Cell、Nature三篇文章解析p53肿瘤研究新进展

　　

生物通报道：在新近公布的《Nature》和《Cell》杂志上，有三篇文章分别提到了在小鼠体内肿瘤p53功能的恢复会引起肿瘤缩小，其中两篇文章认为肿瘤的维持需要在p53活性缺乏的前提下，这也就说明了p53的恢复也许可以减少人类癌症疾病。

来自哈佛医学院的Ron DePinho教授认为，“这三篇文章同样都有基础性的观察：当你重新恢复p53作用的时候，肿瘤都会逆转，这是个好消息，因为这说明靶向p53功能恢复的机制也许是一种癌症药物研发的新思路。”

原文摘要：
A. Ventura et al., "Restoration of p53 function leads to tumour regression in vivo," 
Nature, advance online publication, DOI:10.1038/nature05541, Jan. 24, 2007. 

W. Xue et al., "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas," Nature, advance online publication, DOI:10.1038/nature05529, Jan. 24, 2007. 

C.P. Martins, L. Brown-Swigart, G.I. Evan, "Modeling the therapeutic efficacy of p53 restoration in tumors," Cell, 127:1323 - 34, Dec. 29, 2006. 
[Abstract]

在上世纪90年代早期，TP53（p53的编码基因）被广泛认为是一个肿瘤抑制基因，它处在细胞各种胁迫反应途径的十字路口上。p53在细胞周期捕获，DNA修复，细胞衰老、分化、调亡等过程中都起着重要的作用，它能修复损伤细胞，或者除去严重损伤的细胞从而避免这些细胞对机体的危害作用。由于p53的多功能性，在它的编码基因TP53上发现很多突变都会影响到p53的功能。因此p53多年以来一直是肿瘤研究的热点领域。

这三篇，分别由麻省理工的Tyler Jacks，冷泉港实验室的Scott Lowe，以及加州大学旧金山分校的Gerard Evan领导完成的文章主要针对的问题是：在肿瘤发育的早期，p53的失活是否是唯一的必需条件，或者说是在肿瘤整个生命周期里都是必需的？

Jacks表示，“我们都知道p53突变在许多癌症发育过程中是十分重要的，但是从我们的研究来看，p53的缺失可能会促进其它改变发生，而一旦其它改变发生了，那么p53的缺少就变得无关紧要了”，“这种可能是否存在，这就是我们这一研究的目的。”

无论是冷泉港实验室Lowe的四环素诱导的RNA干扰实验（tetracycline-inducible RNA interference）（Nature杂志），加州大学Evan的雌激素应答p53实验（estrogen-responsive p53）（Cell杂志），还是麻省理工Jacks的雌激素应答Cre重组酶（estrogen-responsive Cre recombinase）实验（Nature杂志），研究人员都建立了一种缺乏p53，能自发生成肿瘤小鼠模型，这些小鼠在收到药物治疗刺激后能激活p53。他们发现p53复原会导致快速p53活化，从而引起肿瘤消退退。

总而言之，这些研究在淋巴瘤（lymphomas）, 肝癌肿瘤（hepatocarcinomas)和恶性肉瘤（sarcomas）上都发现了p53引起的肿瘤消退，所不同的就是肿瘤消退类型：淋巴瘤是通过细胞掉亡，而恶性肉瘤和肝脏肿瘤则是通过天然免疫系统被清除的。而后者，正如其作者Lowe说的，“是完全没有预料到的”，“我们认为p53也许会杀死细胞，但是没有，p53只是抑制了肿瘤细胞生长，然后这些细胞向天然免疫系统发出了信号。”

但是有科学家认为这些小鼠研究结果要转移到人类临床应用上还存在一定的困难，因为要治愈人类肿瘤要比治愈小鼠困难的多，迄今为止已经有了许多这方面的例子。目前利用恢复p53活性机理的药物也正在考虑发展，其中包括了能帮助突变的p53正常折叠的小分子，阻断p53上游抑制因子mdm2的药物，以及能激活p19-Arf（p53上游的促进因子）的转甲基酶抑制剂。

但是，像大多数癌症治疗一样，肿瘤能找到防御的方式，比如在Evan实验中，肿瘤能很快是适应p53的恢复，在最初的肿瘤消退之后，所有的小鼠会故态复萌，无论是p53缺失的还是p19-Arf缺失的。Evan认为复合性治疗，比如在使得致癌基因失活的同时恢复p53的活性可能可以解决这个问题。
（生物通：张迪）

附：
The Jacks Lab 


The Jacks Lab is interested in the genetic events that contribute to the development of cancer. The focus of our research has been a series of mouse strains engineered to carry mutations in genes known to be involved in human cancer. We also study the effects of these mutations on normal embryonic development and use cells derived from mutant animals to study the function of these genes in cell culture models. Current research remains centered on the use of gene targeting to create more powerful and accurate mouse models of human cancer and to explore the pathways regulated by cancer-associated genes. We have generated mouse models of several major human cancer types, including lung cancer, pancreatic cancer, ovarian cancer, astrocytoma, retinoblastoma, peripheral nervous system tumors, soft tissue sarcoma, and invasive colon cancer. The mouse models are being evaluated with cutting-edge tools in genetics, genomics, and imaging, as well as with various chemotherapeutic agents.

The Jacks Lab is comprised of post-docs (10), grad students (6), technicians (7), undergraduate students (8), and support staff (2). It is funded by NIH and DOD research grants, and the Howard Hughes Medical Institute. The Jacks Lab is part of the MIT Center for Cancer Research. This website contains a research summary for the lab, contact information for all lab members, links to all of our PubMed abstracts, information on requesting reagents, lab protocols, and glimpses of our lab social activities. 


Scott Lowe
Professor
Investigator, Howard Hughes Medical Institute
Ph.D., Massachusetts Institute of Technology, 1994
Modulation of apoptosis; chemosensitivity; senescence by cancer genes 

email [e-mail], phone [phone], fax [phone] 


Apoptosis is a genetically-controlled form of cell death that is important for normal development and tissue homeostasis. Senescence produces "genetic death" in that the senescent cell is incapable of further propagation. Both processes are frequently disrupted in cancer cells, implying that each can limit tumor development. Moreover, radiation and many chemotherapeutic agents can induce either apoptosis or senescence, and there is substantial evidence that the integrity of these programmed responses influences the outcome of cancer therapy in patients. The goal of our research is to understand how cancer genes control apoptosis and senescence in normal cells, and how mutations that disrupt these processes impact tumor development and therapy.

Much of our research effort stems from our studies on the p53 tumor suppressor. p53 functions as a key component of several cellular stress responses and, as such, acts at a variety of levels to protect against cancer. Our laboratory has identified factors that act upstream or downstream of p53, and we are beginning to assemble these components into a tumor suppressor "network." We are currently interested in how oncogenes or DNA damaging agents signal p53, how p53 executes a biological response, and the factors that influence whether p53 induces a cell-cycle checkpoint, senescence, or apoptosis. Our approach emphasizes genetics, and we often exploit primary cell culture models to study cancer gene function. More recently, we have studied human tumors and animal models to confirm the relevance of our simple systems for tumor development and cancer therapy in vivo.


Gerard I. Evan, PhD, FRS 

RESEARCH SUMMARY 
Making and Breaking Tumors 
Our laboratory is interested in the molecular processes that underlie tumorigenesis, tumor progression and tumor maintenance. Cancers appear very different from the normal tissues from which they are presumably derived, and this has engendered the widely held contemporary view that cancers are the protracted end result of a bewildering complexity of molecular lesions that between them drive the formation of the equally complex neoplastic phenotype. However, appearances can be deceiving. We know that many oncogenes are highly pleiotropic "master" switches that modulate a wide variety of mechanistically diverse processes. Consequently, the apparent complexity of cancers may be instructed by a relatively simple, and hence therapeutically tractable, set of molecular lesions. Our overarching aim is to establish what such molecular lesions might be, what effects they have on specific cell types, alone and in combination, and how critical such lesions are not only to drive tumor formation but also to maintain an established tumor. 
Some years ago we noted an unexpected link between the processes that drive cell proliferation and those that promote programmed cell death (apoptosis). We showed that the ubiquitous Myc oncoprotein was a potent trigger of apoptosis in cells deprived of survival factors or subjected to any of a diverse range of insults including DNA damage, interferon and death receptor signaling, hypoxia and nutrient privation. On the basis of such observations, we proposed the now generally accepted notion that the coupling of cell proliferation with cell death represents an innate tumor suppressive mechanism that efficiently restrains the emergence of autonomous clones within the soma. Thus, no cancer can arise without concomitant suppression of cell death. This, in turn, raises some critical questions. First, how does cell death become suppressed during tumorigenesis? Second, besides deregulated cell proliferation and suppressed cell death, what else (if anything) is needed for a cancer to arise? Third, how important is suppression of cell death for the maintenance of established cancers? In particular, might reconstitution of cell death offer an effective and tumor-specific general therapeutic strategy for treating cancer? Much of the work in our laboratory addresses these key questions using a variety of novel experimental systems and technologies.