TITLE:
AUTHOR:
分两部分翻译：
第1部分：
Three recent reports1,2,3 have shown that cancers in mice can be eliminated through the activation of a single gene, Tp53, which encodes the protein p53. The power of p53 with respect to killing cancer cells had been suspected for decades, but the elimination of malignant tumors by the activation of p53 had not been observed.
The p53 protein is arguably the most important sensor of stress that mammals possess. Under normal, basal conditions, this protein is inconsequential, because of the rapidity of its degradation. But almost any type of stress, including damage to DNA and oncogenic signaling, halts the degradation of p53 and effects its activation. Activated p53 unleashes a complex transcriptional program in the stressed cells that can result in their elimination from the proliferative pool through apoptosis or senescence.
Tumors are highly stressful environments that impose strong pressure to eliminate the "safeguard" system mediated by p53. Almost all human cancers have some type of impairment in the p53 pathway: about 50% have inactivating mutations in TP53 or carry a deletion encompassing it. The other 50% retain gene function but have dented the pathway by increasing the rate of p53 degradation, extinguishing the signaling events that collude in activating p53, or countering the downstream effects of p53 by increasing levels of cell-cycle activators or antiapoptotic proteins. There is therefore a great deal of effort being put into finding drugs that increase p53 activity in such tumors. Xue et al.,1 Ventura et al.,2 and Martins et al.3 report the results of experiments in mouse models of cancer — hepatocarcinoma,1 lymphoma,2,3 and sarcoma2 — in which p53 can be turned on and off with the use of an exogenously applied stimulus (of no practical application in the clinical setting). The investigators were therefore able to induce cancers with a silent p53 gene; after the cancers were established and growing, the investigators "turned on" p53 expression.
Xue et al. and Ventura et al. observed that p53 is able to effectively eliminate all three of these types of cancer. The results were spectacular: in some cases, near-complete regression (with tumor size monitored by magnetic resonance imaging and other imaging techniques) was achieved just 2 days after p53 activation.2 In other cases, regression took longer (about 10 days).1
Martins et al. used a slightly different system. They transplanted Myc-driven lymphoma cells into wild-type mice and then turned on p53 expression in the lymphoma cells. Myc-driven lymphoma is a particularly aggressive malignant disease similar to Burkitt's lymphoma, so it came as no surprise that the onset of tumor development was delayed in the treated mice (as compared with controls), rather than completely repressed. The "delayed" lymphomas had lost the Arf gene — which encodes an activator of p53 and is expressed in response to stress — or Tp53 itself, indicating that p53 activity is incompatible with tumor growth.
第2部分：
Turning on p53 had no effect on the normal mice tissue2; normal tissue lacks the stress signals (which are present in tumors) that activate and stabilize p53. This fact also suggests that a p53-targeted therapy may have few or minimal undesired toxic effects on the organism.
These studies by Xue et al., Ventura et al., and Martins et al., while impressive, should be interpreted with caution. The results were obtained in mice in which tumors developed in the complete absence of p53, and thus selective pressure to desensitize p53 activators or p53 downstream effectors was lacking. In contrast, human cancers that retain an intact p53 usually have a corrupted p53 pathway. For this reason, reactivation of p53 with a targeted drug would occur in a cellular environment that may be resistant to the effect of p53. This does not mean that such a therapy would be inefficient, but it would be unlikely to be as effective as the methods used by these investigators.1,2,3
Perhaps the biggest surprise provided by the three studies was the discovery of senescence as a primary mechanism of tumor regression (Figure 1). In the case of radiation-induced lymphomas, regression occurred rapidly and was associated with abundant apoptosis.2 In contrast, the hepatocarcinomas and sarcomas regressed more slowly than lymphomas and showed no signs of apoptosis.1,2 This finding inspired the investigators to determine whether p53 induced tumor senescence. Like apoptosis, senescence is a stress response, but instead of inducing cell death, it puts a permanent brake on cell proliferation. It had been established that premalignant tumors, but not malignant tumors, have a large proportion of senescent cells.4 This fact is consistent with the concept that tumors are stressful environments and that senescence can be an efficient brake on tumor progression. Xue et al. investigated the basis for the regression of senescent tumors and observed that they became infiltrated by neutrophils, macrophages, and natural killer cells that eventually destroyed the tumor cells and the tumoral vasculature. This finding indicates an alternative mechanism to cell death that can also explain cancer regression. These three studies strongly support the search for targeted p53-activating drugs and indicate that senescence, in addition to cell death, is a relevant outcome of anticancer therapies.
Figure 1. Models of Tumor Regression.
A cancer with functional p53 might respond to a p53-targeted therapy by undergoing apoptosis or senescence. Apoptotic and senescent cells are recognized and phagocytosed by macrophages, resulting in regression of the tumor.
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RESOURCE: NEJM,Volume 356:1996-1997 May 10, 2007 Number 19
TITLE: 题目
Cancer Regression by Senescence
癌细胞的衰老
AUTHOR:
Manuel Serrano, Ph.D.
分两部分翻译：
第1部分：
Three recent reports1,2,3 have shown that cancers in mice can be eliminated through the activation of a single gene, Tp53, which encodes the protein p53.
最近3个报告1，2，3的研究显示，通过激活p53蛋白的编码基因Tp53，在小鼠体内的癌症可以被清除。
The power of p53 with respect to killing cancer cells had been suspected for decades, but the elimination of malignant tumors by the activation of p53 had not been observed. 几十年前人们就怀疑p53蛋白具有杀死癌细胞的能力，但是激活p53蛋白对恶性肿瘤的清除得现象还没有被观察过。
The p53 protein is arguably the most important sensor of stress that mammals possess. 对于p53蛋白是哺乳动物最重要的应激传感器这一说法是由争议的。
Under normal, basal conditions, this protein is inconsequential, because of the rapidity of its degradation.
在正常的基础情况下，因为可以迅速降解，这个蛋白是不连贯存在。
But almost any type of stress, including damage to DNA and oncogenic signaling, halts the degradation of p53 and effects its activation.
但是在几乎所有应激，包括DNA的降解和肿瘤信号，p53蛋白可以停止降解，并且启动激活。
Activated p53 unleashes a complex transcriptional program in the stressed cells that can result in their elimination from the proliferative pool through apoptosis or senescence. 激活p53蛋白在应激细胞内启动一个复杂的转录程序，这个程序可以通过凋亡和衰老从增生池清除这个细胞。
Tumors are highly stressful environments that impose strong pressure to eliminate the "safeguard" system mediated by p53.
在肿瘤高应激得环境中，这种环境压力可以促进p53蛋白调节的清除系统。
Almost all human cancers have some type of impairment in the p53 pathway: about 50% have inactivating mutations in TP53 or carry a deletion encompassing it.
几乎所有的癌症患者P53通路都由损害，50%的TP53有激活突变或者缺失突变。
The other 50% retain gene function but have dented the pathway by increasing the rate of p53 degradation, extinguishing the signaling events that collude in activating p53, or countering the downstream effects of p53 by increasing levels of cell-cycle activators or antiapoptotic proteins. There is therefore a great deal of effort being put into finding drugs that increase p53 activity in such tumors. 其他50%的癌症患者保留了TP53基因功能，但是由于P53蛋白的降解率增加，激活P53蛋白的信号消减，增加细胞周期激活物或者抗凋亡蛋白水平升而减低P53蛋白的下游作用。因此研究者花费了大量的努力寻找可以激活如肿瘤内P53蛋白的药物。
Xue et al.,1 Ventura et al.,2 and Martins et al.3 report the results of experiments in mouse models of cancer — hepatocarcinoma,1 lymphoma,2,3 and sarcoma2 — in which p53 can be turned on and off with the use of an exogenously applied stimulus (of no practical application in the clinical setting). The investigators were therefore able to induce cancers with a silent p53 gene; after the cancers were established and growing, the investigators "turned on" p53 expression.Xue et al、Ventura et al.和Martins等的报告中，采用外源性的刺激，在小鼠体内分别激活肝癌、淋巴瘤和肉瘤细胞内的P53蛋白。因此这个研究可以在开始时诱导P53基因的沉默，当肿瘤建立并生长后，在开启P53基因表达。
Xue et al. and Ventura et al. observed that p53 is able to effectively eliminate all three of these types of cancer.
Xue et al和Ventura et al观察到P53蛋白能高效的清除所有这三种癌症细胞。
The results were spectacular: in some cases, near-complete regression (with tumor size monitored by magnetic resonance imaging and other imaging techniques) was achieved just 2 days after p53 activation.结果令人震惊，在一些病例，在P53蛋白被激活的两天内肿瘤近似完全的退化（肿瘤的大小通过核磁共振成像和其他成像技术）
In other cases, regression took longer (about 10 days).
在其他的 一些病例退化可能用的时间更长一些。（大约10天）
Xue et al. and Ventura et al. Martins et al. used a slightly different system. Xue et al和Ventura等，Martins 等用的是一个略有差别的系统。
They transplanted Myc-driven lymphoma cells into wild-type mice and then turned on p53 expression in the lymphoma cells. Myc-driven lymphoma is a particularly aggressive malignant disease similar to Burkitt's lymphoma, so it came as no surprise that the onset of tumor development was delayed in the treated mice (as compared with controls), rather than completely repressed. 他们将原癌基因诱导的淋巴瘤移植到野生型小鼠，然后在淋巴瘤细胞启动p53表达。原癌基因诱导的淋巴瘤与伯基特淋巴瘤相似，是恶性程度很高的侵袭性疾病，所以当与完全抑制相比较，肿瘤进展延迟（与对照组相比），人们并不感觉奇怪。
The "delayed" lymphomas had lost the Arf gene — which encodes an activator of p53 and is expressed in response to stress — or Tp53 itself, indicating that p53 activity is incompatible with tumor growth.延迟生长的淋巴瘤缺少Arf基因，Arf基因在细胞受到应激或者p53本身诱导时表达，编码一个p53蛋白的激活物，这表明p53的活性与肿瘤的生长是不相容的。
第一部分编译
新英格兰医学杂志,Volume 356:1996-1997 May 10, 2007 Number 19
最近3个报告1，2，3的研究显示，通过激活p53蛋白的编码基因Tp53，在小鼠体内的癌症可以被清除。几十年前人们就怀疑p53蛋白具有杀死癌细胞的能力，但是激活p53蛋白对恶性肿瘤的清除得现象还没有被观察过。
对于p53蛋白是哺乳动物最重要的应激传感器这一说法是由争议的。在正常的基础情况下，因为可以迅速降解，这个蛋白是不连贯存在的。但是在几乎所有应激，包括DNA的降解和肿瘤信号，都可以使p53蛋白停止降解，并且启动激活。激活p53蛋白在应激细胞内启动一个复杂的转录程序，这个程序可以通过凋亡和衰老从增生池清除这个细胞。
在肿瘤高应激的环境中，这种环境压力可以促进p53蛋白调节的清除系统。几乎所有的癌症患者P53通路都由损害，50%的TP53有激活突变或者缺失突变。
其他50%的癌症患者保留了TP53基因功能，但是由于P53蛋白的降解率增加，激活P53蛋白的信号消减，增加细胞周期激活物或者抗凋亡蛋白水平升而减低P53蛋白的下游作用。因此研究者花费了大量的努力寻找可以激活如肿瘤内P53蛋白的药物。Xue et al、Ventura et al.和Martins等的报告中，采用外源性的刺激，在小鼠体内分别激活肝癌、淋巴瘤和肉瘤细胞内的P53蛋白。因此这个研究可以在开始时诱导P53基因的沉默，当肿瘤建立并生长后，在开启P53基因表达。
Xue et al和Ventura et al观察到P53蛋白能高效的清除所有这三种癌症细胞。结果令人震惊，在一些病例，在P53蛋白被激活的两天内肿瘤近似完全的退化（肿瘤的大小通过核磁共振成像和其他成像技术确定）在其他的 一些病例退化可能用的时间更长一些。（大约10天）
Xue et al和Ventura等，Martins 等用的是一个略有差别的系统。他们将原癌基因诱导的淋巴瘤移植到野生型小鼠，然后在淋巴瘤细胞启动p53表达。原癌基因诱导的淋巴瘤与伯基特淋巴瘤相似，是恶性程度很高的侵袭性疾病，所以当与完全抑制相比较，肿瘤进展延迟（与对照组相比），人们并不感觉奇怪。延迟生长的淋巴瘤缺少Arf基因，Arf基因在细胞受到应激或者p53本身诱导时表达，编码一个p53蛋白的激活物，这表明p53的活性与肿瘤的生长是不相容的。
稍候奉上第二部分！
第二部分
Turning on p53 had no effect on the normal mice tissue2; normal tissue lacks the stress signals (which are present in tumors) that activate and stabilize p53. 启动p53基因对正常小鼠组织没有影响，正常的组织缺乏激活稳定的p53基因的应激信号（只在存在肿瘤细胞）。
This fact also suggests that a p53-targeted therapy may have few or minimal undesired toxic effects on the organism.这个事实也暗示p53定向的治疗对器官几乎没有或者只有很小的毒副作用。
These studies by Xue et al., Ventura et al., and Martins et al., while impressive, should be interpreted with caution.
Xue et al., Ventura et al和Martins et al的这些研究给人印象深刻，需要认真的解释。
The results were obtained in mice in which tumors developed in the complete absence of p53, and thus selective pressure to desensitize p53 activators or p53 downstream effectors was lacking.
这个实验的结果来源于小鼠，在p53缺乏的小鼠培养肿瘤，所以去除p53激活物的选择性压力或者p53下游的效应分子缺乏。
In contrast, human cancers that retain an intact p53 usually have a corrupted p53 pathway.
相反，人类癌症组织保留了完整的p53基因，但是经常有一个错误的通路。
For this reason, reactivation of p53 with a targeted drug would occur in a cellular environment that may be resistant to the effect of p53.
针对这个问题，如果用靶向药物再激活p53会导致细胞内环境对p53效应分子的耐受。
This does not mean that such a therapy would be inefficient, but it would be unlikely to be as effective as the methods used by these investigators.1,2,3
这不意味着这样的治疗就是无效的，但是在实验中用的这些方法是不可能有效的。
Perhaps the biggest surprise provided by the three studies was the discovery of senescence as a primary mechanism of tumor regression (Figure 1). 也许这三个研究最令人惊奇的发现就是衰老是肿瘤退化的基本机制。
In the case of radiation-induced lymphomas, regression occurred rapidly and was associated with abundant apoptosis.对于辐射诱发的淋巴瘤，退化出现的很快，并且伴随着大量的凋亡。
In contrast, the hepatocarcinomas and sarcomas regressed more slowly than lymphomas and showed no signs of apoptosis.1,2相反肝癌和肉瘤与淋巴瘤相比较，退化比较慢，并且没有凋亡的迹象。
This finding inspired the investigators to determine whether p53 induced tumor senescence. 这个发现启发这个研究确定是否p53诱导肿瘤衰老。
Like apoptosis, senescence is a stress response, but instead of inducing cell death, it puts a permanent brake on cell proliferation.
与凋亡相似，衰老是一种应激反应，与诱导细胞死亡不同，它是细胞增殖的长期抑制机制。
It had been established that premalignant tumors, but not malignant tumors, have a large proportion of senescent cells.
已经确定，恶化前的肿瘤有一部分衰老细胞，而在恶化的肿瘤细胞则没有。
4 This fact is consistent with the concept that tumors are stressful environments and that senescence can be an efficient brake on tumor progression. 这个事实与肿瘤存在于应激环境和衰老可能是肿瘤进展的一个有效的抑制的概念相符。
Xue et al. investigated the basis for the regression of senescent tumors and observed that they became infiltrated by neutrophils, macrophages, and natural killer cells that eventually destroyed the tumor cells and the tumoral vasculature.
Xue et al 研究肿瘤衰老退化的基础，观察到退化的肿瘤细胞被中性粒细胞、巨噬细胞和自然杀伤细胞浸润，直至破坏肿瘤细胞和肿瘤脉管系统。
This finding indicates an alternative mechanism to cell death that can also explain cancer regression. 这个发现说明，有两种机制都可以解释癌症的退化。
These three studies strongly support the search for targeted p53-activating drugs and indicate that senescence, in addition to cell death, is a relevant outcome of anticancer therapies.
这三个研究有力的支持了定向的p53激活药物研究，说明出细胞死亡，衰老也是抗癌治疗的相关结果。
第二部分编译
启动p53基因对正常小鼠组织没有影响，而且正常的组织也缺乏激活稳定的p53基因的应激信号（只在存在肿瘤细胞）。这个事实也暗示p53定向的治疗对器官几乎没有或者只有很小的毒副作用。
Xue et al，Ventura的研究小组和Martins的研究小组，他们的这些研究给人印象深刻，同时也需要认真的解释。这个实验的结果来源于小鼠，在p53缺乏的小鼠培养肿瘤，所以这些小鼠去除p53激活物的选择性压力或者p53下游的效应分子缺乏。人与小鼠不同，人类癌症组织保留了完整的p53基因，但是经常有一个错误的通路。针对这个问题，如果用靶向药物再激活p53会导致细胞内环境对p53效应分子的耐受。这不意味着这样的治疗就是无效的，但是在实验中用的这些方法是不可能有效的。
也许这三个研究最令人惊奇的发现就是衰老是肿瘤退化的基本机制。对于辐射诱发的淋巴瘤，退化出现的很快，并且伴随着大量的凋亡。相反肝癌和肉瘤与淋巴瘤相比较，退化比较慢，并且没有凋亡的迹象。这个发现启发这个研究需要确定是否p53诱导肿瘤衰老。与凋亡相似，衰老是一种应激反应，与诱导细胞死亡不同，它是细胞增殖的长期抑制机制。已经确定，恶化前的肿瘤有一部分衰老细胞，而在恶化的肿瘤细胞则没有。这个事实与肿瘤存在于应激环境和衰老可能是肿瘤进展的一个有效的抑制的概念相符。研究肿瘤衰老退化的基础，观察到退化的肿瘤细胞被中性粒细胞、巨噬细胞和自然杀伤细胞浸润，直至破坏肿瘤细胞和肿瘤脉管系统。这个发现说明，有两种机制都可以解释癌症的退化。这三个研究有力的支持了定向的p53激活药物研究，说明出细胞死亡，衰老也是抗癌治疗的相关结果。
第一部分校对：
through the activation of a single gene, Tp53, which encodes the protein p53. 通过激活p53蛋白的编码基因Tp53
译成：通过激活编码p53蛋白的单一基因Tp53
but the elimination of malignant tumors by the activation of p53 had not been observed. 但是激活p53蛋白对恶性肿瘤的清除得现象还没有被观察过。
译成：但一直未证实通过激活p53蛋白杀灭恶性肿瘤
The p53 protein is arguably the most important sensor of stress that mammals possess. 对于p53蛋白是哺乳动物最重要的应激传感器这一说法是由争议的。
译成：证据表明p53蛋白是哺乳动物最重要的应激传感器
Under normal, basal conditions, this protein is inconsequential, because of the rapidity of its degradation. 在正常的基础情况下，因为可以迅速降解，这个蛋白是不连贯存在。
译成：在常态、基本状况下，因为这种蛋白迅速降解，所以并不重要。
including damage to DNA and oncogenic signaling, halts the degradation of p53 and effects its activation. 包括DNA的降解和肿瘤信号，p53蛋白可以停止降解，并且启动激活。
译成：包括DNA及致癌信号的破坏，阻断了p53的降解，并使其活化
The other 50% retain gene function but have dented the pathway by increasing the rate of p53 degradation, extinguishing the signaling events that collude in activating p53, or countering the downstream effects of p53 by increasing levels of cell-cycle activators or antiapoptotic proteins. 其他50%的癌症患者保留了TP53基因功能，但是由于P53蛋白的降解率增加，激活P53蛋白的信号消减，增加细胞周期激活物或者抗凋亡蛋白水平升而减低P53蛋白的下游作用。
译成：通过P53降解速率的增加、活化的P53蛋白相关的信号事件的削弱、增加细胞周期活化子或抗凋亡蛋白抵销P53下游效应，其他50%保留的基因作用几乎已经消弱了这种途径
Tumors are highly stressful environments that impose strong pressure to eliminate the "safeguard" system mediated by p53.
在肿瘤高应激得环境中，这种环境压力可以促进p53蛋白调节的清除系统。
肿瘤形成高应激环境，而这种环境压力迫使p53蛋白清除“防卫”体系。
Almost all human cancers have some type of impairment in the p53 pathway: about 50% have inactivating mutations in TP53 or carry a deletion encompassing it.
几乎所有的癌症患者P53通路都由损害，50%的TP53有激活突变或者缺失突变。
几乎所有的癌症患者P53通路都有一些类型的损害，大约50%的患者TP53基因失活或者缺失突变。
The other 50% retain gene function but have dented the pathway by increasing the rate of p53 degradation, extinguishing the signaling events that collude in activating p53, or countering the downstream effects of p53 by increasing levels of cell-cycle activators or antiapoptotic proteins. 其他50%的癌症患者保留了TP53基因功能，但是由于P53蛋白的降解率增加，激活P53蛋白的信号消减，增加细胞周期激活物或者抗凋亡蛋白水平升而减低P53蛋白的下游作用。
其他50％的患者保留了TP53基因功能，却通过其他方式损害这一通路。这些方式包括增加p53蛋白降解速率，降低参与激活p53的信号事件，或者通过增加细胞周期激活因子和抗凋亡蛋白的水平抵消p53下游调节功能。
but it would be unlikely to be as effective as the methods used by these investigators.1,2,3
但是在实验中用的这些方法是不可能有效的
但这意味着研究中使用的这些方法效果可能没有那么明显。[color=purple][/color]