Chapter 5 Chapter 5 Huitai novel: the multi-step development of tumors

The story of tumor origin is deceptively simple.A chemical mutagen invades the cell, attacks a key proto-oncogene, and turns it into an oncogene.Cells respond to the instructions of the oncogene and embark on a journey of unbridled expansion.All descendants of the cell that mutated in the first place have a copy of the oncogene, driven by the oncogene to start a relentless process of growth and fission.Winter turns to spring, year after year, and finally, billions of cells come together to form a deadly tumor.This speculation cheers those who would like to simplify the complex process of tumor evolution.It's a perfect example of how molecular biology research can uncover hidden truths—so simple and logical that scientists can't help but say, "Awesome."

But, to some, this speculation is too simplistic.They call it an "oversimplification," meaning that those who hold this view deliberately ignore much that is known about how cancer develops.To these skeptics, the discovery of point mutations in bladder cancer in 1982 in the laboratories of myself, Marino Bawashid, and Mikael Vigler was a hasty conclusion, not enough. convincing. Skeptics cite overwhelming evidence that cancer is a gradual, complex process that turns a perfectly normal cell into a highly malignant cancer.At the moment, one school of thought describes the development of cancer as a simple process in which normal cells become cancerous in one fell swoop, while the other school of thought sees cancer as the result of a chain of events. For the rest of the 1980s, the two factions were at odds with each other.

Epidemiologists have investigated the incidence of cancer in different groups of people and in different age groups, and the results have become the most convincing evidence for the theory of multi-step formation of cancer. The incidence rate of colon cancer in the 70-year-old group is a thousand times that of the 10-year-old group.Rates of most other adult cancers also rise sharply with age. All of a sudden, the one-act play that plays cancer down and out loses its believability.If cancer is caused by a single event, that event will occur with approximately equal probability over a lifetime.A day in the 10th year of life is as likely to develop cancer as a day in the seventies.Based on this equal-risk mathematical approach, we can clearly predict that, as a variable of age, an individual's risk of developing cancer at some point in his or her life will rise in a straight line. A 20-year-old has a cumulative risk twice that of a 10-year-old, and a 70-year-old has a seven-fold risk.

The straight line above bears no resemblance to the sharply rising curves with age reported by epidemiologists.Early in life, the lines for cancer risk were nearly horizontal.However, as the age of the surveyed population increases, the line of the incidence of tumors rises sharply, showing an unprecedented steep slope. Such a sharply rising curve describes a rather complex process.It shows that a large number of antecedents occur in sequence before the consequences, namely the appearance of a clearly diagnosed tumor.Four to six of these antecedent events appear to be required for the development of most cancers.The probability of a single event occurring is itself so low that it appears to take many years.It is only when all steps in the process have been completed that a medically detectable cancer builds up.

The chances of all these events (let alone what kind of events) happen to a young person in a short period of time are very small.This explains why most cancers do not actually occur in children.But as the body ages, the probability rises rapidly, and all necessary events—a random event—will converge in one cell inside the body.At this point, all the elements to generate cancer are in place. The prolonged course of cancer development helps explain many stark observations about cancer in adults.The most famous example of this is that of lung cancer. The disease was almost unknown in women in the early 20th century, and remained rare in women until the middle of this century.After World War II, a large number of American women began to smoke, many of whom developed the habit while working in factories during the war.A quarter of a century later, these women are dying of lung cancer in large numbers.It takes decades for a lung tumor to develop from start to finish.

What happened to those who worked briefly in naval shipyards during World War II and the decade that followed was even more shocking.The hulls of warships used asbestos as an insulating component, and many of them were exposed to asbestos in large quantities.Most of these people are painful gentlemen who swallow clouds and smoke. 20, 30, 40 years later, they start dying from a rare cancer called mesothelioma that attacks the outer lining of both lungs.This type of cancer is almost invariably directly related to asbestos exposure.As with lung cancer and smoking-associated cases, decades elapsed between the initial exposure and the appearance of the life-threatening tumor in this case.

These observations by epidemiologists lend credence to the 'multistep delay theory' of cancer development. The idea is appealing because it implies that the normal human body puts many obstacles in place to prevent the development of cancer. Only when these roadblocks When they are surpassed one by one, the tumor will show its hideous face. However, the discovery in 1982 demonstrated that a single major event such as a point mutation in the ras oncogene can create a highly cancerous cell that expands directly to form a fully developed tumor.It is difficult to reconcile with the multi-step theory of cancer formation.Those who agree with the epidemiology of cancer dismiss it on the grounds of naivety and simple-mindedness that "oncogenes say it all at once".

As a result, two major theories of cancer formation emerged that were in sharp contradiction to each other.The theory advocated by cancer epidemiology is far from the molecular research inside cells and tissues, and believers who say that cancer gene mutation can be done overnight can take some comfort from this.Do normal cells really need to go through multiple steps to become cancerous?Or is epidemiology just another dry mathematical abstraction that has nothing to do with the real biology of human cells?cell game Scholars who study genes and cells are interested in epidemiology, but consider it insufficient.Didn't they succeed in turning normal cells into cancer cells simply by injecting oncogenes?Through a chemical mutagen, an oncogene pops up.Therefore, a single step is undoubtedly enough to create a malignant cancer cell.

However, Meiyu has time.Some experimenters have looked back and reexamined the experiment—that is, by gene transplantation, the injection of oncogenes turned normal cells into cancerous ones in one simple event.It turned out that there was one detail that most researchers seemed to overlook in these experiments.The detail concerns the cells—in this case, mouse connective tissue cells—that were used to receive the genes in the gene-transplant experiments designed to find cancer genes in human DNA.These mouse cells can undoubtedly transform into tumor cells in one step, but at the moment when the gene transplantation experiment started, were these cells really normal?Or have they already begun part of their cancerous journey?

In fact, there is something unique about this question.The mouse cells used in the gene-transplant experiments were somewhat unusual.The cells had been harvested from mouse embryos many years earlier and conditioned to grow in lab dishes.This tweak allows them to reproduce infinitely.When the mouse cells filled the bottom of the dish, the researchers moved some cells to another empty dish to restart the growth cycle, a process that could be repeated indefinitely, over and over again.The cells, which were used to pick out oncogenes in tumor DNA, had been passed from one dish to another for more than 10 years before the human bladder cancer gene was injected into the cells.

Cell biologists call those cells that can reproduce indefinitely in the laboratory "immortal."This statement means that cell immortality is not abnormal.Most perfectly normal cells, taken from mouse embryos and placed in a dish, have a limited number of rounds of fission, after which they stop growing.Populations of mouse cells in a dish usually stop multiplying after 30 or 40 generations, and such populations are therefore "mortal." Very occasionally, a mortal population of cells will give rise to a subpopulation of mutant cells capable of unlimited growth.These cells become immortal.Oddly enough, cancer cells of all kinds also seem to be immortal.When cancer cells are extracted from a tumor and placed in a petri dish, the cancer cells can divide indefinitely.This observation suggests that cell immortality is a routine phenomenon in tumor development, and perhaps an essential part of the process. That set off alarm bells among scientists reexamining gene-transplant experiments.Their conclusion: Initial experiments designed to measure the oncogene's ability to induce cancer were flawed from the start because they were performed with immortalized mouse cells.These mouse cells had already undergone overt precancerous changes long before receiving the oncogene.Maybe they were already on the brink of a precipice, and the injection of the oncogene just pushed them into the abyss of cancer, beyond redemption. In 1983, this view was severely tested.The cancer gene was injected into really normal cells—rat cells that had been growing in rat embryos a few days earlier.These cells have no chance of developing abnormally for prolonged periods of time in the culture dish.They are as close to normal as possible, and of course, they are mortal. Suspicions were confirmed.Injection of oncogenes alone, even the potent ras bladder oncogene, cannot turn perfectly normal cells into cancerous ones.In other words, unlike immortal cells, mortal cells respond indifferently to the injection of oncogenes.Before they can be pushed off a cliff by oncogenes, they need certain special circumstances.They'd have to be gunpowdered, perhaps immortalized, before they became cancerous.Only then can they respond to oncogenes and become cancerous. This conclusion means that at least two different changes are required to transform a completely normal cell into a true cancer cell: a normal cell becomes an immortal cell and an immortal cell becomes a cancer cell.Cancer is thus a serial process in which cells undergo at least two, and perhaps more, transitions. Only since then has it been discovered that the first of these steps—immortality—can be mimicked, or at least facilitated, by certain other oncogenes such as my or EIA.This correlation led to another idea: Perhaps injecting two different oncogenes into a normal cell could make all the changes that turn it into a cancer cell.The two may each have their own strengths in two of the changes needed to make cancer cells. So researchers in Earl Ruley's and my own labs set out to simultaneously inject pairs of oncogenes into rat embryonic cells.Only then did they observe cancerous changes in rat embryonic cells.When two DNA clones carrying the mp c oncogene and the ras oncogene were simultaneously injected into perfectly normal rat embryonic cells, the cells responded by becoming cancerous!Neither of these two oncogenes alone produced this result. Thinking about the origin of cancer cells can now be attributed to the characteristics of certain oncogenes.The c and ras oncogenes are independent of each other, but they can work together to create cancer.This combination means that each oncogene is unique in how it alters cells. The theory of multistep origin of cancer is now becoming conclusive.Perhaps each step in the making of a cancer cell is a rare mutation affecting this or that proto-oncogene in the cell's genome.Only when two or more of these mutations accumulate does cell growth go completely out of control. Soon, the cooperation mode of Zhouyc and Gui was also found in other oncogene pairs.The overall impression given by these results is that two mutations are sufficient to produce most types of cancer cells.But that number is still a misunderstanding, a simplistic fantasy.Based on scientific research in the 1980s, human tumor cells are known to carry far more than two, and perhaps as many as six, mutated genes.Careful molecular analysis of tumor cell genomes yielded a figure that seemed closer to the number of steps epidemiologists have deduced from the steeper curve of cancer incidence in older age groups. The theory of cancer formation can now be rephrased as the rare sequence of events that lead to human tumors, consisting of a series of mutations that progressively alter a cell's genetic profile, pushing it step by step towards uncontrolled growth.