“ We now understand a lot about cancer. We know that it results from a series of genetic changes having to do with cell division and growth control and genetic instability, mortality, the suicide mechanism in cells; the ability of the cells to migrate; the ability of the cells to attract to them a blood supply. And so that’s pretty profound that in a few sentences one can summarize a sophisticated, fundamental understanding of what a cancer is. ” LELAND HARTWELL Molecular to Global.
Perspectives Introduction A multicellular organism can thrive only when all its cells function in accordance with the rules that govern cell growth and reproduction. Why does a normal cell suddenly become a “rebel,” breaking the rules, dividing recklessly, invading other tissues, usurping resources, and in some cases eventually killing the body in which it lives? To understand how and why cells rebel, we need to understand the normal functions of cell growth and reproduction.
From the midnineteenth century on, research in cell biology, biochemistry, and molecular biology has provided astonishingly detailed information about the molecules and processes that allow cells to divide, grow, differentiate, and perform their essential functions. This basic knowledge of cell biology has also led to practical discoveries about the mechanisms of cancer. Specific molecules that control the progression of a cell through the cell cycle regulate cell growth. An understanding of normal cell cycle processes and how those processes go awry provides key information about the mechanisms that trigger cancer.
Loss of control of the cell cycle is one of the critical steps in the development of cancer. Although cancer comprises at least 100 different diseases, all cancer cells share one important characteristic: they are abnormal cells in which the processes regulating normal cell division are disrupted. That is, cancer develops from changes that cause normal cells to acquire abnormal functions. These changes are often the result of inherited mutations or are induced by environmental factors such as UV light, X-rays, chemicals, tobacco products, and viruses.
All evidence suggests that most cancers are not the result of one single event or factor. Rather, around four to seven events are usually required for a normal cell to evolve through a series of premalignant stages into an invasive cancer. Often many years elapse between the initial event and R E D I S C OV E R I N G B I O L O GY the development of cancer. The development of molecular biological techniques may help in the diagnosis of potential cancers in the early stages, long before tumors are visible. What Is Cancer?
Cancer results from a series of molecular events that fundamentally alter the normal properties of cells. In cancer cells the normal control systems that prevent cell overgrowth and the invasion of other tissues are disabled. These altered cells divide and grow in the presence of signals that normally inhibit cell growth; therefore, they no longer require special signals to induce cell growth and division. As these cells grow they develop new characteristics, including changes in cell structure, decreased cell adhesion, and production of new enzymes.
These heritable changes allow the cell and its progeny to divide and grow, even in the presence of normal cells that typically inhibit the growth of nearby cells. Such changes allow the cancer cells to spread and invade other tissues. The abnormalities in cancer cells usually result from mutations in protein-encoding genes that regulate cell division. Over time more genes become mutated. This is often because the genes that make the proteins that normally repair DNA damage are themselves not functioning normally because they are also mutated.
Consequently, mutations begin to increase in the cell, causing further abnormalities in that cell and the daughter cells. Some of these mutated cells die, but other alterations may give the abnormal cell a selective advantage that allows it to multiply much more rapidly than the normal cells. This enhanced growth describes most cancer cells, which have gained functions repressed in the normal, healthy cells. As long as these cells remain in their original location, they are considered benign; if they become invasive, they are considered malignant.
Cancer cells in malignant tumors can often metastasize, sending cancer cells to distant sites in the body where new tumors may form. Genetics of Cancer Only a small number of the approximately 35,000 genes in the human genome have been associated with cancer. (See the Genomics unit. ) Alterations in the same gene often are associated with different forms of cancer. These malfunctioning genes can be broadly classified into three groups. The first group, called proto-oncogenes, produces protein products that normally enhance cell division or inhibit normal cell death. The mutated forms of these genes are called oncogenes.
The second group, called tumor suppressors, makes proteins that normally prevent cell division or cause cell death. The third group contains DNA repair genes, which help prevent mutations that lead to cancer. Proto-oncogenes and tumor suppressor genes work much like the accelerator and brakes of a car, respectively. The normal speed of a car can be maintained by controlled use of both the accelerator and the brake. Similarly, controlled cell growth is maintained by regulation of proto-oncogenes, which accelerate growth, and tumor suppressor genes, which slow cell growth.
Mutations that produce oncogenes accelerate growth while those that affect tumor suppressors prevent the normal inhibition of growth. In either case, uncontrolled cell growth occurs. Cell Biology and Cancer 2 R E D I S C OV E R I N G B I O L O GY Oncogenes and Signal Transduction In normal cells, proto-oncogenes code for the proteins that send a signal to the nucleus to stimulate cell division. These signaling proteins act in a series of steps called signal transduction cascade or pathway (Fig. 1). (See the Genetics and Development unit.)
This cascade includes a membrane receptor for the signal molecule, intermediary proteins that carry the signal through the cytoplasm, and transcription factors in the nucleus that activate the genes for cell division. In each step of the pathway, one factor or protein activates the next; however, some factors can activate more than one protein in the cell. Oncogenes are altered versions of the proto-oncogenes that code for these signaling molecules. The oncogenes activate the signaling cascade continuously, resulting in an increased production of factors that stimulate growth.
For instance, MYC is a proto-oncogene that codes for a transcription factor. Mutations in MYC convert it into an oncogene associated with seventy percent of cancers. RAS is another oncogene that normally functions as an “on-off” switch in the signal cascade. Mutations in RAS cause the signaling pathway to remain “on,” leading to uncontrolled cell growth. About thirty percent of tumors — including lung, colon, thyroid, and pancreatic carcinomas — have a mutation in RAS. Figure 1. Signal transduction pathway. A signal (in this example, a growth factor) binds to a tyrosine kinase receptor on the outside of the cell.
This activates the membrane protein (through the addition of phosphate groups), which in turn activates proteins, such as kinases, in the cytoplasm. Several other proteins may be involved in the cascade, ultimately activating one or more transcription factors. The activated transcription factors enter the nucleus where they stimulate the expression of the genes that are under the control of that factor. This is an example of the RAS pathway, which results in cell division. Growth Factor Tyrosine kinase receptor RAS (G protein) Protein kinases
Nucleus Photo-illustration — Bergmann Graphics Protein that stimulates cell cycle DNA Transcription factor Gene expression Cell Biology and Cancer 3 R E D I S C OV E R I N G B I O L O GY The conversion of a proto-oncogene to an oncogene may occur by mutation of the proto-oncogene, by rearrangement of genes in the chromosome that moves the proto-oncogene to a new location, or by an increase in the number of copies of the normal proto-oncogene. Sometimes a virus inserts its DNA in or near the proto-oncogene, causing it to become an oncogene.
The result of any of these events is an altered form of the gene, which contributes to cancer. Think again of the analogy of the accelerator: mutations that convert protooncogenes into oncogenes result in an accelerator stuck to the floor, producing uncontrolled cell growth. Most oncogenes are dominant mutations; a single copy of this gene is sufficient for expression of the growth trait. This is also a “gain of function” mutation because the cells with the mutant form of the protein have gained a new function not present in cells with the normal gene.
If your car had two accelerators and one were stuck to the floor, the car would still go too fast, even if there were a second, perfectly functional accelerator. Similarly, one copy of an oncogene is sufficient to cause alterations in cell growth. The presence of an oncogene in a germ line cell (egg or sperm) results in an inherited predisposition for tumors in the offspring. However, a single oncogene is not usually sufficient to cause cancer, so inheritance of an oncogene does not necessarily result in cancer. Tumor Suppressor Genes
The proteins made by tumor suppressor genes normally inhibit cell growth, preventing tumor formation. Mutations in these genes result in cells that no longer show normal inhibition of cell growth and division. The products of tumor suppressor genes may act at the cell membrane, in the cytoplasm, or in the nucleus. Mutations in these genes result in a loss of function (that is, the ability to inhibit cell growth) so they are usually recessive. This means that the trait is not expressed unless both copies of the normal gene are mutated.
Using the analogy to a car, a mutation in a tumor suppressor gene acts much like a defective brake: if your car had two brakes and only one was defective, you could still stop the car. How is it that both genes can become mutated? In some cases, the first mutation is already present in a germ line cell (egg or sperm); thus, all the cells in the individual inherit it. Because the mutation is recessive, the trait is not expressed. Later a mutation occurs in the second copy of the gene in a somatic cell.
In that cell both copies of the gene are mutated and the cell develops uncontrolled growth. An example of this is hereditary retinoblastoma, a serious cancer of the retina that occurs in early childhood. When one parent carries a mutation in one copy of the RB tumor suppressor gene, it is transmitted to offspring with a fifty percent probability. About ninety percent of the offspring who receive the one mutated RB gene from a parent also develop a mutation in the second copy of RB, usually very early in life. These individuals then develop retinoblastoma.
Not all cases of retinoblastoma are hereditary: it can also occur by mutation of both copies of RB in the somatic cell of the individual. Because retinoblasts are rapidly dividing cells and there are thousands of them, there is a high incidence of a mutation in the second copy of RB in individuals who inherited one mutated copy. This disease afflicts only young children because only individuals younger than about eight years old Cell Biology and Cancer 4 R E D I S C OV E R I N G B I O L O GY have retinoblasts. In adults, however, mutations in RB may lead to a predisposition to several other forms of cancer.
Three other cancers associated with defects in tumor suppressor genes include familial adenomatous polyposis of the colon (FPC), which results from mutations to both copies of the APC gene; hereditary breast cancer, resulting from mutations to both copies of BRCA2; and hereditary breast and ovarian cancer, resulting from mutations to both copies of BRCA1. While these examples suggest that heredity is an important factor in cancer, the majority of cancers are sporadic with no indication of a hereditary component.
Cancers involving tumor suppressor genes are often hereditary because a parent may provide a germ line mutation in one copy of the gene. This may lead to a higher frequency of loss of both genes in the individual who inherits the mutated copy than in the general population. However, mutations in both copies of a tumor suppressor gene can occur in a somatic cell, so these cancers are not always hereditary. Somatic mutations that lead to loss of function of one or both copies of a tumor suppressor gene may be caused by environmental factors, so even these familial cancers may have an environmental component. Table 1.
Some Genes Associated with Cancer NAME FUNCTION EXAMPLES of Cancer/Diseases TYPE of Cancer Gene APC BCL2 BLM BRCA1 BRCA2 HER2 MYC p16 p21 p53 RAS RB SIS XP regulates transcription of target genes involved in apoptosis; stimulates angiogenesis DNA repair may be involved in cell cycle control DNA repair tyrosine kinase; growth factor receptor involved in protein-protein interactions with various cellular factors cyclin-dependent kinase inhibitor cyclin-dependent kinase inhibitor apoptosis; transcription factor GTP-binding protein; important in signal transduction cascade regulation of cell cycle growth factor DNA repair.
Familial Adenomatous Polyposis Leukemia; Lymphoma Bloom Syndrome Breast, Ovarian, Prostatic, & Colonic Neoplasms Breast & Pancreatic Neoplasms; Leukemia Breast, Ovarian Neoplasms Burkitt’s Lymphoma Leukemia; Melanoma; Multiple Myeloma; Pancreatic Neoplasms Colorectal Neoplasms; Li-Fraumeni Syndrome Pancreatic, Colorectal, Bladder Breast, Kidney, & Lung Neoplasms; Leukemia;
Melanoma Retinoblastoma Dermatofibrosarcoma; Meningioma; Skin Neoplasms Xeroderma pigmentosum tumor suppressor oncogene DNA repair tumor suppressor tumor suppressor oncogene oncogene tumor suppressor tumor suppressor tumor suppressor oncogene tumor suppressor oncogene DNA repair DNA Repair Genes A third type of gene associated with cancer is the group involved in DNA repair and maintenance of chromosome structure. Environmental factors, such asionizing radiation, UV light, and chemicals, can damage DNA. Errors in DNA replication can also lead to mutations. Certain gene products repair damage to chromosomes, thereby minimizing mutations in the cell.
When a DNA repair gene is mutated its product is no longer made, preventing DNA repair and allowing further mutations to accumulate in the cell. These mutations can increase the Cell Biology and Cancer 5 R E D I S C OV E R I N G B I O L O GY frequency of cancerous changes in a cell. A defect in a DNA repair gene called XP (Xeroderma pigmentosum) results in individuals who are very sensitive to UV light and have a thousand-fold increase in the incidence of all types of skin cancer. There are seven XP genes, whose products remove DNA damage caused by UV light and other carcinogens.
Another example of a disease that is associated with loss of DNA repair is Bloom syndrome, an inherited disorder that leads to increased risk of cancer, lung disease, and diabetes. The mutated gene in Bloom syndrome, BLM, is required for maintaining the stable structure of chromosomes. Individuals with Bloom syndrome have a high frequency of chromosome breaks and interchanges, which can result in the activation of oncogenes. Cell Cycle Normal cells grow and divide in an orderly fashion, in accordance with the cell cycle.
(Mutations in proto-oncogenes or in tumor suppressor genes allow a cancerous cell to grow and divide without the normal controls imposed by the cell cycle. ) The major events in the cell cycle are described in Fig. 2. Figure 2. The cell cycle is an ordered process of events that occurs in four stages. During the two gap phases, G1 and G2, the cell is actively metabolizing but not dividing. In S (synthesis) phase, the chromosomes duplicate as a result of DNA replication. During the M (mitosis) phase, the chromosomes separate in the nucleus and the division of the cytoplasm (cytokinesis) occurs.
There are checkpoints in the cycle at the end of G1 and G2 that can prevent the cell form entering the S or M phases of the cycle. Cells that are not in the process of dividing are in the G0 stage, which includes most adult cells. Quiescence G1/S checkpoint DNA synthesis cell growth & accumulation of cyclins M/G1 checkpoint Mitosis G2/M checkpoint Preparation for Mitosis Photo-illustration — Bergmann Graphics Several proteins control the timing of the events in the cell cycle, which is tightly regulated to ensure that cells divide only when necessary.
The loss of this regulation is the hallmark of cancer. Major control switches of the cell cycle are cyclin-dependent kinases. Each cyclindependent kinase forms a complex with a particular cyclin, a protein that binds and activates the cyclin-dependent kinase. The kinase part of the complex is an enzyme that adds a phosphate to various proteins required for progression of a cell through the cycle. These added phosphates alter the structure of the protein and can activate or inactivate the protein, depending on its function.
There are specific cyclin-dependent kinase/cyclin complexes at the entry points into the G1, S, and M phases of the cell cycle, as well as additional factors that help prepare the cell to enter S phase and M phase. Cell Biology and Cancer 6 R E D I S C OV E R I N G B I O L O GY One important protein in the cell cycle is p53, a transcription factor (see the Genes and Development unit) that binds to DNA, activating transcription of a protein called p21. P21 blocks the activity of a cyclindependent kinase required for progression through G1.
This block allows time for the cell to repair the DNA before it is replicated. If the DNA damage is so extensive that it cannot be repaired, p53 triggers the cell to commit suicide. The most common mutation leading to cancer is in the gene that makes p53. Li-Fraumeni syndrome, an inherited predisposition to multiple cancers, results from a germ line (egg or sperm) mutation in p53. Other proteins that stop the cell cycle by inhibiting cyclin dependent kinases are p16 and RB. All of these proteins, including p53, are tumor suppressors. Cancer cells do not stop dividing, so what stops a normal cell from dividing?
In terms of cell division, normal cells differ from cancer cells in at least four ways. • Normal cells require external growth factors to divide. When synthesis of these growth factors is inhibited by normal cell regulation, the cells stop dividing. Cancer cells have lost the need for positive growth factors, so they divide whether or not these factors are present. Consequently, they do not behave as part of the tissue — they have become independent cells. • Normal cells show contact inhibition; that is, they respond to contact with other cells by ceasing cell division.
Therefore, cells can divide to fill in a gap, but they stop dividing as soon as there are enough cells to fill the gap. This characteristic is lost in cancer cells, which continue to grow after they touch other cells, causing a large mass of cells to form. • Normal cells age and die, and are replaced in a controlled and orderly manner by new cells. Apoptosis is the normal, programmed death of cells. Normal cells can divide only about fifty times before they die. This is related to their ability to replicate DNA only a limited number of times. Each time the chromosome replicates, the ends (telomeres) shorten.
In growing cells, the enzyme telomerase replaces these lost ends. Adult cells lack telomerase, limiting the number of times the cell can divide. However, telomerase is activated in cancer cells, allowing an unlimited number of cell divisions. • Normal cells cease to divide and die when there is DNA damage or when cell division is abnormal. Cancer cells continue to divide, even when there is a large amount of damage to DNA or when the cells are abnormal. These progeny cancer cells contain the abnormal DNA; so, as the cancer cells continue to divide they accumulate even more damaged DNA.
What Causes Cancer? The prevailing model for cancer development is that mutations in genes for tumor suppressors and oncogenes lead to cancer. However, some scientists challenge this view as too simple, arguing that it fails to explain the genetic diversity among cells within a single tumor and does not adequately explain many chromosomal aberrations typical of cancer cells. An alternate model suggests that there are “master genes” controlling cell division. A mutation in a master gene leads to abnormal replication of chromosomes, causing whole sections of chromosomes to be missing or duplicated.
This leads to a change in Cell Biology and Cancer 7 R E D I S C OV E R I N G B I O L O GY gene dosage, so cells produce too little or too much of a specific protein. If the chromosomal aberrations affect the amount of one or more proteins controlling the cell cycle, such as growth factors or tumor suppressors, the result may be cancer. There is also strong evidence that the excessive addition of methyl groups to genes involved in the cell cycle, DNA repair, and apoptosis is characteristic of some cancers. There may be multiple mechanisms leading to the development of cancer.
This further complicates the difficult task of determining what causes cancer. Tumor Biology Cancer cells behave as independent cells, growing without control to form tumors. Tumors grow in a series of steps. The first step is hyperplasia, meaning that there are too many cells resulting from uncontrolled cell division. These cells appear normal, but changes have occurred that result in some loss of control of growth. The second step is dysplasia, resulting from further growth, accompanied by abnormal changes to the cells.
The third step requires additional changes, which result in cells that are even more abnormal and can now spread over a wider area of tissue. These cells begin to lose their original function; such cells are called anaplastic. At this stage, because the tumor is still contained within its original location (called in situ) and is not invasive, it is not considered malignant — it is potentially malignant. The last step occurs when the cells in the tumor metastasize, which means that they can invade surrounding tissue, including the bloodstream, and spread to other locations.
This is the most serious type of tumor, but not all tumors progress to this point. Non-invasive tumors are said to be benign. The type of tumor that forms depends on the type of cell that was initially altered. There are five types of tumors. • Carcinomas result from altered epithelial cells, which cover the surface of our skin and internal organs. Most cancers are carcinomas. • Sarcomas result from changes in muscle, bone, fat, or connective tissue. • Leukemia results from malignant white blood cells. • Lymphoma is a cancer of the lymphatic system cells that derive from bone marrow.
• Myelomas are cancers of specialized white blood cells that make antibodies. Angiogenesis Although tumor cells are no longer dependent on the control mechanisms that govern normal cells, they still require nutrients and oxygen in order to grow. All living tissues are amply supplied with capillary vessels, which bring nutrients and oxygen to every cell. As tumors enlarge, the cells in the center no longer receive nutrients from the normal blood vessels. To provide a blood supply for all the cells in the tumor, it must form new blood vessels to supply the cells in the center with nutrients and oxygen.
In a process called angiogenesis, tumor cells make growth factors which induce formation of new capillary blood vessels. The cells of the blood vessels that divide to make new capillary vessels are inactive in normal tissue; however, Cell Biology and Cancer 8 R E D I S C OV E R I N G B I O L O GY tumors make angiogenic factors, which activate these blood vessel cells to divide. Without the additional blood supplied by angiogenesis, tumors can grow no larger than about half a millimeter. Without a blood supply, tumor cells also cannot spread, or metastasize, to new tissues.
Tumor cells can cross through the walls of the capillary blood vessel at a rate of about one million cells per day. However, not all cells in a tumor are angiogenic. Both angiogenic and nonangiogenic cells in a tumor cross into blood vessels and spread; however, non-angiogenic cells give rise to dormant tumors when they grow in other locations. In contrast, the angiogenic cells quickly establish themselves in new locations by growing and producing new blood vessels, resulting in rapid growth of the tumor. How do tumors begin to produce angiogenic factors?
An oncogene called BCL2 has been shown to greatly increase the production of a potent stimulator of angiogenesis. It appears, then, that oncogenes in tumor cells may cause an increased expression of genes that make angiogenic factors. There are at least fifteen angiogenic factors and production of many of these is increased by a variety of oncogenes. Therefore, oncogenes in some tumor cells allow those cells to produce angiogenic factors. The progeny of these tumor cells will also produce angiogenic factors, so the population of angiogenic cells will increase as the size of the tumor increases.
How important is angiogenesis in cancer? Dormant tumors are those that do not have blood vessels; they are generally less than half a millimeter in diameter. Several autopsy studies in which trauma victims were examined for such very small tumors revealed that thirtynine percent of women aged forty to fifty have very small breast tumors, while forty-six percent of men aged sixty to seventy have very small prostate tumors. Amazingly, ninety-eight percent of people aged fifty to seventy have very small thyroid tumors.
However, for those age groups in the general population, the incidence of these particular cancers is only one-tenth of a percent (thyroid) or one percent (breast or prostate cancer). The conclusion is that the incidence of dormant tumors is very high compared to the incidence of cancer. Therefore, angiogenesis is critical for the progression of dormant tumors into cancer. Viruses and Cancer Many viruses infect humans but only a few viruses are known to promote human cancer. These include both DNA viruses and retroviruses, a type of RNA virus.
(See the HIV and AIDS unit. ) Viruses associated with cancer include human papillomavirus (genital carcinomas), hepatitis B (liver carcinoma), Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma), human T-cell leukemia virus (T-cell lymphoma); and, probably, a herpes virus called KSHV (Kaposi’s sarcoma and some B cell lymphomas). The ability of retroviruses to promote cancer is associated with the presence of oncogenes in these viruses. These oncogenes are very similar to protooncogenes in animals.
Retroviruses have acquired the proto-oncogene from infected animal cells. An example of this is the normal cellular c-SIS proto-oncogene, which makes a cell growth factor. The viral form of this gene is an oncogene called v-SIS. Cells infected with the virus that has v-SIS overproduce the growth factor, leading to high levels of cell growth and possible tumor cells. Cell Biology and Cancer 9 R E D I S C OV E R I N G B I O L O GY Viruses can also contribute to cancer by inserting their DNA into a chromosome in a host cell.
Insertion of the virus DNA directly into a proto-oncogene may mutate the gene into an oncogene, resulting in a tumor cell. Insertion of the virus DNA near a gene in the chromosome that regulates cell growth and division can increase transcription of that gene, also resulting in a tumor cell. Using a different mechanism, human papillomavirus makes proteins that bind to two tumor suppressors, p53 protein and RB protein, transforming these cells into tumor cells. Remember that these viruses contribute to cancer, they do not by themselves cause it.
Cancer, as we have seen, requires several events. Environmental Factors Several environmental factors affect one’s probability of acquiring cancer. These factors are considered carcinogenic agents when there is a consistent correlation between exposure to an agent and the occurrence of a specific type of cancer. Some of these carcinogenic agents include X-rays, UV light, viruses, tobacco products, pollutants, and many other chemicals. X-rays and other sources of radiation, such as radon, are carcinogens because they are potent mutagens.
Marie Curie, who discovered radium, paving the way for radiation therapy for cancer, died of cancer herself as a result of radiation exposure in her research. Tobacco smoke contributes to as many as half of all cancer deaths in the U. S. , including cancers of the lung, esophagus, bladder, and pancreas. UV light is associated with most skin cancers, including the deadliest form, melanoma. Many industrial chemicals are carcinogenic, including benzene, other organic solvents, and arsenic.
Some cancers associated with environmental factors are preventable. Simply understanding the danger of carcinogens and avoiding them can usually minimize an individual’s exposure to these agents. The effect of environmental factors is not independent of cancer genes. Sunlight alters tumor suppressor genes in skin cells; cigarette smoke causes changes in lung cells, making them more sensitive to carcinogenic compounds in smoke. These factors probably act directly or indirectly on the genes that are already known to be involved in cancer.
Individual genetic differences also affect the susceptibility of an individual to the carcinogenic affects of environmental agents. About ten percent of the population has an alteration in a gene, causing them to produce excessive amounts of an enzyme that breaks down hydrocarbons present in smoke and various air pollutants. The excess enzyme reacts with these chemicals, turning them into carcinogens. These individuals are about twenty-five times more likely to develop cancer from hydrocarbons in the air than others are. Detecting and Diagnosing Cancer.
The most common techniques for detecting cancer are imaging techniques such as MRI, X-rays (such as mammograms), CT, and ultrasound, which can provide an image of a tumor. Endoscopy allows a physician to insert a lighted instrument to look for tumors in organs such as the stomach, colon, and lungs. Most of these techniques are used to detect visible tumors, which must then be removed by biopsy and examined microscopically by a pathologist. The pathologist looks for abnormalities in the cells in terms of their shape, size, and Cell Biology and Cancer 10.
R E D I S C OV E R I N G B I O L O GY structure, especially the nucleus. In addition, the pathologist looks at the borders of the tumor to see whether those cells are normal. Based on examination of the tumor cells, the pathologist determines whether the tumor is benign or malignant, and determines whether is in an early or late stage of development. Diagnosis may also include the removal and examination of lymph nodes to determine whether the cancer cells have spread. Tumor markers are proteins found more often in the blood of individuals with the tumor than in normal individuals.
These are not ideal compounds for diagnosing of cancer for two reasons. First, individuals without cancer may have elevated levels of the marker, leading to false positives. Second, tumor markers are not sufficiently elevated in all individuals with cancer to allow their detection. This leads to false negatives. One of the most commonly used tumor markers is prostate-specific antigen (PSA). It is present in all adult males, but its level is increased after both benign and malignant changes in the prostate.
Therefore, high levels of PSA indicate only that further tests are required to determine whether the condition is cancer. If prostate cancer is diagnosed, the levels of PSA can help to determine the effectiveness of treatment and detect recurrence. Another tumor marker is CA125, which is produced by a number of different cells, particularly ovarian cancer cells. It is used primarily to monitor the treatment efficacy of ovarian cancer. When the cancer is responding to treatment, CA125 levels fall. It is not used as a routine test for ovarian cancer because many common conditions.
<unk> Sasa tunaelewa mengi kuhusu kansa. "Kama matokeo ya mabadiliko ya maumbile yanayohusiana na mgawanyiko wa seli na udhibiti wa ukuaji, na kutoeleweka kwa maumbile, vifo, utaratibu wa kujiua katika seli, uwezo wa seli kuhamia, uwezo wa seli kuvutia damu.""" Na hivyo hiyo ni ya kina sana kwamba katika sentensi chache mtu anaweza kufupisha ufahamu wa kisasa, wa msingi wa kansa ni nini. <unk> LELAND HARTWELL Molecular kwa Global. Uwezo wa kuendeleza uhai wa chembe nyingi ni muhimu kwa sababu chembe zote za chembe zinafanya kazi kulingana na sheria zinazosimamia ukuzi na uzazi wa chembe. Kwa nini ghafula chembe ya kawaida inakuwa "mupinzani", ikivunja sheria, ikigawanyika bila kufikiri, ikivamia tishu nyingine, ikinyang'anya rasilimali, na katika visa fulani hatimaye kuua mwili inayokaa? Ili kuelewa jinsi na kwa nini chembe huasi, tunahitaji kuelewa utendaji wa kawaida wa ukuzi na uzazi wa chembe. Tangu katikati ya karne ya 19, utafiti katika biolojia ya chembe, biokemia, na biolojia ya molekuli umetoa habari za kina kuhusu molekuli na taratibu zinazoruhusu chembe kugawanyika, kukua, kutofautika, na kutimiza kazi zao muhimu. Ujuzi huo wa msingi wa biolojia ya chembe pia umesababisha uvumbuzi wa vitendo kuhusu utaratibu wa kansa. Molekuli hususa zinazodhibiti maendeleo ya chembe kupitia mzunguko wa chembe husimamia ukuzi wa chembe. Kuelewa kwa utaratibu wa kawaida wa mzunguko wa chembe na jinsi mchakato huo unavyoenda vibaya hutoa habari muhimu kuhusu utaratibu unaosababisha kansa. Kupoteza udhibiti wa mzunguko wa chembe ni mojawapo ya hatua muhimu katika ukuzi wa kansa. Ingawa kansa ni ugonjwa unaohusisha angalau magonjwa 100 tofauti, seli zote za kansa zina sifa moja muhimu: ni seli zisizo za kawaida ambazo mchakato wa kudhibiti mgawanyiko wa kawaida wa seli umevurugwa. Yaani, kansa hutokea kutokana na mabadiliko yanayofanya chembe za kawaida ziwe na utendaji usio wa kawaida. Mabadiliko hayo mara nyingi hutokana na mabadiliko ya urithi au husababishwa na mambo ya mazingira kama vile mwangaza wa UV, miale ya X, kemikali, bidhaa za tumbaku, na virusi. Uthibitisho wote unaonyesha kwamba saratani nyingi si matokeo ya tukio au sababu moja tu. Kwa kawaida, hatua nne hadi saba zinahitajika ili chembe ya kawaida itokeze kupitia hatua kadhaa za kabla ya ugonjwa wa kansa. Mara nyingi miaka mingi hupita kati ya tukio la kwanza na R E D I S C OV E R I N G B I O L O G Y maendeleo ya kansa. Maendeleo ya mbinu za biolojia ya molekuli yanaweza kusaidia katika utambuzi wa saratani zinazowezekana katika hatua za mapema, muda mrefu kabla ya uvimbe kuonekana. Saratani Ni Nini? Saratani hutokana na mfululizo wa matukio ya molekuli ambayo hubadili sana sifa za kawaida za chembe. Katika chembe za kansa mifumo ya kawaida ya kudhibiti ambayo huzuia ukuzi wa kupita kiasi wa chembe na uvamizi wa tishu nyingine huondolewa. Chembe hizi zilizobadilishwa hugawanyika na kukua kwa kuwapo kwa ishara ambazo kwa kawaida huzuia ukuaji wa seli; kwa hivyo, hazihitaji tena ishara maalum ili kusababisha ukuaji wa seli na mgawanyiko. Chembe hizo zinapokua, zinapata sifa mpya, kutia ndani mabadiliko katika muundo wa chembe, kupungua kwa mshikamano wa chembe, na kutokezwa kwa vimeng'enya vipya. Mabadiliko haya ya urithi huruhusu chembe na wazao wake kugawanyika na kukua, hata katika uwepo wa chembe za kawaida ambazo kwa kawaida huzuia ukuaji wa chembe za karibu. Mabadiliko hayo huruhusu chembe za kansa kuenea na kuvamia tishu nyingine. Kwa kawaida kasoro katika chembe za kansa hutokana na mabadiliko katika chembe za urithi zinazotunga protini ambazo husimamia mgawanyiko wa chembe. Baada ya muda, chembe nyingine za urithi hubadilika. Hii ni kwa sababu mara nyingi jeni zinazotengeneza protini ambazo kwa kawaida husahihisha uharibifu wa DNA hazifanyi kazi kwa kawaida kwa sababu pia zimebadilika. Kwa hiyo, mabadiliko huanza kuongezeka katika chembe hiyo, yakisababisha kasoro zaidi katika chembe hiyo na chembe za binti. Baadhi ya chembe hizo zilizobadilika hufa, lakini mabadiliko mengine yanaweza kumpa chembe hiyo isiyo ya kawaida faida ya kuchagua ambayo humruhusu kuzidisha kwa kasi zaidi kuliko chembe za kawaida. Ukuaji huu ulioimarishwa unaelezea seli nyingi za kansa, ambazo zimepata kazi zilizokandamizwa katika seli za kawaida, zenye afya. Maadamu chembe hizo ziko katika eneo lao la awali, zinaonwa kuwa zenye madhara; zikivamia, zinaonwa kuwa zenye madhara. Chembe za kansa katika uvimbe mbaya mara nyingi zinaweza kuenea, na kutuma chembe za kansa kwenye maeneo ya mbali mwilini ambapo uvimbe mpya unaweza kuundwa. Genetics ya kansa ni moja ya jeni 35,000 za binadamu ambazo zinahusishwa na kansa. (Tazama kitengo cha Genomics. ) Mara nyingi mabadiliko katika jeni moja huhusianishwa na aina tofauti za kansa. Chembe hizo za urithi zinazofanya kazi vibaya zaweza kugawanywa katika vikundi vitatu. Kikundi cha kwanza, kinachoitwa proto-oncogenes, hutokeza protini ambazo kwa kawaida huongeza mgawanyiko wa chembe au huzuia kifo cha kawaida cha chembe. Aina zilizobadilika za chembe hizo za urithi huitwa oncogenes. Kikundi cha pili, kinachoitwa vificho vya uvimbe, hutokeza protini ambazo kwa kawaida huzuia kugawanyika kwa chembe au kusababisha kifo cha chembe. Kikundi cha tatu kina chembe za urithi za kurekebisha DNA, ambazo husaidia kuzuia mabadiliko ya chembe za urithi yanayoongoza kwenye kansa. Proto-oncogenes na jeni za kuzuia uvimbe hufanya kazi kama gesi na breki za gari, kwa mtiririko huo. Kasi ya kawaida ya gari yaweza kudumishwa kwa kutumia kwa udhibiti wote wawili kichocheo na breki. Vivyo hivyo, ukuaji wa chembe unaodhibitiwa huhifadhiwa kwa udhibiti wa proto-oncogenes, ambayo huongeza kasi ya ukuaji, na jeni za kuzuia uvimbe, ambazo hupunguza ukuaji wa chembe. Mabadiliko ambayo hutokeza oncogenes huongeza kasi ya ukuzi huku yale yanayoathiri vificho vya uvimbe yakizuia kizuizi cha kawaida cha ukuzi. Katika visa vyote viwili, ukuzi wa chembe usioweza kudhibitiwa hutokea. Oncogenes na Signal Transduction Katika seli za kawaida, proto-oncogenes code kwa ajili ya protini kwamba kutuma ishara kwa kiini kuchochea mgawanyiko wa seli. Protini hizi za ishara hufanya kazi katika mfululizo wa hatua zinazoitwa mtiririko wa maambukizi ya ishara au njia (Fig. 1) (Tazama sehemu ya Genetics and Development.) Mzunguko huu unajumuisha kipenyo cha membrane kwa molekuli ya ishara, protini za kati ambazo hubeba ishara kupitia cytoplasm, na sababu za maandishi katika kiini ambayo huamsha jeni kwa mgawanyiko wa seli. Katika kila hatua ya njia, sababu moja au protini huamsha inayofuata; hata hivyo, sababu zingine zinaweza kuamsha protini zaidi ya moja katika seli. Oncogenes ni matoleo yaliyotengenezwa ya proto-oncogenes ambayo huandika code kwa molekuli hizi za ishara. Oncogenes huamsha mtiririko wa ishara kwa kuendelea, ikisababisha ongezeko la uzalishaji wa mambo yanayochochea ukuaji. Kwa mfano, MYC ni proto-oncogene ambayo code kwa ajili ya transcription sababu. Mabadiliko katika MyC hufanya oncogene ya kansa ya kisukari kuwa muhimu kwa asilimia 70 ya saratani. RAS ni oncogene nyingine ambayo kawaida kazi kama <unk>on-off<unk> kubadili katika ishara cascade. Mabadiliko katika RAS husababisha njia ya ishara kubaki <unk>on,<unk> kuongoza kwa ukuaji wa seli uncontrolled. Karibu asilimia thelathini ya uvimbe - kutia ndani kansa ya mapafu, utumbo mzito, tezi-kibofu, na kongosho - huwa na mabadiliko katika RAS. Picha ya 1. Njia ya kuhamisha ishara. Ishara (katika mfano huu, sababu ya ukuaji) huunganisha kwa receptor ya tyrosine kinase nje ya seli. Hii huamsha protini ya utando (kupitia kuongezwa kwa vikundi vya phosphate), ambayo kwa upande huamsha protini, kama vile kinases, katika cytoplasm. Protini nyingine kadhaa zinaweza kuhusika katika mtiririko huo, hatimaye kuamsha sababu moja au zaidi za maandishi. Vipengele vya maandishi vilivyoamilishwa huingia kwenye kiini ambapo huchochea usemi wa jeni ambazo ziko chini ya udhibiti wa kipengele hicho. Hii ni mfano wa njia ya RAS, ambayo husababisha mgawanyiko wa seli. Tiroxin kinase receptor (TKR) - ni chombo cha protini kinase (PK) ambacho huchochea mzunguko wa chembe za DNA, na huchangia mabadiliko ya chembe za DNA katika chembe za DNA. Nyakati nyingine virusi huingiza DNA yake ndani au karibu na proto-oncogene, na hivyo kuifanya iwe oncogene. Matokeo ya matukio hayo yote ni mabadiliko ya chembe za urithi, ambayo huchangia kansa. Fikiria tena mfano wa kiharakishi: mabadiliko ambayo hubadilisha proto-oncogenes kuwa oncogenes husababisha kiharakishi kushikamana na sakafu, na kuzalisha ukuaji wa seli usioweza kudhibitiwa. Oncogenes nyingi ni mabadiliko ya kutawala; nakala moja ya jeni hili ni ya kutosha kwa ajili ya usemi wa tabia ya ukuaji. Hii pia ni "kuongezeka kwa kazi" mabadiliko kwa sababu seli na aina mutant ya protini wamepata kazi mpya si sasa katika seli na jeni ya kawaida. Ikiwa gari lako lina gesi mbili na moja imeshikamana na sakafu, gari bado litaenda haraka sana, hata ikiwa kuna gesi ya pili inayofanya kazi kikamilifu. Vivyo hivyo, nakala moja ya oncogene inatosha kusababisha mabadiliko katika ukuzi wa chembe. Uwepo wa oncogene katika chembe ya mstari wa kijusi (yai au shahawa) husababisha mwelekeo wa urithi wa uvimbe katika watoto. Hata hivyo, kwa kawaida oncogene moja haitoshi kusababisha kansa, kwa hiyo urithi wa oncogene hauhusishi kansa. Protini zinazotengenezwa na jeni za kuzuia uvimbe kwa kawaida huzuia ukuzi wa chembe, na kuzuia kuundwa kwa uvimbe. Mabadiliko katika chembe hizo husababisha chembe zisionyeshe tena vizuizi vya kawaida vya ukuzi na mgawanyiko wa chembe. Bidhaa za jeni za kuzuia uvimbe zaweza kutenda kwenye utando wa chembe, katika cytoplasm, au katika kiini. Mabadiliko katika jeni hizi husababisha kupoteza kazi (yaani, uwezo wa kuzuia ukuaji wa seli) kwa hivyo kwa kawaida ni ya kurudi nyuma. Hilo lamaanisha kwamba sifa hiyo haionyeshwi isipokuwa nakala zote mbili za jeni la kawaida zimebadilika. Kwa mfano, mutation katika chembe ya urithi ya suppressor ya uvimbe hufanya kazi kama breki iliyoharibika: ikiwa gari lako lilikuwa na breki mbili na moja tu ilikuwa na kasoro, bado ungeweza kuacha gari. Ni kwa nini chembe zote mbili za urithi zinaweza kubadilika? Katika baadhi ya kesi, mabadiliko ya kwanza tayari ipo katika kiini cha mstari wa kijusi (yai au shahawa); kwa hivyo, seli zote katika mtu huirithi. Kwa sababu mabadiliko hayo ni ya kurudi nyuma, sifa hiyo haionyeshwi. Baadaye mabadiliko hutokea katika nakala ya pili ya jeni katika chembe ya mwili. Katika chembe hiyo nakala zote mbili za jeni hubadilika-badilika na chembe hiyo hukua bila kudhibitiwa. Mfano mmoja ni retinoblastoma ya urithi, kansa mbaya ya retina ambayo hutokea katika utoto wa mapema. Ikiwa mzazi mmoja ana mutation katika nakala moja ya jeni la suppressor ya uvimbe wa RB, inawezekana kuipitisha kwa watoto kwa asilimia 50. Karibu asilimia 90 ya watoto ambao hupokea jeni moja ya RB kutoka kwa mzazi wao pia hupata mabadiliko katika nakala ya pili ya RB, kwa kawaida mapema sana maishani. Kisha watu hao hupata retinoblastoma. retinoblastoma ni ya urithi na inaweza kutokea kwa mabadiliko ya chembe zote mbili za RNA katika seli ya somatic. Kwa sababu retinoblasts ni haraka kugawanyika seli na kuna maelfu yao, kuna high incidence ya mabadiliko katika nakala ya pili ya RBC katika watu ambao kurithi nakala moja mutated. Ugonjwa huu huathiri watoto wadogo tu kwa sababu watu wadogo zaidi ya umri wa miaka minane tu wana retinoblasts. Hata hivyo, kwa watu wazima, mabadiliko katika RB yaweza kusababisha uwezekano wa kupatwa na aina nyingine kadhaa za kansa. Ugonjwa wa kansa unaosababishwa na kasoro katika jeni la suppressor ya uvimbe ni pamoja na familia ya adenoma polyposis ya colon (FAPC), ambayo hutokana na mabadiliko ya chembe zote mbili za jeni la APC; kansa ya matiti ya urithi, inayotokana na mabadiliko ya chembe zote mbili za BRCA2 na kansa ya matiti na ya ovari. Ingawa mifano hii inaonyesha kwamba urithi ni sababu muhimu katika kansa, idadi kubwa ya kansa ni sporadic bila dalili ya sehemu ya urithi. Saratani zinazohusisha jeni la kuzuia uvimbe mara nyingi ni za urithi kwa sababu mzazi anaweza kutoa mabadiliko ya mstari wa kijusi katika nakala moja ya jeni. Hii inaweza kusababisha mzunguko wa juu wa kupoteza jeni zote mbili katika mtu ambaye anarithi nakala iliyobadilika kuliko katika idadi ya watu kwa ujumla. Hata hivyo, mabadiliko katika nakala zote mbili za jeni la kuzuia uvimbe yanaweza kutokea katika seli ya somati, kwa hiyo kansa hizi si za urithi sikuzote. Mabadiliko ya somatic ambayo husababisha kupoteza kazi ya nakala moja au zote mbili za jeni la kuzuia uvimbe yanaweza kusababishwa na sababu za mazingira, kwa hivyo hata saratani hizi za familia zinaweza kuwa na sehemu ya mazingira. Jedwali la 1. Kuhusu chembe za urithi, kuna chembe za urithi za BCL2 (BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-BLAM-L-BLAM-L-BLAM-L-BLAM-L-BLAM-L-L-B-L-L-L-B-L-L-L-L-L-L-L-L-L-L-L-L-L-L Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Ugonjwa wa Leukemia: Mambo ya mazingira, kama vile mnururisho unaoweza kuharibu, nuru ya UV, na kemikali, yaweza kuharibu DNA. Makosa katika kuiga DNA yanaweza pia kusababisha mabadiliko ya chembe za urithi. Bidhaa fulani za chembe za urithi husahihisha uharibifu wa kromosomu, na hivyo kupunguza mabadiliko katika chembe. Wakati jeni la ukarabati wa DNA limebadilika, bidhaa yake haifanyiwi tena, ikizuia ukarabati wa DNA na kuruhusu mabadiliko zaidi kujilimbikiza kwenye seli. Mabadiliko haya yanaweza kuongeza mzunguko wa mabadiliko ya kansa katika seli. Uharibifu katika jeni la kurekebisha DNA linaloitwa X-Pigmentum (XP) husababisha watu kuwa nyeti sana kwa mwangaza wa UV na kuwa na ongezeko la mara elfu katika matukio ya aina zote za kansa ya ngozi. Kuna jeni saba za X-ray ambazo huondoa uharibifu wa DNA unaosababishwa na mwangaza wa UV na vitu vingine vinavyosababisha kansa. Ugonjwa mwingine unaohusishwa na kupoteza uwezo wa kurekebisha DNA ni ugonjwa wa Bloom, ugonjwa unaosababishwa na urithi ambao husababisha hatari ya kansa, ugonjwa wa mapafu, na kisukari. Jeni ya Bloom syndrome (BLM) ni muhimu kwa kudumisha muundo wa kromosomu. Watu walio na ugonjwa wa Bloom wana mara nyingi kuvunjika kwa kromosomu na kubadilishana, jambo ambalo laweza kusababisha uanzishaji wa oncogenes. Mzunguko wa Chembe Chembe za kawaida hukua na kugawanyika kwa utaratibu, kulingana na mzunguko wa chembe. Mabadiliko katika proto-oncogenes au katika jeni la suppressor ya uvimbe huruhusu seli ya kansa kukua na kugawanyika bila udhibiti wa kawaida uliowekwa na mzunguko wa seli. Matukio makuu katika mzunguko wa seli yanaelezwa katika Mchoro. 2. Uwezekano wa kupata Picha ya 2. Mzunguko wa chembe ni mchakato uliopangwa wa matukio ambayo hutokea katika hatua nne. Katika kipindi cha G1 na G2, chembe huanza kufanya kazi ya kimetaboliki lakini haigawanyiki. Katika hatua ya S (synthesis), kromosomu huongezeka kwa sababu ya kuiga DNA. Wakati wa awamu ya M (mitosis), kromosomu hutenganishwa katika kiini na mgawanyiko wa cytoplasm (cytokinesis) hutokea. Katika hatua za mwisho za mzunguko wa G1, G2, na G3, hatua za mwisho za mzunguko wa G2 zinahitajika ili kuzuia chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe za chembe. Chembe ambazo hazijagawanyika ziko katika hatua ya G0, ambayo inajumuisha chembe nyingi za watu wazima. Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitoid (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) - Mitosis (Mitosis) Kupoteza utaratibu huo ni alama ya kansa. Vipuli vikubwa vya kudhibiti mzunguko wa chembe ni kinases zinazotegemea cyclin. Kila kinase ya kujitegemea ya mzunguko huunda tata na cyclin fulani, protini ambayo huunganisha na kuamsha kinase inayotegemea cyclin. Kinase ni enzyme ambayo huongeza phosphate kwa protini mbalimbali zinazohitajika kwa maendeleo ya seli kupitia mzunguko. Phosphates hizi zilizoongezwa hubadilisha muundo wa protini na zinaweza kuamsha au kuzima protini, kulingana na kazi yake. Kuna kinase cyclin-kutegemea (CKC) complexes katika hatua za kuingia katika awamu ya G1, S, na M ya mzunguko wa seli, pamoja na mambo ya ziada ambayo kusaidia kuandaa seli kuingia katika awamu ya S na awamu ya M. "Kama ilivyoelezwa hapo juu, ""kila kitu kinaweza kuathiri mfumo wa kibofu cha binadamu, na kwa hivyo, kwa sababu ya kuunganisha na DNA, p53 ni ""sababishi"" ya maandishi ya maandishi ya DNA, ambayo huwezesha maandishi ya maandishi ya DNA." P21 inazuia shughuli ya kinase ya kipekee ya mzunguko inayohitajika kwa maendeleo kupitia G1. Kizuizi hicho huruhusu chembe hiyo kurekebisha DNA kabla ya kuiga. Ikiwa uharibifu wa DNA ni mkubwa sana hivi kwamba hauwezi kurekebishwa, p53 huchochea seli kujiua. Mabadiliko ya kawaida ya chembe za urithi ya p53 ndiyo husababisha kansa. Ugonjwa wa Li-Fraumeni ni ugonjwa wa kuambukiza ambao unatokana na mabadiliko ya chembe za uzazi (yai au shahawa) katika p53. Protini nyingine ambazo huzuia mzunguko wa seli kwa kuzuia kinases zinazotegemea cyclin ni p16 na RB. Protini zote, ikiwa ni pamoja na p53, ni suppressors ya uvimbe. Chembe za kansa haziachi kugawanyika, kwa hiyo ni nini kinachomzuia chembe ya kawaida isigawanyike? Kwa habari ya kugawanyika kwa chembe, chembe za kawaida hutofautiana na chembe za kansa kwa angalau njia nne. • Chembe za kawaida huhitaji mambo ya nje ya ukuzi ili kugawanyika. Wakati utengenezaji wa mambo haya ya ukuzi unapozuiwa na udhibiti wa kawaida wa chembe, chembe hizo huacha kugawanyika. Chembe za kansa hazihitaji tena sababu za ukuzi, kwa hiyo zinagawanyika, hata kama kuna sababu hizo. Kwa hiyo, hazitendeki kama sehemu ya tishu - zimekuwa chembe huru. • Chembe za kawaida huonyesha kuzuia mawasiliano; yaani, zinaitikia kuwasiliana na chembe nyingine kwa kukomesha mgawanyiko wa chembe. Kwa hiyo, chembe zinaweza kugawanyika ili kujaza pengo, lakini huacha kugawanyika mara tu zinapokuwa na chembe za kutosha kujaza pengo hilo. Sifa hii hupoteza katika seli za kansa, ambazo huendelea kukua baada ya kugusa seli nyingine, na kusababisha wingi wa seli kuunda. • Chembe za kawaida huzeeka na kufa, na zinabadilishwa kwa njia iliyoongozwa na yenye utaratibu na chembe mpya. Apoptosis ni kifo cha kawaida, kilichopangwa cha chembe. Chembe za kawaida zinaweza kugawanyika mara hamsini tu kabla ya kufa. Hii inahusiana na uwezo wao wa kuiga DNA mara chache tu. Kila mara chromosome inapozidi kuenea, ncha zake (telomere) hupungua. Katika chembe zinazokua, enzyme telomerase inachukua mahali pa ncha hizo zilizopotea. Chembe za watu wazima hazina telomerase, na hivyo zinapunguza idadi ya mara ambazo chembe hiyo inaweza kugawanyika. Hata hivyo, telomerase huanzishwa katika chembe za kansa, na hivyo kuruhusu idadi isiyo na kikomo ya mgawanyiko wa chembe. • Chembe za kawaida huacha kugawanyika na kufa wakati kuna uharibifu wa DNA au wakati mgawanyiko wa chembe ni wa kawaida. Chembe za saratani huendelea kugawanyika hata wakati kuna uharibifu mkubwa wa DNA au wakati seli haziko kawaida. Chembe za kansa za kizazi hiki zina DNA isiyo ya kawaida; kwa hiyo, kwa kuwa chembe za kansa zinaendelea kugawanyika, hukusanya DNA zaidi iliyoharibiwa. Ni Nini Kinachosababisha Kansa? Mfano unaoenea wa maendeleo ya kansa ni kwamba mabadiliko katika jeni kwa ajili ya suppressors uvimbe na oncogenes kusababisha kansa. Hata hivyo, wanasayansi fulani wanashutumu maoni hayo kuwa sahili sana, wakisema kwamba hayawezi kueleza tofauti za urithi kati ya chembe ndani ya uvimbe mmoja na hayawezi kueleza kwa usahihi kasoro nyingi za kromosomu zinazotokea kwa chembe za kansa. Mfano mwingine unaonyesha kwamba kuna "jini kuu" zinazodhibiti mgawanyiko wa chembe. Mabadiliko katika jeni kuu husababisha kugawanyika kwa kromosomu kwa njia isiyo ya kawaida, na kusababisha sehemu nzima za kromosomu kutoweka au kugawanyika. Hii inaongoza kwa mabadiliko katika molekuli ya chembe za urithi (REDO) na kiwango cha jeni ya GY, kwa hivyo chembe zinazalisha protini kidogo sana au nyingi sana. Ikiwa kasoro za kromosomu huathiri kiasi cha protini moja au zaidi zinazodhibiti mzunguko wa seli, kama vile sababu za ukuaji au kizuizi cha uvimbe, matokeo yanaweza kuwa kansa. Kuna ushahidi mkubwa kwamba kuongezwa kwa kiasi kikubwa kwa vikundi vya methyl kwa jeni zinazohusika katika mzunguko wa chembe, ukarabati wa DNA, na apoptosis ni sifa ya baadhi ya kansa. Huenda kukawa na utaratibu mbalimbali unaosababisha kansa. Hilo hufanya kazi ngumu ya kujua kisababishi cha kansa iwe ngumu zaidi. Seli za kansa hujiendesha kama chembe za kujitegemea, zikikua bila kudhibitiwa na kufanyiza uvimbe. Uvimbe hukua kwa hatua kadhaa. Hatua ya kwanza ni hyperplasia, ikimaanisha kwamba kuna chembe nyingi sana zinazotokana na mgawanyiko wa chembe usioweza kudhibitiwa. Chembe hizo huonekana kuwa za kawaida, lakini mabadiliko yametokea ambayo husababisha kupoteza udhibiti fulani wa ukuzi. Hatua ya pili ni dysplasia, inayotokana na ukuzi zaidi, ikiambatana na mabadiliko yasiyo ya kawaida katika chembe. Hatua ya tatu inahitaji mabadiliko ya ziada, ambayo husababisha seli ambazo ni mbaya zaidi na sasa zinaweza kuenea juu ya eneo pana la tishu. Chembe hizo huanza kupoteza kazi yao ya awali; chembe hizo huitwa anaplastic. Katika hatua hii, kwa sababu uvimbe bado uko ndani ya eneo lake la awali (inaitwa in situ) na sio ya uvamizi, haichukuliwi kuwa mbaya <unk> ina uwezekano wa kuwa mbaya. Hatua ya mwisho ni wakati seli za uvimbe zinapopiga, na hivyo kuvamia tishu zinazozunguka, kutia ndani damu, na kuenea kwenye sehemu nyingine. Hii ni aina mbaya zaidi ya uvimbe, lakini si uvimbe wote unaendelea hadi hatua hii. Vimelea visivyo vya uvamizi husemwa kuwa vyenye afya nzuri. Aina ya uvimbe unaotokezwa inategemea aina ya chembe iliyobadilishwa mwanzoni. Kuna aina tano za uvimbe. • Karsinoma hutokana na mabadiliko ya chembe za epithelial, ambazo hufunika uso wa ngozi yetu na viungo vya ndani. Aina nyingi za kansa ni kansa. • Sarcomas hutokana na mabadiliko katika misuli, mifupa, mafuta, au tishu za kuunganisha. • Leukemia hutokana na chembe nyeupe za damu zenye kasoro. • Lymphoma ni kansa ya chembe za mfumo wa limfu zinazotokana na uti wa mgongo. • Myeloma ni kansa ya chembe nyeupe za damu zinazotengeneza kingamwili. Angiogenesis: Ingawa seli za uvimbe hazitegemei tena mifumo ya udhibiti inayodhibiti seli za kawaida, bado zinahitaji virutubisho na oksijeni ili kukua. Viungo vyote vya uhai vimefunikwa kwa kiasi kikubwa na mishipa ya nyuzinyuzi, ambayo huleta virutubisho na oksijeni kwa kila chembe. Ugonjwa huo unapozidi kupanuka, chembe zilizo katikati ya tumori hazipati virutubisho kutoka kwa mishipa ya damu ya kawaida. Ili kuandaa damu kwa ajili ya seli zote katika uvimbe, ni lazima kuunda mishipa mpya ya damu ili kutoa seli katika kituo na virutubisho na oksijeni. Katika mchakato unaoitwa angiogenesis, chembe za uvimbe hutokeza mambo ya ukuzi ambayo husababisha kuundwa kwa mishipa mipya ya damu. Chembe za mishipa ya damu ambazo hugawanyika ili kutengeneza mishipa mpya ya nywele hazifanyi kazi katika tishu ya kawaida, hata hivyo, tumors za seli hufanya sababu za angiogenic ambazo huamsha seli hizi za mishipa ya damu kugawanyika. Bila damu ya ziada inayotolewa na angiogenesis, uvimbe hauwezi kukua kwa ukubwa wa karibu nusu milimita. Bila ugavi wa damu, chembe za uvimbe haziwezi kuenea, au kuenea, kwenye tishu mpya. Chembe za uvimbe zinaweza kuvuka kuta za mishipa ya damu kwa kiwango cha chembe milioni moja kwa siku. Hata hivyo, si chembe zote katika uvimbe ni angiogenic. Chembe za angiogenic na zisizo za angiogenic katika uvimbe hupita kwenye mishipa ya damu na kuenea; hata hivyo, seli zisizo za angiogenic husababisha uvimbe wa usingizi zinapokua katika maeneo mengine. Kwa kulinganisha, seli za angiogenic hujiweka haraka katika maeneo mapya kwa kukua na kutengeneza mishipa mipya ya damu, na kusababisha ukuaji wa haraka wa uvimbe. Ugonjwa wa tumors huanzaje kutokeza angiogenic factors? Oncogen inayoitwa BCL2 imeonyeshwa kuongeza sana uzalishaji wa kichocheo cha nguvu cha angiogenesis. Kwa hiyo, inaonekana kwamba oncogenes katika chembe za uvimbe zaweza kusababisha ongezeko la maonyesho ya chembe za urithi zinazotengeneza mambo ya angiogenic. Kuna angalau sababu kumi na tano angiogenic na uzalishaji wa wengi wa haya ni kuongezeka na aina mbalimbali ya oncogenes. Kwa hiyo, oncogenes katika baadhi ya chembe za uvimbe kuruhusu chembe hizo kuzalisha sababu angiogenic. Kwa sababu ya kuenea kwa seli za uvimbe, idadi ya seli za angiogenic huongezeka kadiri uvimbe unavyoongezeka. Angiogenesis ni muhimu kadiri gani katika kansa? Tumors zilizopo katika hali ya kupumzika ni zile ambazo hazina mishipa ya damu; kwa kawaida zina kipenyo cha chini ya nusu milimita. Uchunguzi wa maiti uliofanywa kwa watu waliopatwa na majeraha ulifunua kwamba asilimia 39 ya wanawake wenye umri wa miaka 40 hadi 50 wana uvimbe mdogo sana wa matiti, huku asilimia 46 ya wanaume wenye umri wa miaka 60 hadi 70 wakiwa na uvimbe mdogo sana wa tezi-kibofu. Kwa kushangaza, asilimia 98 ya watu wenye umri wa miaka 50 hadi 70 wana uvimbe mdogo sana wa tezi-kibofu. Hata hivyo, kwa makundi hayo ya umri katika idadi ya watu kwa ujumla, visa vya saratani hizi maalum ni moja tu ya kumi ya asilimia (thyroid) au asilimia moja (sanduku la matiti au kansa ya tezi). Kwa hivyo, matokeo ya utafiti huu ni kwamba idadi ya uvimbe wa kimya ni kubwa sana ikilinganishwa na idadi ya saratani. Kwa hiyo, angiogenesis ni muhimu kwa maendeleo ya uvimbe wa usingizi katika kansa. Virusi na Kansa Virusi vingi huambukiza wanadamu lakini ni virusi vichache tu vinavyojulikana kuendeleza kansa ya binadamu. Hizi zinatia ndani virusi vya DNA na retrovirusi, aina ya virusi vya RNA. (Tazama kitengo cha UKIMWI na UKIMWI.) Virusi vinavyohusishwa na kansa ni pamoja na virusi vya papillomavirus (karsinoma ya viungo vya uzazi), virusi vya hepatitis B (karsinoma ya ini), virusi vya Epstein-Barr (burkitt's lymphoma na nasopharyngeal carcinoma), virusi vya leukemia ya seli za T (T-cell lymphoma), na, labda, virusi vya herpes vinavyoitwa KSHV (Kaposi's sarcoma na baadhi ya seli za B lymphoma). Uwezo wa retroviruses kukuza kansa unahusishwa na uwepo wa oncogenes katika virusi hivi. Oncogenes hizi ni sawa sana na protooncogenes katika wanyama. Virusi vya nyuma vimepata proto-oncogene kutoka kwa chembe za wanyama zilizoambukizwa. Mfano wa hii ni c-SIS proto-oncogene ya kawaida ya seli, ambayo hufanya sababu ya ukuaji wa seli. Aina ya virusi ya jeni hili ni oncogene inayoitwa v-SIS. Chembe zilizoambukizwa virusi vya SARS-CoV-2 hutengeneza overproduction ya sababu ya ukuaji, na kusababisha viwango vya juu vya ukuaji wa seli na uwezekano wa seli za uvimbe. Virusi vya saratani na saratani 9 R E D I S C O V E R I N G B I O L O G Y Virusi pia vinaweza kuchangia saratani kwa kuingiza DNA yao katika kromosomu katika seli ya mwenyeji. Kuingizwa kwa DNA ya virusi moja kwa moja katika proto-oncogene kunaweza kubadilisha jeni kuwa oncogene, na kusababisha seli ya uvimbe. Kuingizwa kwa DNA ya virusi karibu na jeni katika kromosomu inayodhibiti ukuaji wa seli na mgawanyiko kunaweza kuongeza maandishi ya jeni hilo, pia ikisababisha seli ya uvimbe. Kwa kutumia utaratibu tofauti, virusi vya papilloma vya binadamu hufanya protini ambazo huunganisha na vifungo viwili vya uvimbe, protini ya p53 na protini ya RB, na kugeuza seli hizi kuwa seli za uvimbe. Kumbuka kwamba virusi hivyo huchangia kansa, si kwamba vinaisababisha. Kama tulivyoona, kansa inahitaji matukio kadhaa. Sababu za Mazingira Sababu kadhaa za mazingira huathiri uwezekano wa mtu kupata kansa. Vifaa hivyo huonwa kuwa vinasababisha kansa wakati kuna uhusiano wa kudumu kati ya kuambukizwa na aina fulani ya kansa. Baadhi ya vitu hivyo vinavyosababisha kansa ni pamoja na miale ya X, nuru ya UV, virusi, bidhaa za tumbaku, vichafuzi, na kemikali nyingine nyingi. Miale ya X na vyanzo vingine vya mnururisho, kama vile radoni, ni vitu vinavyosababisha kansa kwa sababu ni vitu vinavyofanya mabadiliko ya chembechembe. Marie Curie, ambaye alianzisha radium, aliwahi kuambukizwa kansa na kuuawa kwa sababu ya kuambukizwa na radiation. Nuru ya tumbaku huchangia karibu nusu ya vifo vyote vya kansa nchini Marekani, ikiwa ni pamoja na kansa ya mapafu, esophagus, kibofu cha mkojo, na kongosho. Mwanga wa UV unahusishwa na saratani nyingi za ngozi, kutia ndani aina yake hatari zaidi, melanoma. Kemikali nyingi za viwandani ni zenye kusababisha kansa, kutia ndani benzeni, vimumunyifu vingine vya kikaboni, na arseniki. Baadhi ya kansa zinazohusiana na mambo ya mazingira zaweza kuzuiwa. Kuelewa tu hatari ya vitu vinavyosababisha kansa na kuepuka vitu hivyo kwa kawaida kunaweza kupunguza mtu kuathiriwa na vitu hivyo. Athari za mambo ya mazingira hazitegemei chembe za urithi za kansa. Nuru ya jua hubadilisha chembe za kuondoa uvimbe katika seli za ngozi; moshi wa sigareti husababisha mabadiliko katika seli za mapafu, na kuzifanya ziwe nyeti zaidi kwa misombo ya kansa katika moshi. Yaelekea mambo hayo huathiri moja kwa moja au kwa njia isiyo ya moja kwa moja chembe za urithi ambazo tayari zinajulikana kuwa zinahusika katika kansa. Tofauti za maumbile za mtu binafsi pia huathiri uwezekano wa mtu binafsi wa kuathiriwa na athari za kansa za viungo vya mazingira. Takriban asilimia kumi ya watu wana mabadiliko katika jeni, na kusababisha wao kuzalisha kiasi kikubwa cha enzyme ambayo huvunja hydrocarbons zilizopo katika moshi na uchafuzi mbalimbali hewa. Enzyme nyingi hutenda na kemikali hizo, na kuzigeuza kuwa vitu vinavyosababisha kansa. Watu hao wana uwezekano wa mara ishirini na tano zaidi ya kupata kansa kutokana na hidrokarboni katika hewa kuliko wengine. Kuchunguza na Kuchunguza Kansa. Utafiti wa saratani unafanywa kwa kutumia mbinu za upimaji wa picha kama vile MRI, X-ray (kama vile mammogram), CT, na ultrasound, ambazo zinaweza kutoa picha ya uvimbe. Endoscopy inaruhusu daktari kuingiza kifaa chenye mwangaza ili kutafuta uvimbe katika viungo kama vile tumbo, utumbo, na mapafu. Utafiti huu unafanywa kwa njia ya kugundua tumors inayoonekana, ambayo lazima iondolewe kwa njia ya biopsy na kuchunguzwa kwa microscopically na mtaalamu wa pathologist. Mtaalamu wa magonjwa ya chembe za urithi huchunguza chembe za urithi kwa kuzingatia umbo, ukubwa, na aina ya chembe. R D I S C OV E R I N G B I O L O G Y muundo, hasa kiini. Kwa kuongezea, mtaalamu wa magonjwa huchunguza mipaka ya uvimbe ili kuona kama chembe hizo ni za kawaida. Kwa kuchunguza chembe za uvimbe, mtaalamu wa magonjwa huamua ikiwa uvimbe ni mbaya au mbaya, na huamua ikiwa uko katika hatua ya mapema au ya mwisho ya maendeleo. Uchunguzi waweza pia kutia ndani kuondolewa na kuchunguzwa kwa kibofu cha limfu ili kujua ikiwa chembe za kansa zimeenea. Vipimo vya uvimbe ni protini zinazopatikana mara nyingi zaidi katika damu ya watu walio na uvimbe kuliko katika watu wa kawaida. Hizi si misombo bora ya kugundua kansa kwa sababu mbili. Kwanza, watu wasio na kansa wanaweza kuwa na viwango vya juu vya kiashiria hicho, na hivyo kupata matokeo mabaya. Pili, alama za uvimbe haziongezeki vya kutosha kwa watu wote walio na kansa ili ziweze kugunduliwa. Hilo husababisha matokeo yasiyofaa. Moja ya alama za uvimbe zinazotumiwa sana ni antigen ya prostate-specific (PSA). Inapatikana katika wanaume wote wazima, lakini kiwango chake huongezeka baada ya mabadiliko ya aina nzuri na mbaya katika tezi-kibofu. Kwa hiyo, viwango vya juu vya PSA vinaonyesha tu kwamba uchunguzi zaidi unahitajika ili kuamua ikiwa ugonjwa huo ni kansa. Ikiwa kansa ya tezi-kibofu imegunduliwa, viwango vya PSA vinaweza kusaidia kuamua ufanisi wa matibabu na kugundua kurudia. Kiashiria kingine cha uvimbe ni CA125, ambayo hutengenezwa na seli kadhaa tofauti, haswa seli za saratani ya ovari. Inatumiwa hasa kufuatilia ufanisi wa matibabu ya kansa ya ovari. Wakati kansa inapoitikia matibabu, viwango vya CA125 hupungua. Haitumiwi kama mtihani wa kawaida wa kansa ya yai kwa sababu ya hali nyingi za kawaida.