癌细胞最终长成癌症的艰辛历程[V3.0]

 (2019-04-12 10:22:15)下一个

癌细胞最终长成癌症的艰辛历程[V3.0]

这篇科普小文，更新一点点内容，重发一遍。这种文章只有读过几遍，尤其不是专业的人，才会有个比较清楚的全景图。

有人问道一些问题，看来是没有理解部分内容真正的含义。如果还有不理解的地方，请继续接着问。这篇科普的东西和时事政治不一样，内容一般不会有颠覆性的改变。稍微增加一点点新的的内容，有些地方做了一些调整，希望能够增加理解。尤其是英文的部分，有不少的有心人，包括一些认真的老美“挑过刺”。有不少的改进，欢迎有心人继续接着挑刺，砸砖！知道川粉们比较不屑于学习这样的信息。他们不敢上门 砸砖，可以理解，不能要求太高了，但还是要鼓励有敢斗胆出来挑刺的，拭目以待。

示意图。左边的部分是在网上找的一个示意图，略加修改。右手边的嵌图是做实验研究的照片。真正的肿瘤细胞在实验室显微镜下的照片。这是一个暗视野的荧光照片。红色的部分是细胞核染色后发出红色的荧光，绿色的部分是细胞膜被染色后发出绿色的荧光。下面是全文，中文／英文，各取所需！

》癌细胞最终长成癌症的艰辛历程（内忧篇）[修改版3.0]
 
这篇小文是属于大众化、科普性质的文字，请提问题，无论是专业性的还大众性的，咱们可以一起讨论解决问题。特别欢迎有人挑毛病，甚至砸砖伺候！

谈癌细胞，这可是谈虎色变。这个家伙不得了，每年致人死地的杀手里，可是高居榜首的前列。不过，这次从癌细胞的立场出发，谈谈癌细胞最终长成癌症实体的艰辛历程。那可以说内忧外患的麻烦一点也不少啊。条件许可的话，争取写成一个系列。这篇算是开篇的[内忧篇]，主要从细胞自身的的遗传背景[Genentic Makeup]的改变入手来展开这个话题。

身体里的癌细胞不断的被产生出来，又不断的被清除，绝大多数的情况下癌细胞是失败的一方。但是，道高一尺，魔高一丈。癌细胞这一个个的小魔头也在思量着、学习着，怎么能够躲过被清除的厄运。

从正常的数字说起:

1，正常成人有大约10万亿个体细胞。
2，每一克或一立方厘米的肝组织细胞或肾组织细胞就有2.5-3亿个之众。
3，每一个细胞内的基因组单倍体DNA碱基数目达高32亿之众。如果用32亿个字母来写书的话，足以写一千本战争与和平的信息量相当的丛书了。这里就不惊叹生物体这方面的奥妙了。

下面有必要首先明确些一些基本概念。

癌细胞可以是单个的癌细胞，或者没有长成势的为数不多的小群细胞，初生的癌细胞恶性度可以不是非常高；也可以是长在的癌症瘤体里面的细胞，恶性生长的能力达超一流的水准。

癌症则是癌细胞生长集聚到了一定的数量，身体靠自身机制已经无法控制其恶性生长的一种状况。这种情况下就是一般所谓的得了癌症。

10万亿个正常成人的体细胞，都是从单一的一个受精卵演变出来的，咱们都不能不惊叹这细胞的精确性了，复制出了10万亿之众都不怎么出错，所以正常人能够活的好好的。但是，话又要说回来，这十万亿之众的细胞，能一点都不出一点问题，这好像也完全办不到，这就是现在咱们要讨论的小概率的事件了。就是亿分之一的细胞出了问题，虽然比例不可想象的低，那人体内也有应该差不多有10万个问题细胞了。

正常的情况下，细胞内有一整套的自保装置，也可以说成是自毁装置，或者用把人锁起来的“镣铐”形象化的来表达。一些细胞不正常了或者简单说就是没有用了，那就得下“地狱”伺候。如果暂时不能或是不愿意彻底的毁掉、除掉的话，那就铐起来放到大牢里，让它们把牢底坐穿一直到到老死。所以啊这“10万个” 问题细胞不停的产生，又不停的消亡或被收监，正常人的机体也就暂时也就相安无事。

人体的组织器官的状况永远都是处于于一个动态的过程，不停的有细胞死亡，又不停的产生新的细胞替代。正常的情况下，细胞一般不会无缘无故的分裂生长，得要有生长信号的刺激。细胞受生长因子的刺激生长，有点像咱们开车的时候踩油门，一脚油门踩下去，车子开始动起来了。正常情况下，车子开起来了，速度要有控制，还得有刹车的配合，该快的时候快，该慢下来避开障碍、要转弯的时候，就得踩刹车减速，不能横冲直闯的。细胞里面还真的有这种对应的“刹车”装置，叫生长抑制因子。负责细胞生长的时候，适时的调整速度。使细胞生长得不快不慢，恰到好处。

细胞的所有活动，都是受遗传的基因控制的。上面提道的问题细胞，如果是其中某些遗传基因发生了变异，发生了突变。突变后产生过量的或超过正常的生长信号，踩油门的力度加大。生长抑制因子没有及时的跟进，刹车的装置跟不上；或者反过来，生长因子没有变，生长抑制因子没有了；那汽车就只好一直加速行驶，停不下来了。发生这样改变的细胞，就已经可以称之为初生的肿瘤或是癌细胞了。这就是这些细胞获得可以持续生长的首个遗传改变，只能不停的长，不能停下来。

这个时候还不需要担心害怕，因为这些细胞身上的剩下的自毁机制的“魔咒”和“镣铐”还没有完全解除。当它们的行为怪异得超过了一定的限度，轻则面临被“关”[Growth rest]，重则面临自毁机制倒计时启动[Apoptosis, 细胞凋亡]。结果是绝大部分的这类问题细胞，或或初生的癌细胞遭被斩被关的命运。

但是，癌细胞们是一个个的各自为政的小魔头。它们不在乎一城一地的得失，它们和机体慢慢地比时间、比数量。革命的先烈英勇就义了，只要留下有它们的火种或是又有新加入队伍的，它们就在那里积极地思量着想办法，去挣脱加在它们身上剩下的“魔咒”和“镣铐”。

[Apoptosis, 细胞凋亡]，细胞凋亡是所有正常细胞具备的一种正常的、又是崇高和伟大的机制。这种机制由一整套基因，有序的控制着。当细胞受损，细胞发现自己已经无力完成自己的正常功能，活在世界上对机体已经是多余的或者是有害的情况下，细胞就会崇高和伟大得开启这种机制，令自己进入自毁的程序，对自己行自杀处置。而且，在自杀的过程中，还会把自己的残余放进‘包装袋’里，不对环境造成污染。

有些比较狡猾的癌细胞小魔头，就在打是不是能够关掉这个伟大的机制坏主意了。管细胞凋亡的是一组有序的基因，恐怕有十几、几十、不知道有没有上百的不同成分。把其中某个关键的基因给突变掉，让这个、这些基因的功能丧失掉。这个癌细胞小魔头就又胜利了一个新的轮回，起码这个癌细胞小魔头“聪明”了一把，知道自己对机体没有用的情况下，可以不需要悲惨的去自杀，把自己送进坟墓了。能够活下来那就可以继续的分裂繁殖。

接下来还得再对另一“魔咒”，细胞老化[Senescence, or Aging]的正常程序使出杀手锏。正常的细胞按其正常的机制可以分裂大约50次左右。细胞每分裂一次，为了记住细胞分裂了多少次，上帝的安排要给细胞分裂了多少次记点，每分裂一次就，要把染色体的末端剪掉一小片段。染色体的末端虽然没有实实在在的基因成分，没有能参加编码产生蛋白质的序列，但是其长短却是决定细胞“年轻”还是“年老”非常重要的指标。细胞分裂的越多，染色体末端就变得越短。当染色体的末端短到最低限度的长度，细胞就无法再分裂了，也就是细胞老化了。这个“魔咒”对癌细胞来说那是太要命了，就算是细胞可以不死，细胞也不能无止境的分裂。

别说啊，咱细胞里面还什么都有，藏着掖着一种非常罕用的复位机制，一般只在产生生殖细胞的时候才拿出来用用。这样咱们人类和动物的下一代，才可以和亲代活差不多长的年限。这种机制可以把细胞的末端因为分裂切掉的片段重新加上或复位到上帝规定的、原来的长度。这样的机制一旦被唤醒，起作用了，那细胞就可以永远保持年轻了，再怎么分裂也没有有老化的问题了。那个失去自杀基因的癌细胞魔头，弄得整个细胞的基因组乱了套，细胞里面乱成了一团。这个管末端复位的基因，混乱的时候受某种调变机制的错误命令的启动，也出来活动了。这样癌细胞魔头就获得的超过三次以上重要的遗传调变，这个时候所谓的癌细胞，也就可以说是一个成熟的[full bloom]癌细胞了。英文称这种细胞获得了[replicative immortality]的特性，可以无限分裂，再也不受分裂次数的限制，成了不朽永生的超级细胞了。

接下来还有两项和营养的供应有关的机制，如果细胞同时或分别获得的话，癌细胞达到顶级的恶性度。

癌细胞从一小群，长成有一定大小的实体瘤。仅仅靠周围血管弥散过来的营养和氧气，已经不足以支撑瘤体中央部位给养的供应和消耗了。就像建一座新城一样，新城的里面和外界得要铺设道路和外界沟通，这样给养和供应才可以源源不断的送过来。增强的血管生成因子[angiogenesis]遗传调变得跟上细胞生长的速度。这样血管源源不断的伸入实体瘤，有如敷设了道路通向了实体瘤的每一个角落，这样实体瘤就不会因为“缺水、缺电、缺食物、缺基本物品”而停止生长了。这个时候的癌细胞魔头，就在那里微笑了，它们真的胜利了，搭建起了它们坚实、牢固的殖民地了！

最后一个获取的机制是途迁功能获得。本来癌细胞在一个地方生长，已经熟悉的当地的情况。一般的情况下，它们不容易搬迁到另外的不熟悉地方去生活。一旦它们获得了新的遗传改变，让他们容易在新的地方定居下来，能够在当地要钱要粮，发展壮大。这个过程称之为，浸润和转移赘生，英文称之为[invasion and metastasis]。癌细胞这个小魔头要是发展到了这一步，可以说基本上对它们没有什么好办法了。在它们还没有致人死地的情况下，它们要是不发生良性的遗传调变的话，绝大多数的情况是机体的死亡为最可能的结局。

当然要是癌细胞成功了，也是昙花一现短时间的成功，把自己赖以生存的环境消灭了，自己最后还是只得能英勇就义。可是，癌细胞们死之前是不会考虑这个问题的，它们很任性要享受完成自己生命过程的乐趣。按下不表了！

癌细胞的内忧篇到此结束。其实癌细胞长成癌症，看来也不是一件容易的事啊。

英文：Rough Journey of Cancer Cells Ultimately Growing into a Cancer Mass 

Part I: Internal Hurdles

[This article is a layman’s version of the story for an important scientific issue. If the use of analogy somehow contradicts with the latest theory, please give me your comments, we can discuss it in detail. Revised on 7-23-18.]

When we mention a cancer cell, it is indeed a terrible thing. This ‘guy’ is a real culprit, that contributes to one of the annual lethal killers and tops the list of the few among them. This time, however, I am taking the cancer cell’s stand, to present the rough journey, in a view of an easy-to-understand language, as how the cancer cell ultimately grows into a cancer mass.  In the journey, the domestic or internal challenges inside the cell and the foreign threats outside of the cell come into play one after another to halter the processes.  Here I would strive for the topic written in a series. This is the first article [Part I: Internal Hurdles], mainly from the cell's own genetic background or makeup, to begin with my series of the topic.

As we know, a bunch of the cancer cells are produced, and then cleared at approximately the same time, so that a cohort of army, or majority of the so-called incipient cancer cells are in play with the consequence of failure.  However, being in parallel with the threats, cancer cells with somewhat of a devilish mindset, are also learning how to avoid being cleared of doom.

Let’s start from the normal data from our human body. We, the human body, have approximately 10 trillion adult cells.  There are roughly 250-300 million cells per gram or cubic centimeter of either liver tissue or renal one. Every cell accommodates haploid genomic DNA bases (A, T, C, G) to as many as 3.2 billion more. It is said that with the number of 3.2 billion letters, which would be more than enough to draft equivalent to 1000 of different copies of the book of [the War and Peace]. Here we will not marvel at the mystery of the organism in that respect. 

To begin with our story, it is necessary to clarify some of the basic concepts. 

Cancer cell(s) could be a single cancer cell in existence, or just a few in numbers, in which its/their malignant potency is/are not very high.  They could also be the cells inside the cancer mass, in which the degree of malignance reaches to the maximum level. 

Cancer is a condition in which cancer cells grow to a certain degree. The body’s own defense mechanism can no longer control and confine its malignant growth, which then is called cancer. 

Ten trillion normal adult somatic cells are from a single fertilized egg. It is amazing how accurate the copies of 10 trillion cells in a human body without apparent mistakes are made, so that we,  normal human beings, could lead a basic healthy life. On the other hand, however, it is also impossible for all the 10 trillion cells to be without any problem at all.  Although there is very low probability for the cells to become abnormal, here we would discuss it in this respect to proceed to our topic. Let us assume that we have an abnormal rate of 1 in 100 million cells.  Although the abnormal rate is unimaginably low, there should be approximately 100 thousand number of the problematic cells available.

Under normal circumstances, there are a set of internal risk-proof devices in the cells.  They can also be called the self-destructive devices, ‘curses’, mechanisms, or an analogy to that of the ‘lock-up’ or ‘shackles’ in figurative expression, to either destroy or confine the problematic cells. Some cells deviate from normal path of growth, or simply they are not going to be in use, they are doomed towards the journey to hell.  And some of them will be quarantined until they wear away to die if they are not applicable to be completely destroyed right away.  So these few amount of abnormal cells are continuously produced, killed or ‘imprisoned’ for their reasonable destiny, and thus, our normal body could function as a whole temporarily in good standing.

Our body tissues and organs are constantly in a dynamic process.  Some cells will die and others more regenerate. Under normal conditions, cells generally do not grow and divide until the growth signal is applied.  That means that the growth factor engages on the cell to make the cell to grow.  An analogy to understand this is the way you drive your car.  When one foots the gas pedal, the car starts to move. Normally, it would be important to coordinate brake and gas pedal for the speed control, in order to go fast and slow to avoid obstacles, and, alternatively, when in need of a turn. It is true that inside the cell there is also an equivalent of a brake device.  It is called a growth inhibitory factor, which is responsible for timely cell adjustment of speed to make the cell to grow, neither fast nor slow, but just in perfect control.

As it is known, all the activities of cells are controlled by the genes. If some cells genetically acquire some altered changes or even mutation related to excessive growth signaling above the normal level, then the equivalent of the ‘throttle is intensified’. In addition, while the growth inhibitory factors are not timely matched up, as that of brake device is thus not effective.  Or alternatively, the growth factor signaling is not escalating, and brake device is malfunctioning, therefore the car goes all the way to accelerate. The cell acquired this kind of capability(ies) or trait(s) is called the primary tumor or incipient cancer cell. 

These are the first 2 genetic changes in the cell for its abnormality, although it is not necessary  to happen in parallel simultaneously. Here to put it in highlighted bold form as a take-home message – GROWTH SIGHNALING increase/ GROWTH SUPPRESSOR decrease.

At this point, no real threat could be clued, because these cells have not yet liberated from all the other applied ‘curses’ and ‘shackles’. If their strange behaviors reach a certain unbearable level, they are doomed to be either escorted to the growth arrest, or to be served for the countdown start of the self-destructive mechanism for clearance. 

But ah, cancer cells are the ones of little devils.  They do not care about the coordination with the body tissue assigned activities. They are trying with every effort to gain in their ground in competing the body with time and numbers. The ‘die-hard revolutionary martyrs’, cancer cells die in a heroic course, but as long as they leave their fire seed available or some newly recruits join their course. They continue to make their great effort to work out a way or ways to take off the rest of the ‘curses’ and/or ‘shackles’ towards a liberation.

APOPTOSIS is a mechanism that all normal cells possess, which is a noble and great trait for an individual cell.  This mechanism involves in a set of genes, which are orderly controlled for the process. While the cells are damaged or somehow something like that to critical extent, they find themselves either unable to fulfill their normal functions, either superfluous or harmful to their environment. For the sake of the body as a whole, the cells will bring this mechanism into practice and transform themselves into a so-called self-destructive program on their own for disposal. In this process, they will even be noble enough to set aside their left-over machineries to put their residuals in a ‘disposal bag’ so that no pollution to the environment will be dispersed.

The machinery of cell apoptosis is controlled by a set of genes, probably a dozen, dozens, or maybe even hundreds of different components, which come into a coordinated play to meet the purpose. One or two of the critical genes in a series become mutated or somehow lose functionality, then the whole of the mechanism will be knocked out. In doing so, these devilish cancer cells thus win a big ‘unshackling’ victory, at least they themselves are smarter than others, even if they know they are useless to the body, they could now choose not to face themselves to the miserable fate into the grave for Dutch act, or suicide, so that they could survive and continue to grow to practice their own individual living journey.

Next effort would, in turn, be made in dealing with another ‘curse’, the aging of the cells, SENESCENCE.  Derailment of this program is in demand for the cancer cells to proceed freely to their course. 

Normally the body cells can split about 50 times. In order to tally how many times each cell divides, in each division cycle the cell itself will cut a small piece of fragment of chromosome ends.  Although the gene or protein coding region rarely sit at end of the chromosome, but its length is of vital importance to the cell to be in either younger or elder status. The more cell division the cell makes, the shorter terminal chromosome ends will become. When the terminal chromosome end is chopped to some critical length, cells are no longer dividable, and thus the aging or senescence of the cell applied. It is a trait to prevent a cell from an unlimited split.

Here is a problem. If this mechanism of cell aging or senescence is universally applied to all body cells without exception, our offspring cells will be served fewer cell division cycles as compared with that of the parent, and then all the species will ultimately be extinct from existence after a few generations. 

Thank God, for us, the body is equipped with a reset machinery for use only in the germinal cell or maybe stem cell.  It is amazing that this mechanism will reset our germinal cell to a time start at point 0 line.   So, for our human beings and animals, the offspring can live a similar life expectancy as the parents do. This mechanism is used very rarely, normally only in germinal cell, to rebuild or refill the chromosome end to the God assigned length or original ones, so that to make the germinal cell with a new start from the very beginning.  

But somehow, with the loss of gene functions in some cancer cells, they coordinate their whole genome activities in harmony into some degree of a little confusing so that a time of chaos is felt by them.  By some kind of weird command, they recall this rare mechanism to render the cancer cell to this reset mechanism into play again.  And now, this cancer cells become the super ones, which have already accumulated more than 3 important genetic changes mentioned above.  At this point the so-called cancer cells can be said to be mature, full bloom cancer cells. Technically it is said that these cells acquire the characteristic of REPLICATIVE IMMORTALITY, they are no longer limited by the number of cell division and could theoretically replicate forever. 

The last two traits, or mechanisms, that the cancer cells are in need of expedited acquisition, are the ones that are nutritional supply related, i.e. ANGIOGENESIS and INVASION and METASTASIS.  When the cells simultaneously or alternatively obtain these two traits, cancer cells will reach the level of top malignancy. 

Cancer cells start to grow from a very small amount into an explicit size of solid tumor, maybe not more than 2 mm in size. It will be shown that some degree of shortage of local supplies is applied just only by the diffusion of nutrients and oxygen from peripheral or adjacent blood vessels to support the consumption of the need in central part of the tumor mass.  Like the construction of a new metropolis, both inside and outside of the city, a new road network for the logistical communication has to be constructed. Angiogenesis factor up -regulated following some genetic changes promotes blood vessels to sprout into the tumor mass, and to leave the mass with no corner or shaded area for necessary logistical exchanges. It likes that the road-building-up to access to any part of the ‘building’ or here solid tumors, is applied, so that every single cell in the solid tumor has no worry about shortage of ‘water, electricity, food, and essential materials’, otherwise the cell would stop growing when there would be a shortage of nutritional supply. Cancer cells at this stage would witness another big victory to have their durable colony!

In order for more colonies, the final trait the cancer cell is in need to acquire is migration and invasion, the technical term as metastasis. Initially, cancer cells are in a local growth and they get familiar with the local situation and adopt to it. Generally, it is not easy for them to migrate to another unfamiliar place to settle down. Once they get a new set of genetic alterations, which, in turn, make them easy to settle down into the new land.  As soon as they settle down in the new land they are going to grab more revenues and resources for their malignant growth, like the ISIS in the real world. 

Cancer cells at this stage like a successful devilish war lord now. They are now witnessing their final win with a big smile!  If cancer cells develop to this stage, the human body has to admit that it basically has no good way to deal with this devilish war lord anymore. Unless some lethal genetic alteration occurs in all those cancer cells, death of the human body would be most likely the final outcome.

Of course, if the cancer cells were successful, they would just enjoy their successful endeavor for a short period of time.  While they destroyed their environment, they finally had to be some heroic martyrdoms too for what they have done. However, before the cancer cells proceed to their final destiny, they are not even going to consider this doomed fate.  They are wayward to enjoy completing their individual life process of fun.   

To this end, we will see how the cancer cell grows into a cancer mass.  It is, as a matter of the fact indeed, not an easy thing!  We take a break to our story here.  

To be continued!