7~8d传代一次。将实验组分两组(缺氧组、缺氧-复氧组),用CoCl2预处理,制备模拟缺氧模型。缺氧4h后去除CoCl2形成复氧,测定两组     

肿瘤干细胞和低氧微环境与肿瘤转移的关系

药品的有效期是指在一定的贮存条件下,能够保持质量的期限。为了保证药品的安全有效,现行的《药品管理法》明确规定,所有的药品都必须注明有效期,未注明有效期、更改有效期或者超过有效期的药品按劣药处理。但在药品制剂检验过程中,我们发现了药品有效期管理的不规范之处,现举例分析,并提出几点建议。     

肿瘤干细胞和低氧微环境与肿瘤转移的关系

恶性肿瘤迄今仍是一种难以根治的疾病.肿瘤干细胞(cancer stem cell, CSC)理论的提出为肿瘤的彻底治愈带来了希望,我们可以从CSC这一与正常干细胞同样具有自我更新功能的细胞群入手对肿瘤进行治疗.研究表明,CSC周围微环境在肿瘤形成、发展、侵袭、转移过程中有重要作用,尤其是低氧微环境与肿瘤转移密切相关[1].     

肿瘤干细胞和低氧微环境与肿瘤转移的关系

恶性肿瘤迄今仍是一种难以根治的疾病.肿瘤干细胞(cancer stem cell, CSC)理论的提出为肿瘤的彻底治愈带来了希望,我们可以从CSC这一与正常干细胞同样具有自我更新功能的细胞群入手对肿瘤进行治疗.研究表明,CSC周围微环境在肿瘤形成、发展、侵袭、转移过程中有重要作用,尤其是低氧微环境与肿瘤转移密切相关[1].     

低氧诱导因子抑制药在抗肿瘤方面的研究进展

低氧诱导因子抑制药(YC-1)是一种小分子物质,最初研究主要集中在心血管系统,如抗血小板聚集、收缩血管等方面。研究发现,YC-1能抑制低氧诱导因子-1α(HIF-1α)的表达,从而开启YC-1在抗肿瘤方面的研究。YC-1抗肿瘤作用是多方面的,包括细胞周期抑制和诱导肿瘤细胞凋亡、抗血管生成、抗炎性反应及抑制金属蛋白酶类(MMPs)等。     

低氧诱导因子抑制剂的研究进展

低氧诱导因子(hypoxia inducible factor,HIF)是机体的一种重要的转录因子,在缺氧状态下介导一系列的细胞低氧反应.低氧诱导因子在肿瘤发生发展过程中发挥重要调控作用,同时也介导了肿瘤放化疗抗性并与肿瘤患者不良预后密切相关.因此,低氧诱导因子抑制剂的相关研究对于肿瘤的理解与治疗具有重要意义.本文总结了低氧诱导因子抑制剂研究的3种思路与代表抑制剂,以期为低氧诱导因子抑制剂在肿瘤治疗中的应用奠定基础.     

低氧诱导因子-1α对细胞信号、细胞凋亡的影响及研究进展

低氧诱导因子-1（hypoxia—induciblefactor-1，HIF-1）是普遍存在于人和哺乳动物细胞内的缺氧应答调控因子，通过调控一系列与缺氧适应有关基因的表达以保持机体的氧稳态。HIF-1（尤其是HIF-1α）的表达水平与糖酵解、细胞周期阻滞、细胞生存与增殖、血管新生、血管舒缩、红细胞生成、肿瘤生长和转移以及肿瘤多药耐药等许多生命活动密切相关。多数肿瘤具有缺氧的微环境。HIF-1α对于肿瘤的效应是多方面的：HIF-1α在上游调控诸多与肿瘤发生密切相关的基因；肿瘤在低氧条件下选择更恶性的表型；增加细胞突变率；增加与血管新生和肿瘤侵袭有关的基因表达；低氧条件下细胞更具有耐药倾向。因此HIF-1α已经成为一个治疗肿瘤的新的关键性靶点。细胞信号、细胞凋亡在多细胞生物的个体发育、自稳平衡等生理以及肿瘤、炎症等病理过程中具有重要意义，理解HIF-1α对于细胞信号、细胞凋亡的调节，对于开发特异性的肿瘤治疗有着现实意义。现就HIF-1α对细胞信号、细胞凋亡的影响及研究进展作一综述。     

Role of microRNAs in maintaining cancer stem cells

Increasing evidence sustains that the establishment and maintenance of many, if not all, human cancers are due to cancer stem cells (CSCs), tumor cells with stem cell properties, such as the capacity to self-renew or generate progenitor and differentiated cells. CSCs seem to play a major role in tumor metastasis and drug resistance, but albeit the potential clinical importance, their regulation at the molecular level is not clear. Recent studies have highlighted several miRNAs to be differentially expressed in normal and cancer stem cells and established their role in targeting genes and pathways supporting cancer stemness properties. This review focuses on the last advances on the role of microRNAs in the regulation of stem cell properties and cancer stem cells in different tumors.     

Role of stem cells in normal liver and cancer

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world because current treatments, including both surgical and non-surgical ones, cannot effectively cure this disease. Increasing evidence has revealed the importance of cancer stem cells (CSCs) in hepatocarcinogenesis, and the idea of targeting CSCs sheds light on more effective therapeutic strategies for HCC. In this review, normal stem cells and putative CSCs in the liver are briefly introduced. Studies about signaling pathways that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs are also summarized and discussed.     

Natural killer cells preferentially target cancer stem cells; role of monocytes in protection against NK cell mediated lysis of cancer stem cells

Mounting effective anti-tumor immune responses by cytotoxic effectors is important for the clearance of tumors. However, accumulated evidence suggests that the cytotoxic function of immune effectors is largely suppressed in the tumor microenvironment by a number of distinct effectors and their secreted factors. The aims of this review are to provide a rationale and potential mechanism for immunosuppression in cancer, and to demonstrate the significance of such immunosuppression in cellular differentiation and tissue regeneration in pathological conditions, and progression of cancer. We have recently shown that increased NK cell function was seen when they were cultured with primary oral squamous carcinoma stem cells (OSCSCs) as compared to their more differentiated oral squamous carcinoma cells (OSCCs). In addition, human embryonic stem cells (hESCs), Mesenchymal Stem Cells (hMSCs), dental pulp stem cells (hDPSCs) and induced pluripotent stem cells (hiPSCs) were significantly more susceptible to NK cell mediated cytotoxicity than their differentiated counterparts or parental cells from which they were derived. We have also reported that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 augmented NK cell function significantly. Total population of monocytes and those depleted of CD16(+) subsets were able to substantially prevent NK cell mediated lysis of OSCSCs, MSCs and DPSCs. Taken together, our results suggest that stem cells are significant targets of the NK cell cytotoxicity. The concept of split anergy in NK cells and its contribution to tissue repair and regeneration and in tumor resistance and progression will be discussed in this review. Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation at the site of the tumor for specific elimination of cancer stem cells.     

Mesenchymal stem cells promote cardiomyocyte hypertrophy in vitro through hypoxia-induced paracrine mechanisms

1. Mesenchymal stem cell (MSC) therapy for myocardial infarction has received increased attention since transplanted MSC were shown to improve cardiac function by transdifferentiating into cardiomyocytes and endothelial cells. However, recent studies have demonstrated that other mechanisms may contribute to the improvement in cardiac function observed after transplantation of MSC. The paracrine effect of MSC on cardiomyocyte is not clear. Thus, in the present study, we investigated the paracrine effect of MSC on the growth of neonatal rat cardiomyocytes in vitro. 2. Samples of MSC-conditioned medium (MSC-CM) were collected after rat MSC had been cultured under conditions of hypoxia and serum deprivation for 0, 3, 6, 9 or 24 h. Cardiomyocytes were then stimulated with the MSC-CM for 48 h. Then, the protein content, cell area, [(3)H]-leucine incorporation and atrial natriuretic factor-luciferase (ANF-Luc) expression of cardiomyocytes were measured. 3. The data showed that MSC-CM collected at different time points had different effects and that MSC-CM collected at 6 h significantly promoted cardiomyocyte hypertrophy by increasing total protein content, cell area, [(3)H]-leucine incorporation and ANF gene expression. 4. In conclusion, MSC-CM promoted cardiomyocyte hypertrophy in a paracrine manner. The results provide a better understanding of the mechanisms underlying the improvement in heart function after MSC transplantation.     

Targeting cancer stem cells

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell–niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.     

Targeting cancer stem cells

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell-niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.     

成球培养法富集胰腺癌肿瘤干细胞的研究

目的 研究成球培养法培养胰腺癌肿瘤干细胞的可行性。方法 通过细胞成球培养体系富集胰腺癌肿瘤干细胞并进行培养,流式细胞术检测分析干细胞的表型特征。结果 光镜下,成球培养细胞形态发生明显变化,细胞由贴壁时的多边形变成圆形,并形成肿瘤细胞微球。流式细胞仪检测发现,与普通细胞培养相比,成球培养体系富集的胰腺癌肿瘤干细胞干性相关基因CD24、CD44共表达水平明显升高。结论 利用成球培养法能够富集得到CD24、CD44高表达的胰腺癌肿瘤干细胞。