章节大纲

  • What makes a cell cancerous?
    ::是什么使细胞癌?

    Luckily, it is not an easy process. A number of things have to go wrong. Many times, in the are involved. And not just one mutation, but more than one is needed.
    ::幸运的是,这不是一个容易的过程。一些事情必须出错。很多时候,其中涉及到很多次。不仅需要一次突变,而且需要不止一次的突变。

    Mutations and Cancer
    ::变异和癌症

    In the : Cancer (Advanced) concept, cancer is described as developing due to unregulated . That is, cancer is a disease characterized by a of that grow and divide without respect to normal limits. These cancerous cells invade and destroy adjacent tissues , and they may spread throughout the body. The process by which normal cells are transformed into cancer cells is known as carcinogenesis . This process is also known as oncogenesis or tumorigenesis. Oncogenes are mutated genes involved in the of cancer.
    ::在癌症(高级)概念中,癌症被描述为由不受管制的疾病导致的发育。也就是说,癌症是一种疾病,其特点是这种生长和分裂,而没有尊重正常限度。这些癌症细胞侵入并摧毁了相邻的组织,它们可能散布在身体上。正常细胞变成癌症细胞的过程被称为致癌细胞。这个过程也被称为致癌或肿瘤产生。肿瘤是癌症的变异基因。肿瘤是肿瘤的变异基因。

    Nearly all cancers are caused by mutations in the DNA of the abnormal cells. These mutations may be due to the effects of carcinogens , cancer causing agents such as tobacco smoke, radiation, chemicals, or infectious agents. These carcinogens may act as an environmental “trigger,” stimulating the onset of cancer in certain individuals and not others. Do all people who smoke get cancer? No. Can secondhand smoke increase a nonsmoking person's chance of developing lung cancer? Yes. It also increases a nonsmoking person's chance of developing heart disease.
    ::几乎所有癌症都是由异常细胞DNA突变引起的,这些突变可能是由于致癌、导致烟草烟雾、辐射、化学物质或传染物等致癌物的影响。这些致癌物可以作为一种环境“触发器 ” , 刺激某些人而不是其他人的癌症发作。所有吸烟者是否都得癌症?不。二手烟能增加不吸烟者患肺癌的机会吗?是的。它也会增加不吸烟者患心脏病的机会。

    Complex interactions between carcinogens and an individual’s genome may explain why only some people develop cancer after exposure to an environmental trigger and others do not. Do all cancers need an environmental trigger to develop? No. Cancer causing mutations may also result from errors incorporated into the DNA during replication, or they may be inherited. Inherited mutations are present in all cells of the organism .
    ::致癌物和个人基因组之间的复杂互动可能解释为什么只有一些人在接触环境触发物后患上癌症,而其他人则没有。 是否所有癌症都需要环境触发物才能发育? 不。 导致突变的癌症也可能是复制过程中纳入DNA的错误造成的,也可能是遗传的。 遗传突变存在于生物体的所有细胞中。

    Oncogenes and Tumor Suppressor Genes
    ::肿瘤和肿瘤抑制基因

    Mutations found in the DNA of cancer cells typically affect two general classes of genes: oncogenes and tumor suppressor genes. In “normal,” non-cancerous cells, the products of proto-oncogenes promote cell growth and prior to cell division; thus, proto-oncogenes encode needed for normal cellular functions. Mutations in proto-oncogenes can modify their expression and the function of the gene product, increasing the amount of activity of the product protein. When this happens, they become oncogenes; thus, the cells have a higher chance of dividing excessively and uncontrollably. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells abnormal properties. The products of these genes result in uncontrolled cell growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Proto-oncogenes cannot be removed from the genome, as they are critical for growth, repair and . It is only when they become mutated that the signals for growth become excessive.
    ::在癌症细胞的DNA中发现的突变通常会影响两大类基因:肿瘤和肿瘤抑制基因。在“正常的”非肿瘤细胞中,原蛋白的产物会促进细胞生长,并且在细胞分裂之前;因此,正常细胞功能所需的蛋白质会编码。原蛋白中的突变可以改变其表达方式和基因产品的功能,增加产品蛋白的活性。一旦发生这种情况,它们就会变成蛋白质;因此,细胞有过度和无法控制的分解的更大机会。癌症细胞中经常会引发癌症对基因的刺激,使细胞产生不正常的特性。这些基因的产物导致无控制的细胞生长和分解,防止计划细胞死亡,丧失对正常组织界限的尊重,以及建立在不同组织环境中的能力。蛋白质无法从基因组中去除蛋白质,因为它们对生长、修复和生长至关重要。只有当它们变形时,生长信号才会变得过度。

    In “normal” cells, the products of tumor suppressor genes temporarily discourage cell growth and division to allow cells to finish routine functions, especially . Tumor suppressors are generally factors , activated by cellular stress or DNA damage. The function of such genes is to stop the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells . However, if the tumor suppressor genes are inactivated, DNA repair cannot occur. Tumor suppressor genes can be inactivated by a mutation that either affects the gene directly or that affects the pathway that activates the gene. The consequence of the lack of DNA repair is that DNA damage accumulates, is not repaired, and inevitably leads to detrimental phenotypes , such as cancer.
    ::在“正常”细胞中,肿瘤抑制基因的产物暂时抑制细胞生长和分裂,使细胞能够完成常规功能,特别是 。肿瘤抑制器通常是由细胞压力或DNA损伤引发的因素。这些基因的作用是停止细胞循环,以便进行DNA修复,防止突变传到后代细胞。但是,如果肿瘤抑制基因没有被激活,DNA无法修复。肿瘤抑制基因可以通过突变而失去活化作用,这种突变直接影响到基因,或影响到激活基因的途径。缺乏DNA修复的后果是DNA损伤积累、没有修复,并不可避免地导致癌症等有害的苯型。

    Oncogenes
    ::肿瘤

    Categories of oncogenes are described in the table below. Oncogenes may be growth factors, protein kinases, GTPases or transcription factors. Growth factors are naturally occurring substances, usually a protein or steroid hormone , capable of stimulating cellular growth, proliferation and differentiation . They are important for regulating a variety of cellular processes. Usually they must bind to an extracellular or intracellular receptor to initiate a cellular reaction. Kinases are that catalyze the transfer a phosphate group from ATP to a protein in a cell. They function as a control switch in many cellular functions, turning a function on or off, and regulating other cellular processes. Many times they are involved in activating a cascade of reactions. Tyrosine kinases may be either membrane bound receptors, with an intracellular kinase , or they may be cytoplasmic kinases. As their names imply, tyrosine kinases phosphorylate tyrosine residues and serene/threonine kinases phosphorylate serene or threonine residues. Transcription factors are DNA binding proteins involved in the regulation of transcription, and GTPases are a large family of enzymes that can bind and hydrolyze GTP (guanosine triphosphate) to GDP. All these processes are related in that they involve phosphate groups and phosphorylation activities. The phosphorylation of a target protein usually is an initial step in a cascade of intracellular processes, and is normally activated under specific conditions. If these processes are constitutively active, then homeostasis will be disrupted and detrimental phenotypes may result. 
    ::肿瘤可能是生长因子、蛋白质异变素、GTPase或转基因因子。生长因子是自然发生的物质,通常是蛋白质或类固醇激素,能够刺激细胞生长、扩散和差异。它们对于调控各种细胞过程很重要。它们通常必须与细胞外细胞或细胞内受体捆绑,以引发细胞反应。Kinas会催化磷酸盐组从ATP转移到细胞内的蛋白质。它们的作用是许多细胞功能的控制开关,功能是开关或关,并调节其他细胞过程。它们经常参与一系列反应的启动过程,通常是蛋白质或类激素激化激素,它们可能是细胞内或细胞内细胞内受体,或者它们可能是细胞内受体反应。它们的名字暗示,磷酸激素磷酸盐的残留和肾内分泌/血清是磷酸酯的切变异性反应,它们通常会包含某种DNA的固定性变异性变异性 。这些种的基因变异性因子是一系列的变异性基因的变异性基因,这些变异性基因的变种的变种在基因的基因变种中,这些变种的变种的变基因变基因变基因的变基因变基因变基因的变基因变基因变基因变基因变的变基因变的变的变基因变基因变基因变的变基因变基因变基因变基因变的变的变基因。

    Category Examples Description
    Growth factors, or mitogens c-Sis Usually secreted by specialized cells to induce cell proliferation in the cell, nearby cells, or distant cells. An oncogene may cause a cell to secrete growth factors that would normally not be secreted. The oncogene will thereby induce its own uncontrolled proliferation, as well as the proliferation of neighboring cells. It may also cause production of growth in other parts of the body.
    Receptor tyrosine kinases epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), HER2/neu Receptor tyrosine kinases add phosphate groups to other proteins to activate or inactivate them. Receptor kinases add phosphate groups to receptor proteins at the surface of the cell. These receptor proteins receive signals from outside the cell and initiate a signal transduction process inside the cell. Tyrosine kinases add phosphate groups to tyrosine residues in the target protein. They can cause cancer by turning the receptor permanently on (constitutively), even without signals from outside the cell.
    Cytoplasmic tyrosine kinases Src-family, Syk-ZAP-70 family, and BTK family of tyrosine kinases, the Abl gene in CML - Philadelphia Cytoplasmic tyrosine kinases are similar to receptor tyrosine kinases, except that they are located within the cell. They in turn phosphorylate tyrosine residues of target proteins, initiating a cascade of intracellular processes.
    Cytoplasmic serine/threonine kinases and their regulatory subunits Raf kinase, and cyclin-dependent kinases. Cytoplasmic serine/threonine kinases are similar to cytoplasmic tyrosine kinases, except that serene or throne residues are phosphorylated.
    Regulatory GTPases Ras protein Ras is a small GTPase that hydrolyses GTP into GDP and phosphate. Ras is activated by growth factor signaling, and activates or inactivates growth signaling pathways. Downstream effectors of Ras include Raf, MEK, MEKK, MAPK, ERK, most of which in turn regulate genes that mediate cell proliferation.
    Transcription factors myc, fos myc gene products regulate transcription of genes that induce cell proliferation. c-fos gene products interacts with c-jun and forms the AP-1 early response transcription factor .

    Several Mutations to Cause Cancer
    ::若干变异致癌

    Typically, a series of several mutations that constitutively activate oncogenes and inactivate tumor suppressor genes is required to transform a normal cell into a cancer cell ( Figure ). Cells have developed a number of control mechanisms to overcome mutations in proto-oncogenes. Therefore, a cell needs multiple mutations to transform into a cancerous cell. A mutation in one proto-oncogene would not cause cancer, as the effects of the mutation would be masked by the normal control of the cell cycle and the actions of tumor suppressor genes. Similarly, a mutation in one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes and enough tumor suppressor genes have been deactivated that the cancerous transformation can begin. Signals for cell growth overwhelm the signals for growth regulation, and the cell quickly spirals out of control. Often, because many of these genes regulate the processes that prevent most damage to the genes themselves, DNA damage accumulates as one ages.
    ::通常情况下,要将正常细胞转化为癌症细胞(Figure ),需要一系列几种构成激活肿瘤蛋白和不活化肿瘤抑制基因的突变,才能将正常细胞转化为癌症细胞(Figure ) 。 细胞已经开发出许多控制机制来克服原生蛋白中的突变。 因此,细胞需要多重突变才能转化成癌症细胞。 一种原生蛋白的突变不会引发癌症, 因为突变的效果会受到细胞循环正常控制以及肿瘤抑制基因的动作的掩盖。 同样, 一种肿瘤抑制基因的突变也不会导致癌症, 因为许多“备份”基因存在重复其功能。 只有当蛋白质变异到肿瘤和足够肿瘤抑制基因时, 才会被控制住。 细胞生长信号会超过细胞生长调节的信号,而细胞会迅速螺旋性地失去控制。 通常是因为许多这些基因的基因会调节过程,防止基因本身的破坏程度。

    Usually, oncogenes are dominant alleles , as they contain gain-of-function mutations . The actions of the mutant gene product, many times resulting in a constitutively activated protein, are dominant to the gene product produced by the "normal" allele. Meanwhile, mutated tumor suppressors are generally recessive alleles , as they contain loss-of-function mutations . A proto-oncogene needs only a mutation in one copy of the gene to generate an oncogene; a tumor suppressor gene needs a mutation in both copies of the gene to render both products defective. There are instances when, however, one mutated allele of a tumor suppressor gene can render the other copy non-functional. These instances result in what is known as a dominant negative effect .
    ::通常情况下,肿瘤抑制器是主要的异象,因为它们含有功能变异。变种基因产品的行为,许多次导致有机活性蛋白,是“正常”异象生产的基因产品的主要结果。同时,突变肿瘤抑制器一般是功能变异的异象,因为它们含有功能变异。原蛋白只需要一个基因复制件的突变来产生肿瘤变异即可产生肿瘤变异;肿瘤抑制器基因需要两种基因的突变才能使两种基因产生缺陷。但是,有时,肿瘤抑制器基因的一个突变的异源可以使另一个基因变异不起作用。这些情况导致一种已知的主要负面效应。

    Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell. In this example, the first mutation inactivates a tumor suppressor gene, the second mutation inactivates a DNA repair gene, the third mutation creates an oncogene, and a fourth mutation inactivates several more tumor suppressor genes, resulting in cancer. It should be noted that it does not necessarily require four or more mutations to lead to cancer.
    ::癌症是由一系列突变引起的。 每一次突变都会改变细胞的行为。 在此例子中, 第一次突变将肿瘤抑制基因活化, 第二次突变将DNA修复基因活化, 第三次突变产生肿瘤, 第四次突变将更多肿瘤抑制基因活化, 导致癌症。 应该指出, 不一定需要4次或4次以上的突变才能导致癌症 。

    Summary
    ::摘要

    • Nearly all cancers are caused by mutations in the DNA of the abnormal cells.
      ::几乎所有癌症都是由异常细胞DNA突变引起的。
    • In non-cancerous cells, proto-oncogenes promote cell growth and mitosis prior to cell division; thus, proto-oncogenes encode proteins needed for normal cellular functions.
      ::在非养分细胞中,原蛋白可促进细胞生长和细胞分裂前的硬化;因此,原蛋白能为正常细胞功能所需的蛋白质编码。
    • In non-cancerous cells, tumor suppressor genes temporarily discourage cell growth and division to allow cells to finish routine functions, especially DNA repair.
      ::在非神经细胞中,肿瘤抑制基因暂时抑制细胞生长和分裂,使细胞能够完成常规功能,特别是DNA修复。
    • Mutations in proto-oncogenes and tumor suppressor genes may lead to cancer.
      ::本蛋白质和肿瘤抑制基因中的突变可能导致癌症。
    • Usually mutations in multiple genes are necessary to develop cancer.
      ::癌症发作通常需要多种基因的突变。

    Review
    ::回顾

    1. Define cancer.
      ::给癌症下定义
    2. Discuss the role of oncogenes and tumor suppressor genes in carcinogenesis.
      ::讨论肿瘤和肿瘤抑制基因在致癌性中的作用。
    3. Why are multiple mutations required for transformation into a cancerous cell?
      ::为什么转换成癌症细胞需要多重突变?
    4. Identify all the categories of oncogenes and describe two categories.
      ::查明所有类肿瘤并描述两类。