Chapter 16 Chapter 16: Using Knowledge About the Origins of Cancer to Develop New Therapies

The scientific revolution that started 20 years ago continues today.We already know a lot about the invisible forces that can cause cancer.Now that we understand the causes of many types of cancer, we should be able to prevent disease from occurring, and if cancer does occur, we should be able to tackle and cure cancer.We have deployed the weapons of genetics and molecular biology to combat this most complex of human diseases.Although there are still many mysteries in the mystery of cancer, a complete answer has highlighted its outline.The research method of modern molecular biology has been confirmed once again: breaking complex problems into parts, making them into simple and understandable parts, and then deriving clear and indestructible truths.In just 20 years, the issue of the origin of cancer is no longer controversial and inconclusive. Today, researchers can not only make detailed descriptions of the mysterious power behind human cancer, but also have been widely accepted by the public.

The main conclusion of this revolution is that cancer is a disease caused by damaged genes.We now understand the properties of many of the genes involved—oncogenes and tumor suppressors.They work in cells, manipulating their behavior; cells respond by forming tumors.Undoubtedly, there are still many genes related to cancer that still need to be identified and isolated with the help of gene cloning technology.The pathways by which many genes influence cellular behavior remain to be uncovered. We know that factors that induce cancer contribute directly or indirectly to gene mutations.We know that human tumor formation requires a series of mutations, each of which disrupts a different gene that controls cell growth.We also know that processes that compromise the integrity of a cell's genome, including maintenance and repair of defects, powerfully influence cancer incidence.

The discovery of distinct growth-controlling genes has prompted us to explore the complex decision-making systems inside every human cell. For more than 100 years, biologists have documented the behavior of cells of all shapes and sizes.The behavior of cells seems to have its own logic, manipulated by the submicroscopic life force hidden deep in the cell.We now understand the logic of the cell in terms of the key signal-processing proteins that determine how the cell responds to a host of stimuli; All have new understandings.Its planning—its interconnections and activities of its constituent parts—determines the cell's every move.

For those working to understand cancer, an understanding of signal processing systems will provide the ultimate answer.There is no deeper, more subtle mechanism than this in the hidden corners of any cell.The answers are all here, or will be here soon.And 20 years ago, we didn't know anything about it. Research in this area has led us to the heart and master of human cells - the cell cycle clock.As the master of cell fate, it makes the decision to grow or differentiate.Although the search for the cell cycle clock is in its infancy, it is known that the cell cycle clock is compromised in most if not all types of human tumors.Here, too, we have drawn a clear outline, but there are many key details that need to be fleshed out.

Whereas familial cancer syndromes are predestined at the moment of conception, sporadic cancers are the result of genetic accidents that occur randomly throughout an individual's lifetime.Many of the genes we've discovered in the past 10 years have allowed us to bridge the gap between these two types of cancer.These two types of cancer are not as distinct as ordinary people imagine, but are the expression of a group of common gene damage. The only difference is the time of damage before and after the egg is fertilized.nip in the bud What apparent impact will the wealth of information presented in this book have on cancer mortality?The reason is very simple, to cure a certain disease, the most common way is to find out the cause.Thus, our recent knowledge about genes and proteins will lead us to conquer cancer.However, the most fundamental cause of cancer is not actually buried deep inside individual cells, but far away in the environment, in the food we ingest, in the cigarettes we inhale.Before significantly reducing cancer rates, we must emphasize that these are the culprits of cancer.Genes and proteins are nothing but minions for tigers and nothing more.

The prevention and control of other major human diseases in the past 200 years has set a stark example for us: reducing mortality depends on personal hygiene, improved nutrition, access to clean water, and epidemic prevention campaigns.Extended, the substantial reduction in cancer mortality also depends on prevention, rather than blindly finding new treatments. Reducing cancer mortality depends largely on identifying and eliminating the different causes of cancer—particularly certain aspects of diet and lifestyle.Many of these fall within the purview of epidemiologists.And we do benefit a lot from epidemiologists.They frame the problem and define its scope, breadth and depth.They also remind us of two ideas that have prevailed in some small circles: that the cancer epidemic is rampant in the industrialized West, and that the vast majority of cases can be traced to chemical pollution in the air and food.

With the exception of breast cancer and tobacco-related cancers, the incidence of most cancers has remained flat over the past half century despite a marked increase in environmental pollution.At best, only one percent of cancers can be attributed to man-made environmental factors. In 1930, the annual cancer death rate in the United States was 143 per 100,000 people.By 1990, the rate had risen to 190 per 100,000 people.The above figures take into account changes in the age distribution of the population, as well as our repeated fact that cancer incidence is strongly age-dependent. Almost all of this age-adjusted increase in cancer mortality is directly attributable to tobacco consumption.By the 1990s, the century-long increase in male lung cancer mortality was in reverse.Excluding the lung cancer component, the age-adjusted cancer death rate overall fell by 14% between 1950 and 1990.

There was a small increase in breast cancer death rates -- rising between 1960 and 1990.up about 10%.The increase in the incidence of the disease has been much more dramatic, but most cases of breast cancer are curable, mainly through surgery.There are many theories about the cause of breast cancer, but one view quickly gained ample evidence.It largely blames modern nutrition and reproductive habits for the rise in breast cancer rates, which combine to lead to an increasing number of menstrual cycles women experience over a lifetime.Another confounding factor is the protective effect of early childbearing, which seems to make breast tissue resistant to cancer that may develop later.Late childbearing will lead to an increase in the incidence of breast cancer.

About half of cancers are closely related to diet, but the carcinogenic components in most food chains are difficult to determine.The incidence of colon cancer in Western countries is 10 to 20 times higher than that in some places in central Africa.One possible reason is that Westerners have a high proportion of meat and fat in their diet.Cooking methods also have a significant impact on cancer rates; when meat, especially red meat, is heated to high temperatures, it produces potent carcinogens.Asia also suffers from high rates of diet-related cancers.The eating habits of the Japanese cause the incidence rate of stomach cancer to be 6 times higher than that of the Americans.Sun-cured, fermented, and smoked foods are also likely to be the cause of cancer.

Plant-based foods are a double-edged sword because they contain both carcinogenic and anticancer ingredients.Vitamins provided by vegetables, such as vitamins A, C, and E, can neutralize some important carcinogens, such as oxidants and free radicals produced by normal cell metabolism.On the other hand, there are some plant components that are positively associated with cancer development.Plants have developed sophisticated chemical defenses against the harassment of insect predators.Among them are the potent mutagenic ingredients documented in the Ames test.Ames also gave the example of a new line of celery that required fewer synthetic insecticides to grow than other lines; The routine rose about 10 times.

Like all other plants, celery contains dozens of carcinogenic and anticancer ingredients.But celery is just one of dozens of plants that regularly appear on the dinner table, each providing its own simple or complex organic component to our diet.There is an intricate correlation between the mixture of these natural ingredients and their effects on human metabolism.It will take decades of research to determine which common, whole foods will keep us healthy and live our lives, and which will kill us. Despite the mountain and water, but there are still some conclusions have emerged.As mentioned earlier, almost half of modern cancers can be prevented by avoiding smoking and diets high in fat and meat.But what about the other half?Undoubtedly, future generations will still be haunted by cancer, even those with the most blameless lifestyles.How do we deal with these seemingly indefensible tumors?Using genes and proteins to fight cancer Even if we identify all external carcinogenic factors, human beings will never be able to fully follow the recommendations of epidemiologists.And, more importantly, the extreme complexity of the human body suggests the inevitability of cancer.All complex machinery will break down sooner or later.Given enough time, no one can escape the clutches of cancer.At this moment, only newly discovered genes and proteins can turn the tide and save people in distress.They allow humans to deal with the ever-present cancer. Early detection of cancer is becoming more and more important.Early detection and removal of tumor masses can cure cancer.But early detection faces two major difficulties.First, we have to find the cancer cell population when it is still very small.As mentioned earlier, a tumor with a diameter of 1 cm is less than 0.01% of the human body.At present, there are almost few biochemical methods that can detect such tiny material structures with such sensitivity. Second, cancer cells, especially those in the early stages of tumor development, resemble normal cells in almost all respects.Finding out how cancer cells are different can be a dauntingly onerous task.Almost every protein that was once called "tumor-specific" was later found in some normal tissue in the human body. Despite the difficulties, one of the most attractive avenues for discovering tumors is identifying genes and proteins that are unique to cancer cells.Mutated oncogenes, tumor suppressor genes and their protein products have come into view.Mutated ras oncogenes are present in about a quarter of human tumors.It has a DNA sequence that normal cells don't have, and it gives the ras protein product a unique, unnatural structure. With this in mind, some researchers are trying to find cells in the colon that carry the mutated ras oncogene.The job is greatly simplified because tumor cells, like normal cells, are constantly shed in large numbers into the excrement.David Sidransky of Johns Hopkins University used an ultra-sensitive DNA analysis technique to find the mutated ras gene in stool samples.Although the technique still needs to be refined and its sensitivity is high, its long-term promise is clear: It could allow colon tumors to be found in their cancerous stages before they can be treated with surgery. Eventually, the approach may also be useful for tumors in other hollow organs, including the bladder, uterus and lungs.In each of these organs, cells are shed into the lumen of the organ.Exfoliated bladder cells can be found in the urine and exfoliated lung cells can be found in the mucus in the upper bronchi.As with the colon site, analysis of exfoliated cells offers the potential for early detection of cancer, increasing the chances of recovery. Familial tumors occupy a prominent place in the pathogenesis of human cancer.Some researchers estimate that about 10 percent of human cancers are genetic in origin.Whether the innate susceptibility to cancer can be predicted is also a very valuable direction for early detection. In colon cancer, familial sarcoma and HNPCC syndrome together account for more than 10% of all cases.The same proportion of breast cancer is also associated with genetic mutations of the two alleles of BRCAI and BRCAZ.In the next 10 years, it will be discovered that some portion of almost every common cancer is caused by inherited mutations in specific genes, usually tumor suppressor genes. Techniques for spotting mutated genes in small tissue samples are advancing by leaps and bounds.Soon, just a few drops of blood can reveal the presence of inherited mutations that confer a predisposition to certain types of cancer.The same analysis will be used for prenatal diagnosis in families with unusually high rates of certain types of cancer.These tests will be able to distinguish between high-risk members of the family and those who have gotten away with it.Family members found to be at risk must receive lifelong guardianship.In life-and-death cases, including familial sarcomas and breast cancers, patients may be able to make up their minds to remove target organs before the malignancy manifests itself. But even with these effective genetic techniques, the protection they offer remains incomplete.A thorough national survey of innate predisposition to cancer is neither economically nor statistically feasible.Even with the most advanced screening techniques, the vast majority of small sporadic tumors slip through the cracks.As a result, we continue to encounter many tumors that can only be detected when they are large and symptomatic.So, for now, the capabilities and limitations of anticancer therapies are the dividing line between life and death.Long-term survival rates for many types of cancer have not improved much over the past decade.Only by inventing a completely new method of treatment can further improvements be made. This is an area where the basic molecular research described in this book will pay off handsomely, though it will take time for those payoffs to come.In the process of unraveling the transduction defects of cancer cells, researchers have discovered that many genes and proteins can be attractive targets for a new generation of anticancer drugs. A new wave of drug development has come.Certain ingredients that pharmaceutical companies are investigating have shown tremendous activity in blocking cells from producing fully functional ras proteins.The most surprising thing is the properties of these drugs. They have a great impact on the growth of tumor cells, but only a relatively small impact on normal cells, although we know that the growth and survival of normal cells cannot be separated from the normal function of ras protein. form. The researchers confirmed that monoclonal antibodies also worked.The antibodies made in mice bind tightly to specific human proteins and remain indifferent to all others.They are invariably correct positioning tools.On the surface of breast cancer cells, the receptors EGF and erb BZ/neu proteins are abnormally dense, and researchers have produced some antibodies that specifically react with these receptor proteins. These antibodies can be used in two ways.First, they can be combined with radioactive particles.Injected into a patient, the antibodies can seek out cells that are densely packed with one of these receptors on their surface, focusing the radiation on the tumor area.This radiation can be scanned with computerized imaging equipment, revealing tumors that cannot be seen with conventional imaging techniques such as CAT scanners.Second, toxins and antibodies can be used in combination.In this way, the antibody becomes a "laser-guided bomb" that can guide the toxin to attack the tumor target cells. Fascinating as the theory is, both applications of monoclonal antibodies tend to be complicated by the fact that the receptor target protein is also distributed on the surface of normal cells, albeit in smaller quantities.Therefore, normal cells that happen to have certain receptor target molecules of antibodies are also not immune to the bombardment of toxin antibodies.Antibodies may successfully outline tumors using radiation localization, but normal cells possessing target antigens can still interfere with imaging, defeating the surgeon's efforts to localize the tumor. The biggest revolution in cancer chemotherapy comes from the new understanding of the importance of apoptosis.Many chemotherapy drugs successfully induce apoptosis in tumor cells.Because the p53 protein makes many cells susceptible to pro-apoptotic drugs, future oncologists could develop certain chemotherapy regimens after ascertaining the genetic role of the p53 gene in tumors.their respective roles in tumorigenesis.However, the vast majority of tumors are the result of a group of genes working together, not genes acting alone.In the future, researchers could use new mathematical methods to understand the origins of polygenic cancers, the process by which groups of genes work together to drive cancer formation.As long as 10 to u years, we can predict the individual suffering from Functional p53 is absent in most tumors, and thus tumor cells are insensitive to currently used chemotherapy.Researchers must pay attention to these tumors in order to find new ways to fight cancer, and perhaps they can develop a way to induce apoptosis in tumor cells even in the absence of a functioning p53 protein.This forces us to ignore the cellular systems that control the apoptotic response. The bC82 proto-oncogene is just one of 12 or more genes that regulate the apoptotic response.The exact role of many genes—promoters or apoptosis inhibitors—requires further study.Once we figure out the logic of the system, we can find new ways to make cells, including cancer cells, commit suicide.We are very confident that we will develop a new way to fight cancer.Changing day by day By the end of the second decade of the next century, the minutiae of cell signaling will be revealed.Each signaling protein has its place in the cell's system of receiving and processing the signals that affect growth and differentiation. By then, a group of talented newcomers will take on the burden of cancer research.Mathematicians who are good at analyzing complex multivariate systems will explain to biologists how the microcomputer inside the cell actually works. They will tell us how the cell works and how it goes wrong during the evolution of tumors. Until recently, the search for the genes and proteins that control cellular life relied on ad hoc solutions to daunting experimental problems, which were then pieced together by biologists who had no choice.While occasional discoveries have repeatedly clarified fragments of the great mystery, there has been no steady progress.Therefore, the vast majority of researchers are searching aimlessly like falling into a sea of ​​smoke.Following the exciting clues, there is still no real gold covered in yellow sand.Significant progress can only be made when hundreds of independent research groups have each made piecemeal progress.We are rich in information thanks to the combined efforts of countless researchers. Soon, this will all change dramatically.In the days to come, we will take a more systematic approach to understanding how cells aggregate.The Human Genome Project, a worldwide collaborative effort to screen all of the genes in human cells, will advance research efforts.We will soon know whether the human genome has 80,000 genes or 100,000 genes.The base sequence of a gene will provide a wealth of clues about the role the gene plays in the life of the cell. Until recently, finding tumor suppressor genes, including those that confer an innate predisposition to cancer, was viewed as daunting, time-consuming, and painful.The technology used is not only imprecise, but also labor-intensive.Finding the key genes is almost like looking for a needle in a haystack.As soon as we understand the human genome in detail, the ranks of tumor suppressor genes will expand rapidly.In just 10 years, we will be able to identify almost all tumor suppressor genes and understand their respective roles in the vast majority of cancers. We will also use other techniques.All people carry genes that affect the body's susceptibility to different cancers.In most cases, it is these genes that subtly affect the detoxification function of the human body against powerful carcinogens, the efficiency of human DNA order, and whether the human body can effectively kill rebellious cells on the way to cancer.Since humans are a genetically diverse species, each individual possesses a different genome.Thus, the emergence of any cancer is the result of the interaction of a large number of different genes and the combined influence of random events. Cancer geneticists are currently working to understand the roles of individual genes and their respective roles in tumor formation.However, the vast majority of tumors are the result of a group of genes working together, not genes acting alone.In the future, researchers could use new mathematical methods to understand the origins of polygenic cancers, the process by which groups of genes work together to drive cancer formation.As long as 10 to 15 years, we can more accurately predict the risk of individuals suffering from various polygenic cancers.Thanks to enormous advances in data processing and the automation of DNA sequence analysis, these predictions will be done quickly and cheaply. The scrolls of genes shown by gene mappers are not a panacea.Currently, the DNA sequence that identifies a protein cannot predict the three-dimensional structure of most proteins.This problem can certainly be resolved within the first decade of the new century.It follows that we will be able to predict how many proteins involved in the cancer process will work without having to perform a direct biochemical analysis of the protein. Despite the sea change in information processing and analysis, the work at hand of biochemists and geneticists remains central.They want to untangle the communication between different proteins inside the cell.Technology has once again worked wonders.Gene cloning technology, which has been partially applied, is a useful tool that will reveal to us the interaction of chaperone proteins in the cytoplasmic fluid inside the cell, and how this interaction forms a huge communication network that allows cells to decide to grow, differentiate or die. Finally, the method of making new cancer drugs will be revolutionized.Until recently, a vast arsenal of myriad different chemical compounds was screened for a handful of potent cancer-fighting properties.The cost of these searches is incalculable, and they are guided by a lack of knowledge about the molecular mechanisms underlying cancer formation. Drug development will be revolutionized in two ways.Screening will increasingly be entrusted to automated controls—a trend that has already begun.The new drug developed will target the unique proteins inside cancer cells and will not harm innocent people.The structures of these proteins will guide pharmacists in designing drugs designed to disrupt their function.Knocking down key cancer-causing proteins is no longer a matter of chance. New "rational drug design" will rapidly lead to effective inhibitors.As our understanding of normal and cancer cell metabolism improves, it will become possible to design highly selective drugs that attack only cancer cells and are relatively harmless to normal tissue cells.Uncomfortable side effects of cancer treatment could be alleviated or even eliminated. Those who made these achievements will regard the discoveries of the last quarter of the 20th century as old relics.But at this moment, we can look at all this with different eyes.We can be proud because we have lived through the foundation years.It is we who split the great chaos and open the door to new knowledge.We have passed through an exciting era.