癌細胞最終長成癌症的艱辛歷程[V3.0]

 (2019-04-12 10:22:15)下一個

癌細胞最終長成癌症的艱辛歷程[V3.0]

這篇科普小文，更新一點點內容，重發一遍。這種文章只有讀過幾遍，尤其不是專業的人，才會有個比較清楚的全景圖。

有人問道一些問題，看來是沒有理解部分內容真正的含義。如果還有不理解的地方，請繼續接着問。這篇科普的東西和時事政治不一樣，內容一般不會有顛覆性的改變。稍微增加一點點新的的內容，有些地方做了一些調整，希望能夠增加理解。尤其是英文的部分，有不少的有心人，包括一些認真的老美“挑過刺”。有不少的改進，歡迎有心人繼續接着挑刺，砸磚！知道川粉們比較不屑於學習這樣的信息。他們不敢上門 砸磚，可以理解，不能要求太高了，但還是要鼓勵有敢斗膽出來挑刺的，拭目以待。

示意圖。左邊的部分是在網上找的一個示意圖，略加修改。右手邊的嵌圖是做實驗研究的照片。真正的腫瘤細胞在實驗室顯微鏡下的照片。這是一個暗視野的熒光照片。紅色的部分是細胞核染色後發出紅色的熒光，綠色的部分是細胞膜被染色後發出綠色的熒光。下面是全文，中文／英文，各取所需！

》癌細胞最終長成癌症的艱辛歷程（內憂篇）[修改版3.0]
 
這篇小文是屬於大眾化、科普性質的文字，請提問題，無論是專業性的還大眾性的，咱們可以一起討論解決問題。特別歡迎有人挑毛病，甚至砸磚伺候！

談癌細胞，這可是談虎色變。這個傢伙不得了，每年致人死地的殺手裡，可是高居榜首的前列。不過，這次從癌細胞的立場出發，談談癌細胞最終長成癌症實體的艱辛歷程。那可以說內憂外患的麻煩一點也不少啊。條件許可的話，爭取寫成一個系列。這篇算是開篇的[內憂篇]，主要從細胞自身的的遺傳背景[Genentic Makeup]的改變入手來展開這個話題。

身體裡的癌細胞不斷的被產生出來，又不斷的被清除，絕大多數的情況下癌細胞是失敗的一方。但是，道高一尺，魔高一丈。癌細胞這一個個的小魔頭也在思量着、學習着，怎麼能夠躲過被清除的厄運。

從正常的數字說起:

1，正常成人有大約10萬億個體細胞。
2，每一克或一立方厘米的肝組織細胞或腎組織細胞就有2.5-3億個之眾。
3，每一個細胞內的基因組單倍體DNA鹼基數目達高32億之眾。如果用32億個字母來寫書的話，足以寫一千本戰爭與和平的信息量相當的叢書了。這裡就不驚嘆生物體這方面的奧妙了。

下面有必要首先明確些一些基本概念。

癌細胞可以是單個的癌細胞，或者沒有長成勢的為數不多的小群細胞，初生的癌細胞惡性度可以不是非常高；也可以是長在的癌症瘤體裡面的細胞，惡性生長的能力達超一流的水準。

癌症則是癌細胞生長集聚到了一定的數量，身體靠自身機制已經無法控制其惡性生長的一種狀況。這種情況下就是一般所謂的得了癌症。

10萬億個正常成人的體細胞，都是從單一的一個受精卵演變出來的，咱們都不能不驚嘆這細胞的精確性了，複製出了10萬億之眾都不怎麼出錯，所以正常人能夠活的好好的。但是，話又要說回來，這十萬億之眾的細胞，能一點都不出一點問題，這好像也完全辦不到，這就是現在咱們要討論的小概率的事件了。就是億分之一的細胞出了問題，雖然比例不可想象的低，那人體內也有應該差不多有10萬個問題細胞了。

正常的情況下，細胞內有一整套的自保裝置，也可以說成是自毀裝置，或者用把人鎖起來的“鐐銬”形象化的來表達。一些細胞不正常了或者簡單說就是沒有用了，那就得下“地獄”伺候。如果暫時不能或是不願意徹底的毀掉、除掉的話，那就銬起來放到大牢裡，讓它們把牢底坐穿一直到到老死。所以啊這“10萬個” 問題細胞不停的產生，又不停的消亡或被收監，正常人的機體也就暫時也就相安無事。

人體的組織器官的狀況永遠都是處于于一個動態的過程，不停的有細胞死亡，又不停的產生新的細胞替代。正常的情況下，細胞一般不會無緣無故的分裂生長，得要有生長信號的刺激。細胞受生長因子的刺激生長，有點像咱們開車的時候踩油門，一腳油門踩下去，車子開始動起來了。正常情況下，車子開起來了，速度要有控制，還得有剎車的配合，該快的時候快，該慢下來避開障礙、要轉彎的時候，就得踩剎車減速，不能橫衝直闖的。細胞裡面還真的有這種對應的“剎車”裝置，叫生長抑制因子。負責細胞生長的時候，適時的調整速度。使細胞生長得不快不慢，恰到好處。

細胞的所有活動，都是受遺傳的基因控制的。上面提道的問題細胞，如果是其中某些遺傳基因發生了變異，發生了突變。突變後產生過量的或超過正常的生長信號，踩油門的力度加大。生長抑制因子沒有及時的跟進，剎車的裝置跟不上；或者反過來，生長因子沒有變，生長抑制因子沒有了；那汽車就只好一直加速行駛，停不下來了。發生這樣改變的細胞，就已經可以稱之為初生的腫瘤或是癌細胞了。這就是這些細胞獲得可以持續生長的首個遺傳改變，只能不停的長，不能停下來。

這個時候還不需要擔心害怕，因為這些細胞身上的剩下的自毀機制的“魔咒”和“鐐銬”還沒有完全解除。當它們的行為怪異得超過了一定的限度，輕則面臨被“關”[Growth rest]，重則面臨自毀機制倒計時啟動[Apoptosis, 細胞凋亡]。結果是絕大部分的這類問題細胞，或或初生的癌細胞遭被斬被關的命運。

但是，癌細胞們是一個個的各自為政的小魔頭。它們不在乎一城一地的得失，它們和機體慢慢地比時間、比數量。革命的先烈英勇就義了，只要留下有它們的火種或是又有新加入隊伍的，它們就在那裡積極地思量着想辦法，去掙脫加在它們身上剩下的“魔咒”和“鐐銬”。

[Apoptosis, 細胞凋亡]，細胞凋亡是所有正常細胞具備的一種正常的、又是崇高和偉大的機制。這種機制由一整套基因，有序的控制着。當細胞受損，細胞發現自己已經無力完成自己的正常功能，活在世界上對機體已經是多餘的或者是有害的情況下，細胞就會崇高和偉大得開啟這種機制，令自己進入自毀的程序，對自己行自殺處置。而且，在自殺的過程中，還會把自己的殘餘放進‘包裝袋’里，不對環境造成污染。

有些比較狡猾的癌細胞小魔頭，就在打是不是能夠關掉這個偉大的機制壞主意了。管細胞凋亡的是一組有序的基因，恐怕有十幾、幾十、不知道有沒有上百的不同成分。把其中某個關鍵的基因給突變掉，讓這個、這些基因的功能喪失掉。這個癌細胞小魔頭就又勝利了一個新的輪迴，起碼這個癌細胞小魔頭“聰明”了一把，知道自己對機體沒有用的情況下，可以不需要悲慘的去自殺，把自己送進墳墓了。能夠活下來那就可以繼續的分裂繁殖。

接下來還得再對另一“魔咒”，細胞老化[Senescence, or Aging]的正常程序使出殺手鐧。正常的細胞按其正常的機制可以分裂大約50次左右。細胞每分裂一次，為了記住細胞分裂了多少次，上帝的安排要給細胞分裂了多少次記點，每分裂一次就，要把染色體的末端剪掉一小片段。染色體的末端雖然沒有實實在在的基因成分，沒有能參加編碼產生蛋白質的序列，但是其長短卻是決定細胞“年輕”還是“年老”非常重要的指標。細胞分裂的越多，染色體末端就變得越短。當染色體的末端短到最低限度的長度，細胞就無法再分裂了，也就是細胞老化了。這個“魔咒”對癌細胞來說那是太要命了，就算是細胞可以不死，細胞也不能無止境的分裂。

別說啊，咱細胞裡面還什麼都有，藏着掖着一種非常罕用的復位機制，一般只在產生生殖細胞的時候才拿出來用用。這樣咱們人類和動物的下一代，才可以和親代活差不多長的年限。這種機制可以把細胞的末端因為分裂切掉的片段重新加上或復位到上帝規定的、原來的長度。這樣的機制一旦被喚醒，起作用了，那細胞就可以永遠保持年輕了，再怎麼分裂也沒有有老化的問題了。那個失去自殺基因的癌細胞魔頭，弄得整個細胞的基因組亂了套，細胞裡面亂成了一團。這個管末端復位的基因，混亂的時候受某種調變機制的錯誤命令的啟動，也出來活動了。這樣癌細胞魔頭就獲得的超過三次以上重要的遺傳調變，這個時候所謂的癌細胞，也就可以說是一個成熟的[full bloom]癌細胞了。英文稱這種細胞獲得了[replicative immortality]的特性，可以無限分裂，再也不受分裂次數的限制，成了不朽永生的超級細胞了。

接下來還有兩項和營養的供應有關的機制，如果細胞同時或分別獲得的話，癌細胞達到頂級的惡性度。

癌細胞從一小群，長成有一定大小的實體瘤。僅僅靠周圍血管彌散過來的營養和氧氣，已經不足以支撐瘤體中央部位給養的供應和消耗了。就像建一座新城一樣，新城的裡面和外界得要鋪設道路和外界溝通，這樣給養和供應才可以源源不斷的送過來。增強的血管生成因子[angiogenesis]遺傳調變得跟上細胞生長的速度。這樣血管源源不斷的伸入實體瘤，有如敷設了道路通向了實體瘤的每一個角落，這樣實體瘤就不會因為“缺水、缺電、缺食物、缺基本物品”而停止生長了。這個時候的癌細胞魔頭，就在那裡微笑了，它們真的勝利了，搭建起了它們堅實、牢固的殖民地了！

最後一個獲取的機制是途遷功能獲得。本來癌細胞在一個地方生長，已經熟悉的當地的情況。一般的情況下，它們不容易搬遷到另外的不熟悉地方去生活。一旦它們獲得了新的遺傳改變，讓他們容易在新的地方定居下來，能夠在當地要錢要糧，發展壯大。這個過程稱之為，浸潤和轉移贅生，英文稱之為[invasion and metastasis]。癌細胞這個小魔頭要是發展到了這一步，可以說基本上對它們沒有什麼好辦法了。在它們還沒有致人死地的情況下，它們要是不發生良性的遺傳調變的話，絕大多數的情況是機體的死亡為最可能的結局。

當然要是癌細胞成功了，也是曇花一現短時間的成功，把自己賴以生存的環境消滅了，自己最後還是只得能英勇就義。可是，癌細胞們死之前是不會考慮這個問題的，它們很任性要享受完成自己生命過程的樂趣。按下不表了！

癌細胞的內憂篇到此結束。其實癌細胞長成癌症，看來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!