肿瘤干细胞的研究新进展

近年来随着肿瘤干细胞（Gamer stem cells，CSC；或Tumour stem cells，TSC）在肿瘤组织中分离成功，并提出了肿瘤于细胞学说，为肿瘤研究提供了新的思路。肿瘤干细胞是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体，均具有自我更新能力和不定向分化潜能，并可导致肿瘤发生。现认为肿瘤干细胞是肿瘤形成及其不断生长的根源。     

癌干细胞研究进展

癌干细胞是癌组织中存在的具有自我更新能力、分化潜能的细胞,是肿瘤发生、发展的关键[1]。近年来,癌干细胞学说提出由于癌干细胞在机体中快速复制,促使肿瘤细胞数量和瘤体体积扩张并侵入邻近组织及迁徙至机体其他组织器官,引起组织器官功能紊乱,最终导致机体死亡。由此可见,深入研究癌干细胞生物学特性,探索靶向治疗方法,对恶性肿瘤的治愈具有重大临床意义。本文介绍了癌干细胞特征、分选和鉴定及其在肿瘤发生发展中的作用,描述了各种癌干细胞研究进展以及临床应用,并对目前存在的问题和展望进行了探讨。     

肿瘤干细胞靶向治疗

多种肿瘤中都存在肿瘤干细胞(cancer stem cell,CSC),这部分细胞具有自我更新能力和分化潜能,是肿瘤生长、增殖和转移的根源。此外,肿瘤干细胞具有正常干细胞的自我保护特性,如有效的DNA修复、高表达多药耐药型膜转运蛋白以及处于相对静止状态及拥有特定的微环境,使其能够逃逸现有的肿瘤治疗手段,导致肿瘤复发。针对这些保护机制,并利用肿瘤干细胞与正常干细胞的之间的差异进行靶向治疗,可能达到根治肿瘤的疗效。     

整合素与肿瘤转移

整合素是细胞表面重要的粘附分子,它在机体内具有重要的生物学作用。本文从肿瘤细胞侵袭转移的过程出发,较全面地阐述了整合素与肿瘤转移的密切关系,为深入探讨整合素在肿瘤发生、发展中的作用,开发肿瘤治疗新思路提供了理论依据。     

E-钙粘蛋白在肿瘤中的作用

E-钙粘蛋白是一类细胞表面糖蛋白,在细胞一细胞间粘附中发挥重要作用,参与组织结构的维持。研究表明细胞粘附分子在肿瘤的发生、发展、侵袭和转移中起着重要作用,已成为肿瘤转移分子机制研究的重要课题之一。既往研究认为E-钙粘蛋白是一种肿瘤抑制因子,然而最近研究表明E-钙粘蛋白的异常表达与肿瘤发生、侵袭转移密切相关,提示E-钙粘蛋白不仅有抑癌作用,还具有促癌作用。而肿瘤的侵袭转移是癌症患者死亡的主要原因,本文将对E-钙粘蛋白在肿瘤发生及转移中的作用机制进行综述,以期为肿瘤的临床治疗提供更多的理论依据。     

干细胞样SP细胞研究进展

摘要： 干细胞样 SP 细胞是近年来在很多正常组织和恶性肿瘤组织及细胞系中发现的一种具有不同程度分化潜能和自我更新能力的细胞群体。虽然 SP 细胞在总体细胞中所占比例很低, 但这部分具有干细胞特性的细胞在干细胞以及肿瘤干细胞研究方面起着越来越重要的作用。本文综述了 SP 细胞的发现、 生物学特性、 与肿瘤干细胞之间的关系以及 SP 细胞的未来临床应用等。最后对 SP 细胞的发展进行了展望。     

低氧诱导因子在肿瘤干细胞介导的肿瘤发生发展中的作用

低氧及低氧诱导因子（HIFs）是肿瘤干细胞、 转移起始细胞及其分化后代在肿瘤发生发展过程中, 能够适应氧气和营养物质缺乏的主要调节因子。在白血病、 胶质母细胞瘤、 黑色素瘤、 前列腺癌、 乳腺癌、 胰腺癌等肿瘤中均发现 HIFs 的表达上调, 尤其集中表达在低氧区域。活化的 HIFs 可以诱导多种干性及多药耐药等基因的表达, 对肿瘤及干性介导的肿瘤细胞的自我更新、 能量代谢改变、 侵袭转移、 血管生成以及治疗抵抗均起着重要作用。因此, 研究 HIFs 分子在干细胞介导的不同肿瘤细胞中的靶向调节作用和代谢通路的改变, 将为肿瘤的靶向治疗提供新线索。     

转化生长因子β在肿瘤微环境中的作用

转化生长因子β（TGF-β）是一类具有多种生物学活性的细胞因子,参与调节细胞的增殖、分化、发育和凋亡等多种生命活动。近期研究表明,TGF-β信号参与调控肿瘤的发生、发展,并可以通过影响肿瘤微环境如间质干细胞（MSCs）、成纤维细胞、免疫应答促进或抑制肿瘤的发展和转移。明确TGF-β与肿瘤微环境的关系,进而明确肿瘤发生、发展、转移过程中发挥重要作用的关键分子,寻找其相应的分子靶点,对肿瘤的诊断及治疗具有重要作用。     

间质干细胞与肿瘤的关系研究进展

间质干细胞(mesenchymal stem cells,MSCs)是来源于中胚层的一类具有高度自我更新能力和多向分化潜能的非造血干细胞,具有很好的组织迁移能力和肿瘤靶向性。MSCs用于抗肿瘤治疗已经开展了广泛的研究,MSCs可以作为细胞载体发挥抗肿瘤作用,同时通过促肿瘤血管生成、免疫抑制、分化为肿瘤相关成纤维细胞等方式促进肿瘤的恶性行为。该文对近年来该领域的研究进展进行简要综述。     

肿瘤干细胞理论及肿瘤干细胞分离和鉴定研究进展

肿瘤是当今社会对人类健康和生命危害最大的疾病之一,即使在人类医学科技迅速发展的今天,对于肿瘤的治疗仍是一大难题,其根本原因是对肿瘤的发生、发展、转移和复发的机制尚不清楚。近些年来,研究人员通过对肿瘤细胞表面标志物、增殖能力和致瘤能力等的深入研究,提出了肿瘤干细胞理论,即肿瘤中存在着少数具有无限自我更新能力和异种免疫缺陷动物致瘤能力的干细胞样肿瘤细胞,它们在肿瘤的发生、生长和转移等生物学过程中起着决定性的作用,该理论的提出给肿瘤治疗提供了新的思路和策略。本文将对肿瘤干细胞理论的形成和发展过程,肿瘤干细胞的特性以及肿瘤干细胞的分离和鉴定最新研究进展进行综述。     

MicroRNA Regulation of Cancer Stem Cells and Therapeutic Implications

MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a variety of cellular, physiological, and developmental processes. Aberrant expressions of miRNAs are connected to human diseases such as cancer. Cancer stem cells are a small subpopulation of cells identified in a variety of tumors that are capable of self-renewal and differentiation. Dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer. Furthermore, cancer stem cells are a very likely cause of resistance to current cancer treatments, as well as relapse in cancer patients. Understanding the biology and pathways involved with cancer stem cells offers great promise for developing better cancer therapies, and might one day even provide a cure for cancer. Emerging evidence demonstrates that miRNAs are involved in cancer stem cell dysregulation. Recent studies also suggest that miRNAs play a critical role in carcinogenesis and oncogenesis by regulating cell proliferation and apoptosis as oncogenes or tumor suppressors, respectively. Therefore, molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation.     

Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells

Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.     

Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells

Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.     

上皮间质转化与乳腺癌

乳腺癌是女性最常见的恶性肿瘤之一,而肿瘤的侵袭与转移是导致乳腺癌患者治疗后复发与死亡的主要原因。上皮-间质细胞转化（EMT）是上皮细胞转变为间充质细胞的过程,参与了肿瘤干细胞的形成以及肿瘤细胞的浸润、迁移和转移,不仅增强了乳腺癌细胞侵袭和转移的能力,还可使癌细胞获得自我更新等干细胞特性,促进乳腺癌干细胞的产生。因此,研究EMT对寻找控制乳腺癌侵袭和转移的有效途径以及降低乳腺癌患者的死亡率有非常重要的意义,亦可为乳腺癌的治疗提供新的靶点。     

Primary brain tumors, neural stem cell, and brain tumor cancer cells: Where is the link?

The discovery of brain tumor-derived cells (BTSC) with the properties of stem cells has led to the formulation of the hypothesis that neural stem cells could be the cell of origin of primary brain tumors (PBT). In this review we present the most common molecular changes in PBT, define the criteria of identification of BTSC and discuss the similarities between the characteristics of these cells and those of the endogenous population of neural stem cells (NPCs) residing in germinal areas of the adult brain. Finally, we propose possible mechanisms of cancer initiation and progression and suggest a model of tumor initiation that includes intrinsic changes of resident NSC and potential changes in the microenvironment defining the niche where the NSC reside.     

Mast cells and basophils: trojan horses of conventional lin- stem/progenitor cell isolates

Cancer microenvironment is increasingly recognized as an important factor affecting cancer onset and progression. Since Wirchow reported in 1863 that tumors contain inflammatory cells, the field shifted significantly forward, and immune cells residing in tumors appear to be attractive targets of cancer therapies. For some methods, such as stem/progenitor cell isolation from both cancer and healthy tissues, removal of contaminating immune cells is crucial to achieve consistent, reproducible and accurate results. Despite current methods of lineage negative selection accounts for removal of over 99 % of immune cells from stem/progenitor cell isolates, the vast majority of lineage antibody cocktails retain basophils, dendritic cells, and mast cells. Here we discuss the ability of the most commonly used lineage markers to bind to the plasma membrane of mast cells and/or basophils, and suggest alternatives, which may be used for negative selection of these cellular populations. Both, mast cells and basophils, were shown to participate actively in cancer-associated angiogenesis, tissue remodeling and recruitment of other immune cell types, including eosinophils, B cells, memory T cells and Treg cells. In turn, tumor-derived peptides and chemotactic factors are known to recruit and activate mast cells in neoplasias, resulting in altered tumor progression. Repeated findings of CD34+ populations of mast cells and basophils further highlight necessity of their separation from stem/progenitor cell isolates in both, preclinical experiments and clinical praxis.     

Tumor associated macrophages in the molecular pathogenesis of ovarian cancer

The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of multiple disorders, as well as ovarian cancer. High plasticity and consequent high ability to adapt to environmental alternations by adjusting their cellular metabolism and immunological phenotype is the notable characteristic of macrophages. Therefore, the critical function of tumor-associated macrophages in ovarian cancer is highlighted in the growing body of recent studies. In this article, we will comprehensively focus on significant impacts of the macrophages on ovarian cancer progression, by discussing the role of macrophages as one of the fundamental immune cells present in tumor milieu, in metabolic reprogramming of transformed cells, and involvement of these cells in the ovarian cancer initiation, progression, invasion, and angiogenesis. Moreover, we will summarise recent studies evaluating the effects of targeting macrophages in ovarian cancer.     

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.     

新颖肿瘤抑制基因染色质修饰蛋白1A的研究进展

染色质修饰蛋白1A（Chromatin modif-ying protein 1A,Chmp1A）属于转运必需内吞体分选复合物-III复合物（ESCRT-III）家族成员,在多泡体（MVB）的形成过程中起着关键作用。最近研究发现,在人类多种肿瘤组织中Chmp1A表达明显降低,且低表达Chmp1A的正常细胞易于肿瘤化。Chmp1A主要聚集在胞质和核基质,对染色质结构、细胞周期和囊泡转运均有重要影响,且有研究表明,Chmp1A可能是一种PcG蛋白。Chmp1A的失活与多种肿瘤的发生、发展关系密切,是一种新颖肿瘤抑制基因。