TRAIL诱导肿瘤细胞凋亡机制研究进展

肿瘤坏死因子相关凋亡诱导配体(TRAIL)与死亡受体结合后,可启动凋亡信号转导.在产生一系列凋亡分子的同时,胞内抗凋亡分子也被诱导产生,但单一因素在TRAIL凋亡信号调控网络中并不起决定作用,而是多因素制衡的一个动态过程决定细胞生死.了解TRAIL通路的精确调控机制及肿瘤的遗传背景,对于研究TRAIL在肿瘤治疗中的应用具有决定性作用.现综述近年来TRAIL诱导肿瘤细胞凋亡胞内机制的研究进展.     

TRAIL诱导肿瘤细胞凋亡机制研究进展

肿瘤坏死因子相关凋亡诱导配体(TRAIL)与死亡受体结合后，可启动凋亡信号转导。在产生一系列凋亡分子的同时，胞内抗凋亡分子也被诱导产生，但单一因素在TRAIL凋亡信号调控网络中并不起决定作用，而是多因素制衡的一个动态过程决定细胞生死。了解TRAIL通路的精确调控机制及肿瘤的遗传背景，对于研究TRAIL在肿瘤治疗中的应用具有决定性作用。现综述近年来TRAIL诱导肿瘤细胞凋亡胞内机制的研究进展。     

MAPK信号转导通路在肿瘤化疗耐药中的作用

丝裂原活化蛋白激酶(MAPK)信号转导通路是调节细胞增殖和凋亡的重要通路.最近研究发现,MAPK信号转导通路可能参与肿瘤化疗耐药,其作用机制可能是调控耐药相关基因的表达,通过对该通路的干预可以提高肿瘤的化疗敏感性,从而逆转化疗耐药.     

大蒜素诱导肿瘤细胞凋亡的研究进展

肿瘤是当前威胁人类生命的主要疾病之一.细胞的增殖和凋亡关系失调是肿瘤发生、发展的重要因素.大蒜素既对肿瘤细胞的增殖有抑制作用,也能诱导肿瘤细胞凋亡.大蒜素对肿瘤细胞的凋亡诱导作用是多因素、多水平的复杂的生物学过程,但其具体机制还不十分清楚.本文就大蒜素诱导肿瘤细胞凋亡的研究进展进行综述,包括抗氧化作用、调控基因表达、调控蛋白表达、改变信号转导通路和阻滞细胞周期等方面.     

MAPK信号转导通路在肿瘤化疗耐药中的作用

丝裂原活化蛋白激酶（MAPK）信号转导通路是调节细胞增殖和凋亡的重要通路。最近研究发现，MAPK信号转导通路可能参与肿瘤化疗耐药，其作用机制可能是调控耐药相关基因的表达，通过对该通路的干预可以提高肿瘤的化疗敏感性，从而逆转化疗耐药。     

乳腺癌相关信号转导通路的研究进展

随着对肿瘤细胞信号转导通路研究的不断深入,人们对肿瘤细胞内部和外部复杂的信号转导机制及其对乳腺癌的发生、发展和复发、转移等的影响有了进一步了解。细胞内部基因直接控制细胞凋亡的发生和发展,而细胞外部因素则通过信号转导影响细胞内基因的突变及表达产物的异常活化,这就提示细胞信号转导通路可能通过影响多种效应因子抑制细胞凋亡,促进细胞增殖,最终导致肿瘤的发生和发展。本文就现阶段与乳腺癌发生发展相关的信号转导通路,如受体酪氨酸激酶（ＲＴＫ）信号转导通路,ＥＲ信号转导通路,Ｎｏｔｃｈ信号转导通路,Ｗｎｔ信号转导通路等方面的研究进展作一简要的综述。     

低氧对肿瘤转移的促进作用

恶性肿瘤组织内异常血管生成、血管灌注减少及肿瘤细胞无限制的生长,导致微环境中氧含量降低,称为低氧。这种现象在恶性肿瘤中广泛存在。低氧微环境会改变肿瘤细胞的代谢方式,诱导细胞代谢发生适应性变化,并调节肿瘤细胞中复杂的细胞信号通路如低氧诱导因子(HIF)、磷脂酰肌醇-3-羟激酶(PI3K)/蛋白激酶B(AKT)/雷帕霉素靶蛋白(MTOR)、丝裂原活化蛋白激酶(MAPK)和核因子-κB(NF-κB)通路。这些信号通路相互作用产生正反馈和负反馈作用,增强或减弱低氧效应。此外,低氧微环境通过上调与上皮-间充质转化(EMT)相关的转录因子或抑制因子来激活与EMT有关的信号通路,从而诱发EMT。本文对肿瘤低氧微环境和促进肿瘤转移的各种信号通路及基本机制进行综述。     

Notch信号通路与肿瘤细胞凋亡的研究进展

Notch信号通路是一种生物进化中高度保守的信号转导通路,在多种细胞的增殖、分化和凋亡中起到关键作用。目前Notch信号通路的配体和受体,以及信号转导途径已经基本研究阐明,有关Notch信号通路与肿瘤细胞凋亡的研究也取得了较大的进展。本文综述了Notch信号通路对血液恶性肿瘤和实体肿瘤细胞凋亡的影响及机制的最新研究结果,重点回顾了Notch信号通路对不同种类肿瘤细胞凋亡的高背景相关性,以及Notch信号通路与其它细胞信号通路之间的串扰,及对肿瘤细胞凋亡的影响。     

细胞凋亡信号转导与肿瘤细胞凋亡抵抗机制

肿瘤细胞凋亡调控失调不仅诱发肿瘤形成,也对治疗形成抵抗.细胞凋亡信号转导和凋亡抵抗机制的阐明对通过调控细胞凋亡治疗肿瘤具有重要意义.现综述近年来有关肿瘤细胞凋亡抵抗机制及其在肿瘤治疗方面的研究进展.     

细胞凋亡信号转导与肿瘤细胞凋亡抵抗机制

肿瘤细胞凋亡调控失调不仅诱发肿瘤形成，也对治疗形成抵抗。细胞凋亡信号转导和凋亡抵抗机制的阐明对通过调控细胞凋亡治疗肿瘤具有重要意义。现综述近年来有关肿瘤细胞凋亡抵抗机制及其在肿瘤治疗方面的研究进展。     

Molecular responses to hypoxia in tumor cells

Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this review, we summarize the current knowledge about the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on intracellular signal transduction, gene regulation, angiogenesis and apoptosis. Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.     

Brain tumor hypoxia: tumorigenesis,angiogenesis, imaging,pseudoprogression, and as a therapeutic target

Hypoxia is implicated in many aspects of tumor development, angiogenesis, and growth in many different tumors. Brain tumors, particularly the highly aggressive glioblastoma multiforme (GBM) with its necrotic tissues, are likely affected similarly by hypoxia, although this involvement has not been closely studied. Invasion, apoptosis, chemoresistance, resistance to antiangiogenic therapy, and radiation resistance may all have hypoxic mechanisms. The extent of the influence of hypoxia in these processes makes it an attractive therapeutic target for GBM. Because of their relationship to glioma and meningioma growth and angiogenesis, hypoxia-regulated molecules, including hypoxia inducible factor-1, carbonic anhydrase IX, glucose transporter 1, and vascular endothelial growth factor, may be suitable subjects for therapies. Furthermore, other novel hypoxia-regulated molecules that may play a role in GBM may provide further options. Emerging imaging techniques may allow for improved determination of hypoxia in human brain tumors to better focus therapeutic treatments; however, tumor pseudoprogression, which may be prompted by hypoxia, poses further challenges. An understanding of the role of hypoxia in tumor development and growth is important for physicians involved in the care of patients with brain tumors.     

Molecular ordering of hypoxia-induced apoptosis: critical involvement of the mitochondrial death pathway in a FADD/caspase-8 independent manner

Dys-regulated growth and improper angiogenesis commonly lead to areas of hypoxia in human tumors. Hypoxia is known to be associated with a worse outcome since a lack of oxygen interferes with the efficacy of chemotherapy or radiotherapy. In parallel, hypoxia-induced apoptosis may also impose a selection pressure favoring growth of more resistant tumor cells. However, the mechanisms of hypoxia-induced apoptosis and the relative contribution of intrinsic and extrinsic apoptotic pathways are not understood. Therefore, Jurkat cell lines with defined defects in the extrinsic or intrinsic signaling cascades were used to evaluate the role of either pathway for induction of apoptosis under hypoxic conditions. Jurkat cells were incubated in hypoxia and the rate of apoptosis induction was determined by Western blotting, fluorescence microscopy and flow cytometry. Hypoxia-induced apoptosis was not affected by lack of caspase-8 or FADD, whereas overexpression of Bcl-2 or expression of dominant-negative caspase-9 mutant rendered the cells resistant to hypoxia-induced apoptosis. These results suggest that hypoxia-induced apoptosis mainly relies on intrinsic, mitochondrial pathways, whereas extrinsic pathways have no significant implications in this process. Thus, in human tumors, hypoxia will mainly lead to the selection of hypoxia-resistant cells with defects in mitochondrial apoptosis signaling pathways.     

Optimizing antiangiogenic strategies: combining with radiotherapy

Tumor response to radiotherapy is influenced by many tumoral intracellular biological factors whose deregulation leads to the modulation of tumor sensitivity to radiotherapy. However, the pathways controlling intracellular radiation resistance are activated by or display common pathways with many factors also controlling the tumoral microenvironment, and particularly angiogenesis. One of the innovative strategies that could improve response to irradiation of aggressive or radiotherapy-insensitive tumors consists of combining radiotherapy with inhibitors of the angiogenesis pathways. This review details four main reasons for this: angiogenic factors control intracellular radioresistance, endothelial cell radiosensitivity controls tumor radiosensitivity, tumor angiogenesis is the cause of hypoxia, a major radiation resistance factor, and stem cells, known to be radiation resistant, are dependent on angiogenic factors. We describe the implication of different factors in the various mechanisms leading to radiation resistance. These factors include vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor 2 (FGF2), along with αvβ3 and αvβ5 integrins as well as their downstream cellular pathways including some small G proteins. The review also explains the radiation-sensitizing effect of the inhibition of these factors by targeted therapies. The optimal sequences of administration between antiangiogenics and radiotherapy are partially elucidated. The success of these combinations will depend on the specific study of the mechanisms of action of antiangiogenic agents and their interaction with ionizing radiations, and on the use in preclinical and clinical studies of metabolic and functional imaging. These techniques represent an essential tool for determining the optimal combination sequence followed by the assessment of these combinations.     

Effects of irradiation on tumor cell survival, invasion and angiogenesis

Ionizing irradiation is a widely applied therapeutic method for the majority of solid malignant neoplasms, including brain tumors where, depending on localization, this might often be the only feasible primary intervention.Without doubt, it has been proved to be a fundamental tool available in the battlefield against cancer, offering a clear survival benefit in most cases. However, numerous studies have associated tumor irradiation with enhanced aggressive phenotype of the remaining cancer cells. A cell population manages to survive after the exposure, either because it receives sublethal doses and/or because it successfully utilizes the repair mechanisms. The biology of irradiated cells is altered leading to up-regulation of genes that favor cell survival, invasion and angiogenesis. In addition, hypoxia within the tumor mass limits the cytotoxicity of irradiation, whereas irradiation itself may worsen hypoxic conditions, which also contribute to the generation of resistant cells. Activation of cell surface receptors, such as the epidermal growth factor receptor, utilization of signaling pathways, and over-expression of cytokines, proteases and growth factors, for example the matrix metalloproteinases and vascular endothelial growth factor, protect tumor and non-tumor cells from apoptosis, increase their ability to invade to adjacent or distant areas, and trigger angiogenesis. This review will try to unfold the various molecular events and interactions that control tumor cell survival, invasion and angiogenesis and which are elicited or influenced by irradiation of the tumor mass, and to emphasize the importance of combining irradiation therapy with molecular targeting.     

Eicosanoids and other lipid mediators and the tumor hypoxic microenvironment

Hypoxia is a pathological hallmark feature of solid tumors. Though hypoxia is an adverse physiological state, tumors have evolved to utilize this unsuitable environment to their own advantage by activating key biochemical and cellular pathways that are important in progression, survival, and metastasis. Several studies have emphasized the importance of lipid mediators in regulating key biomolecules in the hypoxic microenvironment, for example hypoxia inducible factor-1 (HIF-1), the master regulator of hypoxia. Lipid mediators have been reported to enhance the levels and activity of HIF-1, which subsequently signal to stimulate angiogenesis and tumor cell survival under hypoxic conditions. There are also reports of hypoxia and HIF-1 enhancing the levels of some lipid mediators mostly by upregulating the levels of the enzymes responsible for their biosynthesis. This review gives a brief overview of these two mechanisms and the role played by bioactive lipid mediators in the regulation of tumor progression and survival under hypoxia.