癌症治疗原则(ZT)

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Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction
$ {. Y- E7 I: J/ D7 S* c: i* h来自2009《Cell》上的一篇综述，HHMI出品
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  {3 L  x5 g: E% u: ]0 d作者：caiwj2001
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. a* G0 m3 M7 I3 `     癌症，虽然表现为存在一些共性，但总的来说还是一种在机制上非常复杂，在组成上表现高度异质性的遗传性疾病。在本文中，我们扩展了肿瘤的经典特性，如将可以影响肿瘤发生的压力因素作为表观型机制也包括在内讨论。此外，我们描述了一个癌基因和非癌基因因素怎样影响肿瘤特性形成以及怎样通过这些因素来治疗肿瘤的概念性框架，如通过压力致敏和压力过载来选择性杀伤癌细胞。另外，我们也特别列举了一大类的非癌基因证据，它们有时往往可以作为治疗肿瘤的药物作用靶点。最后，我们讨论了肿瘤研究的前景方向和肿瘤综合治疗的前途之路。+ A* ^% F- {/ |

! W3 H3 B, f3 b8 Y+ Q- K* `# O2 u8 @     Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies.! a; X0 M* r6 ~$ J! C8 v* a
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8 V7 C7 K# U! z; n# `+ m/ u7 V4 J癌症研究现状
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       在刚过去的几十年中，我们见证了对癌症发病机制的进一步理解，每一步都是证据充分的。现在已经明确，癌症的发生是通过多步骤、多基因参与的方式形成的，在此进程中，癌细胞获得了一套所有癌症共有的特性，如无限制的增殖潜能、自给自足的生长信号、对抗增殖和凋亡的指令及逃避免疫监督等，此外，随着病情进展，癌组织从周围的间质得到支持，吸引新生血管进入，此可给瘤组织提供营养和氧份，并最终获得可以转移到远处器官的机会(Hanahan and Weinberg, 2000)。
# @# z9 o4 b/ k2 a) J9 u1 F    这些癌症特性可以是由相应基因改变引起的，其中包括了癌基因的获能突变，抑癌基因的失能变异；关键癌基因的过表达、或关键抑癌基因的表观静止等(Hahn and Weinberg, 2002)。
# ?* u# W4 E& x9 w0 W; n. R, O$ D9 X     我们知道，导致癌症发生的这些癌基因和抑癌基因的再激活，大部分其实在机体发育过程中是已用过的正常细胞程序。如胚胎形成中的细胞增殖和分化、细胞迁徒和极性形成、凋亡以及组织稳态的协调进程。与达尔文的理论相一致，癌症的形成是通过基因的随机突变和表观选择来决定的，这些内因的改变和外部环境的“适者生存”导致的结果是细胞的克隆选择，存活下来的异常细胞克隆经过有害事件的影响进一步的增殖壮大。
, J, M* h: o" R& k6 ]1 q- L. o       实验也证明，许多癌基因和抑癌基因，如 PI3K, Ras, p53, PTEN, Rb, and p16INK4a等，在癌细胞中通常有明显地大量突变存在， 此外肿瘤测序项目的数据也显示：在肿瘤组织中存在大量地低频变异。在一个研究中，Stratton和他的同事估计所有激酶的20%发生个体变异可以对肿瘤形成起到激活作用(Greenman et al., 2007)，虽然其他类型的基因发生20%变异是否也会驱动肿瘤的形成尚不好说。对多种癌症大规模的测序除了那些先前确定的变异靶点外，没有再发现新的高频的变异存在(Cancer Genome Atlas Research Network, 2008; Ding et al., 2008; Jones et al., 2008; Parsons et al., 2008; Sjoblom et al., 2006; Wood et al., 2007)。 相反，这些研究发现了每一种肿瘤包含了复杂的低频突变集合，此被认为能驱动癌症表现型产生。而且，不同的癌症类型，如乳腺癌和结肠癌，所有体细胞突变显然是不同的。虽然在统计学上要求区别肿瘤的大量变异集合中无贡献的过路变异是有很多争议的，但可以明确的是，在不同起源的肿瘤中其变异方式有着巨大的复杂性和异质性。
7 C9 F$ ], E, k% a# n      这些个癌症发生中变异的复杂性引出一个与治疗相关的可怕问题：我们如何才能有效地治疗由这么多干扰导致的癌症？癌细胞有着广泛重新配线的基于恶性表现型的生长和生存途径。因此成功治疗癌症的关键是鉴别在癌基因网络中的重要功能性节点，也许对它的抑制可导致整个系统的失败，阻止肿瘤的进一步发展；进而，攻击这些节点的治疗药物必须有足够大的治疗谱，并能杀死肿瘤细胞的同时而不影响正常细胞的存活。借用从酵母和果蝇遗传分析的名词，治疗药物必须具有对癌症基因型/表现型的“综合致死”性能(Kaelin, 2005)。在某些情况下，特定药物能出现与综合致死相似的基因型依赖的致死，而不直接抑制特定的蛋白质。" {/ ^- A3 a& F' A8 g' n  ~9 q
      今天癌症治疗的两个中坚力量：化疗和放疗，虽然我们已经开发了强效的可以敏感性导致DNA损伤的药物，但往往也导致正常无辜细胞的死亡。依据现有的知识，我们仍然无法在分子水平来做到能选择性杀伤肿瘤细胞，相反也不能明白为什么治疗会失败的原因。
2 o: X8 m3 h7 S7 P. O$ W      当今，靶向治疗是一个新开辟的肿瘤治疗战场，目标是针对性的攻击某个癌基因，精密的抑制癌细胞的增值，事实上它已经提供了能综合杀伤癌细胞的例子。如果应用合适的话，这个治疗可能比化疗及放疗来得更有效。' Q! E) X3 }2 a& J
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      The Current State of Cancer Research
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3 X- z1 O3 M, e7 j6 p  W  V/ R+ A       The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. It is now clear that cancer arises through a multistep, mutagenic pro-cess whereby cancer cells acquire a common set of properties including unlimited proliferation potential, self-suffciency in growth signals, and resistance to antiproliferative and apoptotic cues. Furthermore, tumors evolve to garner support from surrounding stromal cells, attract new blood vessels to bring nutrients and oxygen, evade immune detection, and ultimately metastasize to distal organs (Hanahan and Weinberg, 2000). Many of these phenotypic traits can be brought about by genetic alterations that involve the gain-of-function mutation, amplifcation, and/or overexpression of key oncogenes together with the loss-of-function mutation, deletion, and/or epigenetic silencing of key tumor suppressors (Hahn and Weinberg, 2002). Cancer cells achieve these phenotypes in large part by reactivating and modifying many existing cellular programs normally used during development. These programs control coordinated processes such as cell proliferation, migration, polarity, apoptosis, and differentiation during embryogenesis and tissue homeostasis. Consistent with Darwinian principles, cancer evolves through random mutations and epigenetic changes that alter these pathways followed by the clonal selection of cells that can survive and proliferate under circumstances that
8 @" H: [5 g$ G7 @/ Q8 Dwould normally be deleterious. Although a number of oncogenes and tumor suppressors, such as PI3K, Ras, p53, PTEN, Rb, and p16INK4a, are frequently mutated in cancer cells, there also appears to be a large number of low-frequency changes that can contribute to oncogenesis. Indeed, data from tumor sequencing projects reveal an astounding diversity of mutations in tumors. In one study, Stratton and colleagues estimate that individual mutations in as many as 20% of all kinases can play an active role in tumorigenesis (Greenman et al., 2007), although it remains to be seen whether mutations in 20% of other gene classes will also drive tumorigenesis. Large-scale sequencing of multiple cancers has so far failed to identify new, high-frequency mutation targets in addition to those previously identifed (Cancer Genome Atlas Research Network, 2008; Ding et al., 2008; Jones et al., 2008; Parsons et al., 2008; Sjoblom et al., 2006; Wood et al., 2007). Rather, these studies found that every tumor harbors a complex combination of low-frequency mutations thought to drive the cancer phenotype. Furthermore, the repertoires of somatic mutations in different cancer types such as breast and colon cancers appear to be different. Although there is much debate with regard to the statistical requirements needed to distinguish likely driver from noncontributing passenger mutations among the large collection of mutations in tumors, it is clear that there is tremendous complexity and heterogeneity in the patterns of mutations in tumors of different origins.The complexity of alterations in cancer presents a daunting problem with respect to treatment: how can we effectively treat cancers arising from such varied perturbations? Cancer cells have extensively rewired pathways for growth and survival that underlie the malignant phenotype. Thus, a key to successful therapy is the identifcation of critical, functional nodes in the oncogenic network whose inhibition will result in system failure, that is, the cessation of the tumorigenic state by apoptosis, necrosis, senescence, or differentiation. Furthermore, therapeutic agents attacking these nodes must display a suffciently large therapeutic window with which to kill tumor cells while sparing normal cells. To borrow a term from yeast and fy genetic analyses, the therapeutic agents must constitute synthetic lethality” with the cancer genotype/phenotype (Kaelin, 2005). In some cases, particular agents can display geno-
" b5 D% F! X# ?4 Q# K. k2 itype-dependent lethality similar to synthetic lethality without directly inhibiting a particular protein. The two mainstay treatment options for cancer today—chemotherapy and radiation—are examples of agents that exploit the enhanced sensitivity of cancer cells to DNA damage. Despite all of our knowledge, however, we still do not have a clear molecular understanding of why these agents work to selectively kill tumor cells and, conversely, why they eventually fail. The advent of “targeted” therapies, which aim to attack the underlying oncogenic context of tumors, provides more sophisticated examples of synthetic lethality. When properly deployed, these therapies tend
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; @' O: q& j* J) _0 K: W; V' Y, L' Q另外的肿瘤特性：压力表型
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# B, Y* U/ o3 t& o( N" R9 b% j      虽然目前没有一个简单的方法来预测哪一个蛋白可以作为癌生成节点的靶向药物，但多个系统水平的研究正在让我们有了解决问题的指向。从基因点来看，理解以下问题是很重要的，在对癌基因组的研究中观察到的过多的变异可能是起始于一套导致恶性表现型的结果。癌症治疗的目的，不是要转变它们已经改变的恶性质，而是以肿瘤特性为目标的相关靶向治疗，所以我们需要全盘地理解这些肿瘤特性的本质，以更好的联合应用相关的药物。: j6 t# }$ Y) ~; B: G( \
       除了Hanahan and Weinberg在2000年提出的6个肿瘤特征性标志外，我们也应把肿瘤外部环境的影响考虑在内，因为他们同样也可以引起瘤细胞存活和导致瘤细胞的增殖，如DNA损伤/复制压力，蛋白质毒性压力，有丝分裂压力，代谢压力，氧化性压力等，另外加上2008年Kroemer and Pouyssegur提出的免疫逃避机制。: @2 c: @- P2 Q! X- c7 h0 ^
      我们认为这些因素作为与基因变异无关的因素，是癌症发生的表现遗传，他们与癌细胞原来的6个公共特性常常存在着复杂的功能相互作用。虽然这些压力表现型并不只是在癌细胞中出现，在其他条件下如慢性炎症也可以看到。我们认为存在着一套与压力相关的肿瘤形成支持途径，是癌细胞必需接受的压力。这些表现型是如何导致肿瘤形成的，目前了解得并不是很清楚，但在种类繁多的癌肿中，使用针对这些特性和相关脆弱点的靶向治疗的干预措施已经显示出一定的疗效。
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  A5 P8 a4 }" ^, t0 b      Additional Hallmarks: The Stress Phenotypes of Cancer0 G. o* T5 E) l: n/ n- a
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     Although there is no simple way to predict a priori which proteins will act as nodal points to generate cancer drug targets, solutions are likely to emerge from multiple sources, including recent initiatives to understand cancer at the systems level. From a genetic point of view, it is important to appreciate that the plethora of mutations observed in the cancer genome must ultimately result in a common set of hallmarks in order to bring about the malignant phenotype. The goal of cancer therapy is, therefore, to either reverse these properties or target them as tumor-specifc liabilities, preferably through the combinatorial application of a relatively small number of drugs. Thus we need a thorough understanding of the nature of these hallmarks. In addition to the six hallmarks outlined in the seminal review by Hanahan and Weinberg (Hanahan and Weinberg, 2000) that collectively promote survival and proliferation in foreign environments (Figure 1, top), as well as the hallmark of “evading immune surveillance” proposed by Kroemer and colleagues (Kroemer and Pouyssegur, 2008) (Figure 1, left), we propose a number of additional, equally prevalent hallmarks of cancer cells based on recent analyses of cellular phenotypes. Although these cancer phenotypes are not responsible for initiating tumorigenesis, they are common characteristics of 2 c* M% C2 K" i! q8 k) y
many tumor types (Figure 1, bottom). Among these additional hallmarks are DNA damage/replication stress, proteotoxic stress, mitotic stress, metabolic stress, and oxidative stress. We collectively refer to this subset as
5 I8 ]6 z9 \7 p- j& P) Qthe stress phenotypes of cancers. There are often intricate functional interplays among these shared hallmarks of tumor cells, which are illustrated in Figure 1 and discussed below. Although some of these stress phenotypes
% u! K" z9 E( aare not unique to cancer cells and can be observed in other conditions such as chronic infammation, we propose that they represent a common set of oncogenesis-associated cellular stresses that cancer cells must tolerate through stress support pathways. How these phenotypes arise is not well understood, but targeting these hallmarks and their associated vulnerabilities in a wide variety of cancers has shown promise for therapeutic intervention.
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zorro

最后肿瘤能够在体内生存，肯定与周围的环境相适应了，其单一的考虑一个因素或几个因素是不全面的。肿瘤治疗应该是个系统的问题，不能单一的说谁是主要矛盾因素，缺了谁都不行。真正的生命的秘密，还是要融入进哲学的世界中。换一种思维，可能就有不一样的结果。

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DNA损伤和复制压力
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) ?/ W) Y( R0 R/ x5 z      基于染色体组型和基因突变异分析，目前已经明确，肿瘤在形成过程中，，尤其是实体瘤，往往经历了极度基因组不稳定的时期，此过程导致点突变、缺失突变、复杂的染色体重排和广泛的非整倍体的累积(Hartwell and Kastan, 1994)。这中基因组不稳定性部分原因是由于内源性DNA的损伤引起，此可导致DNA损伤压力反应(DDR)途径的激活。- k8 _; n: v3 l6 j  H8 K
     出现在肿瘤早期的DNA损伤水平的提高与很多因素有关：首先是端粒的缩短，由于缺乏充足端粒酶活性，从而导致复制时端粒末梢的双链断裂 (DSBs) ；随后，这些缺乏末端保护的端粒开始形成一断裂-融合-桥循环（breakage-fusion-bridge cycles ）的形成，此导致基因易位和扩增事件的产生。，由于复制压力所致的双链断裂同样可以引起断裂-融合-桥循环的发生。 此外，癌前病变的癌基因活性也可以增加双链断裂的机会和基因组不稳定性的增加，可能通过DNA过度复制导致； 最后，参与DNA修复程序(如切除，交叉连接或错配修复)和DNA损伤压力反应途径(如ATM和P53信号)的基因变异可导致DNA损伤的增加，及不适当的细胞进程和基因组不稳定。
/ n6 R  B: k  N. P- {. G( N      在正常细胞中，DNA的损伤信号可使增殖中止、诱导细胞进入G0期或激发细胞凋亡。而癌细胞的基因变异可克服DNA损伤所致的抗增殖效应，导致在损伤存在时仍然可以持续增殖。9 L8 d) x$ a5 A7 b0 A. S1 G# M

$ X6 ^9 J, d  t$ m2 u2 GDNA Damage and DNA Replication Stress9 E9 k# w3 D% z6 G. a7 O- C

. o8 w, D  t4 D* X     Based on karyotypic and mutational analyses, it is clear that tumors, specially solid tumors, pass through stages of extreme genomic instability that result in the accumulation of point mutations, deletions, complex chromosomal rearrange ments, and extensive aneuploidy (Hartwell and Kastan, 1994). This level of instability is due in part to a constitutive level of endogenous DNA damage, which results in activation of the DNA damage stress response (DDR) pathway (Bartkova et al., 2005; Gorgoulis et al., 2005). Elevated levels of DNA damage observed in early stage tumors are thought to be due to several factors. First, the shortening of telomeres due to replication in the absence of suffcient telomerase activity leads to the appearance of double-strand breaks (DSBs) at telomeric ends. The subsequent fusions of these deprotected ends initiate breakage-fusion-bridge cycles that result in translocations and gene amplifcation events (Maser and DePinho, 2002). DSBs resulting from replication stress can also lead to breakage-fusion-bridge cycles (Windle et al., 1991). Additionally, oncogene activation in precancerous lesions has been shown to increase DSBs and genomic instability (Halazonetis et al., 2008), possibly through DNA hyper-replication (Bartkova et al., 2006; Di Micco et al., 2006). Finally, mutation of genes involved in either DNA repair programs (such as excision, crosslink, or mismatch repair) or the DDR pathways (such as ATM and p53 signaling) can lead to increased DNA damage, inappropriate cell-cycle progression, and genomic instability (Harper and Elledge, 2007). In normal cells, DNA damage signals to halt proliferation, induce cellular senescence, or elicit apoptosis. Cancer cells have evolved to overcome the antiproliferative
- F' I7 k8 W8 q7 D$ \2 aeffects of DNA damage, continuing to replicate in the presence of damage
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蛋白毒性压力- K+ _& Q! p3 _" Q
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       肿瘤存在蛋白毒性压力的证据可以从他们的热休克反应的经常组成型激活显示，我们认为部份原因与实体瘤中通常存在的非整倍体(改变染色体组数量)的严重程度有关。非整倍体和基因拷贝数量的改变可能影响生长与生存的相关平衡信号，从而促进肿瘤发生。. z% T" @+ R" w! o( |4 `
     而且，它们也导致转录水平的上升或下降 ，此产生蛋白质复合物亚单位的化学计量出现不平衡。这些不平衡增加了细胞内有毒蛋白复合物的聚集，和额外蛋白折叠和降解的负担。此蛋白毒性压力部份也是通过热休克反应途径消解的，通过促进合适的蛋白折叠或降解。

hzejian

学习了

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有丝分裂压力6 U, e  G/ C! d! H$ F- \
  
8 |/ n. @% a9 z, \. [       有一些肿瘤显示染色体错误-分裂的发生率增加，此被称为染色体不稳定(CIN，chromosome
9 Z2 F: n  R- y4 U0 N0 V) Vinstability表型。 这种不稳定性可导致染色体分布的改变，从而允许肿瘤细胞快速演变。一般而言，CIN表现型是由于包括在有丝分裂中的多种途径缺陷的结果，包括执行有丝分裂中染色体组分离的蛋白缺陷，纺锤体装配检查点缺陷。
& V1 y; d  g: i& R. ]8 H      此外，CIN表现型也可能来自肿瘤细胞中额外中心体的呈现，或者由于有丝分裂体压力引起，由于分离额外染色体需要的结果。另外，CIN和有丝分裂压力可能间接由癌基因活化后的双链断裂 (DSBs)和基因组不稳定性引起，有丝分裂不完整的部位出现损害。一些癌基因的突变，如Ras或抑癌基因P53，他们的变异被认为与CIN表现型的出现相关，但是有丝分裂压力的准确原因目前在大部分肿瘤中仍然不清楚。- d: _. y+ k: J& f; U- r* D- e- U

, R; x+ Y6 c' e& R* P+ l( u+ g3 ZMitotic Stress
+ `+ @# R- [$ QA subset of tumors display increased rates of chromosome mis-segregation, which is referred to as the CIN (chromosome instability) phenotype (Komarova et al., 2002). This instability results in a shifting chromosome distribution, thus allowing tumor cells to rapidly evolve. In principle, CIN phenotypes can result from defects in a variety of pathways involved in mitosis, including defects in mitotic proteins that execute chromosome segregation and defects in the spindle assembly checkpoint, which coordinates anaphase entry with proper alignment of2 _  ]& C9 G/ N- g% w, a' x) M
chromosomes on the mitotic spindle (Cahill et al., 1998). In addition, the CIN phenotype could result from the  resence of extra centrosomes in tumor cells or from stresses placed on the mitotic apparatus due to the need to segregate supernu merary chromosomes (Ganem et al., 2007). Furthermore, CIN and mitotic stress might arise indirectly as a result of DSBs and genomic instability following oncogene activation, even in lesions where the mitotic machinery is intact (Halazonetis et al., 2008). Mutations in certain oncogenes, such as Ras, and tumor suppressors, such as p53, have been suggested to contribute to the CIN phenotype (Denko et al., 1994). However, the precise cause of mitotic stress is not known for the vast majority of tumors.   ]; D, V$ A! }5 I& y/ d
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代谢压力2 j: T1 g+ G! C: o0 p0 i
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       正常细胞通过氧化磷酸化得到大量的ATP，在所谓的Warburg效应中，绝大部份癌细胞则主要通过低效率的糖酵解方法和释放大量乳酸来获得能量，甚至在氧浓度高的条件下也是这样 (Warburg, 1956)。 / W" b8 Z2 U3 I
       肿瘤细胞显示大量增加对葡萄糖摄入和高水平的糖酵解率 ，此是正电子发射扫描(PET)的肿瘤影像学基础，应用葡萄糖类似物18F-2-脱氧葡萄糖来显示。此利用糖酵解产能的方式转变使肿瘤具有以下优势：便于适应低氧和周围高酸环境，这些可促进肿瘤细胞的侵袭能力和抑制机体的免疫监督。. l* V7 @* a. V1 J" `& c* s2 K
     
9 \) n4 v% ?$ v2 l, w      Metabolic Stress
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      Normal cells derive the bulk of their ATP through mitochondrial oxidative phosphorylation. In what has been referred to as the Warburg effect, most cancer cells are found to predominantly produce energy by the less effcient method of glycolysis and secrete a large amount of lactic acid, even under high oxygen conditions (Warburg, 1956). Tumor cells exhibit dramatically 7 i5 g4 B/ T$ y, e
increased glucose uptake and highly elevated rates of glycolysis (DeBerardinis et al., 2007). This provides the basis for tumorimaging by positron emission tomography (PET) using the glucose analog 18F-2-deoxyglucose. This transition to glycolysis for energy production provides several advantages to the tumor including adaptation to a low oxygen environment and the acidifcation of the surrounding microenvironment, which promotes tumor invasion and suppresses immune surveillance

marrowstem

氧化压力
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       氧化压力的明确性特征是反应性氧物质(ROS，reactive oxygen species ) 的出现，而癌细胞的一个典型特征是比正常细胞生成更多的反应性氧物质。在肿瘤中，癌生成信号(Lee et al., 1999)和线粒体功能的下调(Gogvadze et al., 2008) 都可以促进活性氧(ROS)的生成。观察癌细胞的研究表明活性氧(ROS)具有高度的活性并可能会增加内源性DNA损伤。另外，活性氧(ROS)是一个重要的信号调节因子，它们的出现可能会促进癌细胞的转化。例如，活性氧(ROS)可促进转录因子HIF-1的激活(Dewhirst et al., 2008), 而 HIF-1能启动糖酵解开关，使肿瘤中血管生成。
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Oxidative Stress
5 s) \1 }5 N' e# F, w       The defning characteristic of oxidative stress is the presence of reactive oxygen species (ROS), and cancer cells typically generate more ROS than normal cells (Szatrowski and Nathan, 1991). Both oncogenic signaling (Lee et al., 1999) and the downregulation of mitochondrial function (Gogvadze et al.,   b- y  z9 h6 l4 {
2008) in tumors can contribute to ROS generation. ROS are highly reactive and likely to contribute to the increased levels of endogenous DNA damage observed in cancer cells . In addition, ROS are important signaling mediators, and their presence may contribute to transformation. For example, ROS promote the activation of the transcription factor HIF-1 by hypoxia (Dewhirst et al., 2008), and HIF-1 can promote the glycolytic switch and angiogenesis observed in tumors.
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