How cancer arises
How cancer arises
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DOI：
10.1038/scientificamerican0996-62
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发表时间：
1996-09-01
影响因子：
3
通讯作者：
Weinberg, RA
中科院分区：
文献类型：
--
作者：
Weinberg, RA
癌症如何发展已不再是个谜。在过去的二十年中，研究人员在确定该过程的最深层基础（分子水平）方面取得了惊人的进展。这些发现是强有力的：它们将经受住未来几代研究人员的审查，并将为革命性的治疗方法奠定基础。鉴于将新的理解转化为临床实践是复杂、缓慢且昂贵的，没有人能够准确预测针对癌细胞分子改变的疗法何时会得到广泛应用。但目前这一努力正在进行中。事实上，“癌症”一词指的是 100 多种疾病。几乎身体的每个组织都可能产生恶性肿瘤。有些甚至产生多种类型。更重要的是，每种癌症都有独特的特征。尽管如此，产生这些不同肿瘤的基本过程似乎非常相似。因此，我将在本文中以通用术语提及“癌症”，并利用一种或另一种类型来说明似乎普遍适用的规则。正常、健康身体的 30 万亿个细胞生活在一个复杂、相互依存的共体中，相互调节增殖。事实上，正常细胞只有在受到附近其他细胞的指示时才会进行繁殖。这种不断的合作确保每个组织保持适合身体需求的大小和结构。与之形成鲜明对比的是，癌细胞违反了这一方案。它们对通常的扩散控制充耳不闻，只遵循自己的内部繁殖议程。它们还拥有一个更阴险的特性——从它们开始的部位迁移、侵入附近的组织并在体内远处形成肿块的能力。随着时间的推移，由此类恶性细胞组成的肿瘤变得越来越具有攻击性，当它们破坏整个生物体生存所需的组织和器官时，它们就会变得致命。这并不新鲜。但在过去的 20 年里，科学家们发现了一套控制癌症发展的基本原则。我们现在知道，肿瘤中的细胞起源于一个共同的祖先细胞，该细胞在某一时刻（通常是在肿瘤变得明显之前几十年）启动了不适当的繁殖程序。此外，细胞的恶性转化是通过细胞内特定类别基因突变的积累而发生的。这些基因提供了了解人类癌症根源过程的关键。基因由细胞核中染色体的DNA分子携带。基因指定了必须连接在一起才能形成特定蛋白质的氨基酸序列；然后蛋白质执行基因的工作。当基因被打开时，细胞通过合成编码的蛋白质来做出反应。基因突变可以通过改变蛋白质产物的数量或活性来扰乱细胞。两类基因共同构成整个基因组的一小部分，但在引发癌症方面发挥着重要作用。在正常配置下，它们精心设计细胞的生命周期——细胞扩大和分裂的复杂事件序列。原癌基因促进这种生长，而抑癌基因则抑制这种生长。这两个基因类别共同作用
How cancer develops is no longer a mystery. During the past two decades, investigators have made astonishing progress in identifying the deepest bases of the process—those at the molecular level. These discoveries are robust: they will survive the scrutiny of future generations of researchers, and they will form the foundation for revolutionary approaches to treatment. No one can predict exactly when therapies targeted to the molecular alterations in cancer cells will find wide use, given that the translation of new understanding into clinical practice is complicated, slow and expensive. But the effort is now under way. In truth, the term “cancer” refers to more than 100 forms of the disease. Almost every tissue in the body can spawn malignancies; some even yield several types. What is more, each cancer has unique features. Still, the basic processes that produce these diverse tumors appear to be quite similar. For that reason, I will refer in this article to “cancer” in generic terms, drawing on one or another type to illustrate the rules that seem to apply universally. The 30 trillion cells of the normal, healthy body live in a complex, interdependent condominium, regulating one another’s proliferation. Indeed, normal cells reproduce only when instructed to do so by other cells in their vicinity. Such unceasing collaboration ensures that each tissue maintains a size and architecture appropriate to the body’s needs. Cancer cells, in stark contrast, violate this scheme; they become deaf to the usual controls on proliferation and follow their own internal agenda for reproduction. They also possess an even more insidious property—the ability to migrate from the site where they began, invading nearby tissues and forming masses at distant sites in the body. Tumors composed of such malignant cells become more and more aggressive over time, and they become lethal when they disrupt the tissues and organs needed for the survival of the organism as a whole. This much is not new. But over the past 20 years, scientists have uncovered a set of basic principles that govern the development of cancer. We now know that the cells in a tumor descend from a common ancestral cell that at one point—usually decades before a tumor becomes palpable—initiated a program of inappropriate reproduction. Further, the malignant transformation of a cell comes about through the accumulation of mutations in specific classes of the genes within it. These genes provide the key to understanding the processes at the root of human cancer. Genes are carried in the DNA molecules of the chromosomes in the cell nucleus. A gene specifies a sequence of amino acids that must be linked together to make a particular protein; the protein then carries out the work of the gene. When a gene is switched on, the cell responds by synthesizing the encoded protein. Mutations in a gene can perturb a cell by changing the amounts or the activities of the protein product. Two gene classes, which together constitute only a small proportion of the full genetic set, play major roles in triggering cancer. In their normal configuration, they choreograph the life cycle of the cell—the intricate sequence of events by which a cell enlarges and divides. Proto-oncogenes encourage such growth, whereas tumor suppressor genes inhibit it. Collectively these two gene classes ac-