柳叶刀肿瘤特刊6.doc

Autophagy Mediates Both Tumor Cell Survival and Death自我吞噬能够接到肿瘤细胞的生存和死亡Autophagy represents an important cell physiologic response that, like apoptosis, normally operates at low, basal levels in cells but can be strongly induced in certain states of cellular stress, the most obvious of which is nutrient deciency (Levine and Kroemer, 2008; Mizushima, 2007). The autophagic program enables cells to break down cellular organelles, such as ribosomes and mitochondria, allowing the resulting catabolites to be recycled and thus used for biosynthesis and energy metabolism. As part of this program, intracellular vesicles termed auto phagosomes envelope intracellular organelles and then fuse with lysosomes wherein degradation occurs. In this fashion, low-molecular-weight metabolites are generated that support survival in the stressed, nutrient-limited environments experienced by many cancer cells. Like apoptosis, the autophagy machinery has both regulatory and effector components (Levine and Kroemer, 2008; Mizushima, 2007). Among the latter are proteins that mediate autophagosome formation and delivery to lysosomes. Of note, recent research has revealed intersections between the regulatory circuits governing autophagy, apoptosis, and cellular homeostasis. For example, the signaling pathway involving the PI3 kinase, AKT, and mTOR kinases, which is stimulated by survival signals to block apoptosis, similarly inhibits autophagy; when survival signals are insufcient, the PI3K signaling pathway is downregulated, with the result that autophagy and/or apoptosis may be induced (Levine and Kroemer, 2008; Sinha and Levine, 2008; Mathew et al., 2007).自我吞噬如同细胞凋亡一样是细胞重要的生理功能，通常，自我吞噬只在较低的、基础的水平出现，但是在一些重要的细胞阶段却可以被强力诱导上调，其中营养不良就是一个典型的例子。自我吞噬能够促使细胞分解一些细胞器，这些细胞器包括：核糖体、线粒体。分解这些细胞器所得的一些代谢产物能够用来进行当做生物合成和能量代谢的原料。在细胞内，有一些叫做吞噬体的物质能够包绕着细胞器，然后和溶酶体融合，随后，细胞器就会被降解。就这样，就会产生一些低分子量的物质，这些物质在肿瘤患者严重营养缺乏的情况下可以用来提供能量。和细胞凋亡一样，细胞的自我吞噬也有调控因子和效应元件。效应元件常常是一些蛋白质，他们能够接到自我吞噬的形成，并且将吞噬体运输到溶酶体当中。目前，一个非常有名气的研究已经证实了在调控细胞自我吞噬、凋亡和内平衡的信号转导中有一定的交集。比如说，涉及到PI3激酶、AKT和mTOR激酶的信号通路可以被生存信号激活，从而完成抑制凋亡的效果，同时，也会抑制细胞的自我吞噬。当生存信号不是那么强烈的时候，那么PI3途径就会下调，因而会有凋亡和自我吞噬的加强。Another interconnection between these two programs resides in the Beclin-1 protein, which has been shown by genetic studies to be necessary for induction of autophagy (Levine and Kroemer, 2008; Sinha and Levine, 2008; Mizushima, 2007). Beclin-1 is a member of the BH3-only subfamily of apoptotic regulatory proteins, and its BH3 domain allows it to bind the Bcl-2/Bcl-xL proteins. Stress-sensor-coupled BH3 proteins can displace（取代、置换） Beclin-1 from its association with Bcl-2/Bcl-xL, enabling the liberated Beclin-1 to trigger autophagy, much as（虽然） they can release proapoptotic Bax and Bak to trigger apoptosis. Hence, stress transducing BH3 proteins (e.g., Bid, Bad, Puma, et al.) can induce apoptosis and/or autophagy depending on the physiologic state of the cell.这两种生理功能之间的另一个交集就是Beclin-1蛋白，这个蛋白已经被基因相关实验证实在诱导细胞自我吞噬中起到重要作用了。Beclin-1是一种细胞凋亡相关蛋白，它是仅仅含有BH3结构域的蛋白的一种，而且，他的BH3结构域能够允许他结合在Bcl-2/Bcl-xL蛋白上。BH3结合一些应激感受器可以促使Beclin-1从Bcl-2/Bcl-xL上解体，然后释放Beclin-1去激活细胞自我吞噬途径，当然这一反应液同时释放了可以激活凋亡途径的Bax 和Bak。因此，应激相关的一些BH3蛋白（比如Bid, Bad, Puma）能够依据细胞情况的不同来决定细胞是进入到自我吞噬阶段还是进入到凋亡阶段。Mice bearing inactivated alleles of the gene or of certain other components of the autophagy machinery exhibit increased susceptibility to cancer (White and DiPaola, 2009:Levine and Kroemer, 2008). These results suggest that induction of autophagy can serve as a barrier to tumorigenesis that may operate independently of or in concert with apoptosis. Accordingly, autophagy appears to represent yet another barrier that needs to be circumvented during tumor development (White and DiPaola, 2009). Perhaps paradoxically, nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy that are apparently cytoprotective for cancer cells, impairing rather than accentuating（加强） the killing actions of these stress inducing situations (White and DiPaola, 2009; Apel et al., 2009; Amaravadi and Thompson, 2007; Mathew et al., 2007). Moreover, severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy (White and DiPaola, 2009; Lu et al., 2008). This survival response may enable the persistence and eventual regrowth of some late stage tumors following treatment with potent anticancer agents. Thus, in analogy to TGF-b signaling, which can be tumor suppressing at early stages of tumorigenesis and tumor promoting later on, autophagy seems to have conicting effects on tumor cells and thus tumor progression (Apel et al., 2009; White and DiPaola, 2009). An important agenda for future research will involve clarifying the genetic and cell-physiologic conditions that dictate when and how autophagy enables cancer cells to survive or causes them to die. 那些敲除了调控细胞自我吞噬作用基因的老鼠更容易患得肿瘤。这表明，细胞的自我吞噬可以独立的当做一种阻挡肿瘤发生的机制，当然，也极其有可能和细胞凋亡一起发挥抗肿瘤的作用。因此，自我吞噬在肿瘤发生中显然应当被重视。也许，营养缺乏、放疗、一些细胞毒性药物的使用可以加强细胞自我吞噬的效果，完成抗应激的作用。研究证明，一些严重的肿瘤可以通过细胞吞噬作用收缩，进入一个可逆的细胞冬眠期。但是这一信号通路最终却可以引起肿瘤的生长，导致肿瘤向恶性阶段发展。因此，和TGF-贝塔类似（在初期阶段抗肿瘤，在终末期促进肿瘤发生），自我吞噬作用似乎在肿瘤发生当中也有着这种自相矛盾的作用。从此可见，为了研究的一个重要的方向就是论述细胞替我吞噬作用的基因学、生理学特点，研究什么情况下细胞吞噬可以促进肿瘤生长，什么情况下又起到抗肿瘤的效果。Necrosis Has Proinammatory and Tumor-Promoting Potential坏死具有促进炎症反应的效果，而且有可能会促进肿瘤发生In contrast to apoptosis, in which a dying cell contracts into an almost-invisible corpse that is soon consumed by neighbors, necrotic cells become bloated（膨胀） and explode, releasing their contents into the local tissue microenvironment. Although necrosis has historically been viewed much like organismic death, as a form of system-wide exhaustion（全系统的耗尽） and breakdown, the conceptual landscape is changing: cell death by necrosis is clearly under genetic control in some circumstances, rather than being a random and undirected process (Galluzzi and Kroemer, 2008; Zong and Thompson, 2006). Perhaps more important, necrotic cell death releases proinammatory signals into the surrounding tissue microenvironment, in contrast to apoptosis and autophagy, which do not. As a consequence, necrotic cells can recruit inammatory cells of the immune system (Grivennikov et al., 2010; White et al., 2010; Galluzzi and Kroemer, 2008), whose dedicated function is to survey the extent of tissue damage and remove associated necrotic debris. In the context of neoplasia, however, multiple lines of evidence indicate that immune inammatory cells can be actively tumor promoting, given that such cells are capable of fostering angiogenesis, cancer cell proliferation, and invasiveness (see below). Additionally, necrotic cells can release bioactive regulatory factors, such as IL-1a, which can directly stimulate neighboring viable cells to proliferate, with the potential, once again, to facilitate neoplastic progression (Grivennikovet al., 2010). Consequently, necrotic cell death, while seemingly benecial in counterbalancing cancer-associated hyperproliferation, may ultimately do more damage than good. Accordingly, incipient（初期的） neoplasias and potentially invasive and metastatic tumors