Loss of Normal Growth Control
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Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted. This disruption can result from uncontrolled cell growth or loss of a cell's ability to undergo cell suicide by a process called"apoptosis." Apoptosis, or "cell suicide," is the mechanism by which old or damaged cells normally self-destruct.
To illustrate what is meant by normal growth control, consider the skin. The thin outermost layer of normal skin, called the epidermis, is roughly a dozen cells thick. Cells in the bottom row of this layer, called the basal layer, divide just fast enough to replenish cells that are continually being shed from the surface of the skin. Each time one of these basal cells divides, it produces two cells. One remains in the basal layer and retains the capacity to divide. The other migrates out of the basal layer and loses the capacity to divide. The number of dividing cells in the basal layer, therefore, stays the same.
The Beginning of Cancerous Growth
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During the development of skin cancer, the normal balance between cell division and cell loss is disrupted. The basal cells now divide faster than is needed to replenish the cells being shed from the surface of the skin. Each time one of these basal cells divides, the two newly formed cells will often retain the capacity to divide, thereby leading to an increase in the total number of dividing cells.
This gradual increase in the number of dividing cells creates a growing mass of tissue called a "tumor" or "neoplasm." If the rate of cell division is relatively rapid, and no "suicide" signals are in place to trigger cell death, the tumor will grow quickly in size; if the cells divide more slowly, tumor growth will be slower. But regardless of the growth rate, tumors ultimately increase in size because new cells are being produced in greater numbers than needed. As more and more of these dividing cells accumulate, the normal organization of the tissue gradually becomes disrupted.
Cancers are capable of spreading throughout the body by two mechanisms: invasion and metastasis. Invasion refers to the direct migration and penetration by cancer cells into neighboring tissues. Metastasis refers to the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body.
Malignant versus Benign Tumors
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Depending on whether or not they can spread by invasion and metastasis, tumors are classified as being either benign or malignant. Benign tumors are tumors that cannot spread by invasion or metastasis; hence, they only grow locally. Malignant tumors are tumors that are capable of spreading by invasion and metastasis. By definition, the term "cancer" applies only to malignant tumors.
Why Cancer is Potentially Dangerous
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A malignant tumor, a "cancer," is a more serious health problem than a benign tumor because cancer cells can spread to distant parts of the body. For example, a melanoma (a cancer of pigmented cells) arising in the skin can have cells that enter the bloodstream and spread to distant organs such as the liver or brain. Cancer cells in the liver would be called metastatic melanoma, not liver cancer. Metastases share the name of the original ("primary") tumor. Melanoma cells growing in the brain or liver can disrupt the functions of these vital organs and so are potentially life threatening.
Early Cancer May Not Have Any Symptoms
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Some people visit the doctor only when they feel pain or when they notice changes like a lump in the breast or unusual bleeding or discharge. But don't wait until then to be checked because early cancer may not have any symptoms. That is why screening for some cancers is important, particularly as you get older. Screening methods are designed to check for cancer in people with no symptoms.
Cancer is often perceived as a disease that strikes for no apparent reason. While scientists don't yet know all the reasons, many of the causes of cancer have already been identified. Besides intrinsic factors such as heredity, diet, and hormones, scientific studies point to key extrinsic factors that contribute to the cancer's development: chemicals (e.g., smoking), radiation, and viruses or bacteria.
Among the various factors that can cause cancer, tobacco smoking is the greatest public health hazard. Cigarette smoke contains more than two dozen different chemicals capable of causing cancer. Cigarette smoking is the main cause of lung cancer and contributes to many other kinds of cancer as well, including cancer of the mouth, larynx, esophagus, stomach, pancreas, kidney, and bladder. Current estimates suggest that smoking cigarettes is responsible for at least one out of every three cancer deaths, making it the largest single cause of death from cancer. Other forms of tobacco use also can cause cancer. For example, cigars, pipe smoke, and smokeless tobacco can cause cancers of the mouth.
Some atoms give off radiation, which is energy that travels through space. Prolonged or repeated exposure to certain types of radiation can cause cancer. Cancer caused by the sun's ultraviolet radiation is most common in people who spend long hours in strong sunlight. Ultraviolet radiation from sunlight is a low-strength type of radiation. Effective ways to protect against ultraviolet radiation and to prevent skin cancer are to avoid going into strong, direct sunlight and to wear protective clothing. Sunscreen lotions reduce the risk of some forms of skin cancers.
Increased rates of cancer also have been detected in people exposed to high-strength forms of radiation such as X-rays or radiation emitted from unstable atoms called radioisotopes. Because these two types of radiation are stronger than ultraviolet radiation, they can penetrate through clothing and skin into the body. Therefore, high-strength radiation can cause cancers of internal body tissues. Examples include cancer caused by nuclear fallout from atomic explosions and cancers caused by excessive exposure to radioactive chemicals.
Chemicals and radiation that are capable of triggering the development of cancer are called "carcinogens." Carcinogens act through a multistep process that initiates a series of genetic alterations ("mutations") and stimulates cells to proliferate. A prolonged period of time is usually required for these multiple steps. There can be a delay of several decades between exposure to a carcinogen and the onset of cancer. For example, young people exposed to carcinogens from smoking cigarettes generally do not develop cancer for 20 to 30 years. This period between exposure and onset of disease is the lag time.
In addition to chemicals and radiation, a few viruses also can trigger the development of cancer. In general, viruses are small infectious agents that cannot reproduce on their own, but instead enter into living cells and cause the infected cell to produce more copies of the virus. Like cells, viruses store their genetic instructions in large molecules called nucleic acids. In the case of cancer viruses, some of the viral genetic information carried in these nucleic acids is inserted into the chromosomes of the infected cell, and this causes the cell to become malignant.
Examples of Human Cancer Viruses
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Only a few viruses that infect human cells actually cause cancer. Included in this category are viruses implicated in cervical cancer, liver cancer, and certain lymphomas, leukemias, and sarcomas. Susceptibility to these cancers can sometimes be spread from person to person by infectious viruses, although such events account for only a very small fraction of human cancers. For example, the risk of cervical cancer is increased in women with multiple sexual partners and is especially high in women who marry men whose previous wives had this disease. Transmission of the human papillomavirus (HPV) during sexual relations appears to be involved.
Cancer is not considered an inherited illness because most cases of cancer, perhaps 80 to 90 percent, occur in people with no family history of the disease. However, a person's chances of developing cancer can be influenced by the inheritance of certain kinds of genetic alterations. These alterations tend to increase an individual's susceptibility to developing cancer in the future. For example, about 5 percent of breast cancers are thought to be due to inheritance of particular form(s) of a "breast cancer susceptibility gene."
Because a number of mutations usually must occur for cancer to arise, the chances of developing cancer increase as a person gets older because more time has been available for mutations to accumulate. For example, a 75-year-old person is a hundred times more likely to develop colon cancer than a 25-year-old. Because people are living longer today than they did 50 or 100 years ago, they have a longer exposure time to factors that may promote gene changes linked to cancer.
Chemicals (e.g., from smoking), radiation, viruses, and heredity all contribute to the development of cancer by triggering changes in a cell's genes. Chemicals and radiation act by damaging genes, viruses introduce their own genes into cells, and heredity passes on alterations in genes that make a person more susceptible to cancer. Genes are inherited instructions that reside within a person's chromosomes. Each gene instructs a cell how to build a specific product--in most cases, a particular kind of protein. Genes are altered, or "mutated," in various ways as part of the mechanism by which cancer arises.
One group of genes implicated in the development of cancer are damaged genes, called "oncogenes." Oncogenes are genes whose PRESENCE in certain forms and/or overactivity can stimulate the development of cancer. When oncogenes arise in normal cells, they can contribute to the development of cancer by instructing cells to make proteins that stimulate excessive cell growth and division.
Proto-Oncogenes and Normal Cell Growth
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Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell's normal growth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, and transcription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymes inside the cell that, in turn, activate special proteins called transcription factors inside the cell's nucleus. The activated transcription factors "turn on" the genes required for cell growth and proliferation.
Oncogenes are Mutant Forms of Proto-Oncogenes
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Oncogenes arise from the mutation of proto-oncogenes. They resemble proto-oncogenes in that they code for the production of proteins involved in growth control. However, oncogenes code for an altered version (or excessive quantities) of these growth-control proteins, thereby disrupting a cell's growth-signaling pathway.
By producing abnormal versions or quantities of cellular growth-control proteins, oncogenes cause a cell's growth-signaling pathway to become hyperactive. To use a simple metaphor, the growth-control pathway is like the gas pedal of an automobile. The more active the pathway, the faster cells grow and divide. The presence of an oncogene is like having a gas pedal that is stuck to the floorboard, causing the cell to continually grow and divide. A cancer cell may contain one or more oncogenes, which means that one or more components in this pathway will be abnormal.
A second group of genes implicated in cancer are the "tumor suppressor genes." Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer. In other words, if a pair of tumor suppressor genes are either lost from a cell or inactivated by mutation, their functional absence might allow cancer to develop. Individuals who inherit an increased risk of developing cancer often are born with one defective copy of a tumor suppressor gene. Because genes come in pairs (one inherited from each parent), an inherited defect in one copy will not lead to cancer because the other normal copy is still functional. But if the second copy undergoes mutation, the person then may develop cancer because there no longer is any functional copy of the gene.
Tumor Suppressor Genes Act Like a Brake Pedal
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Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is like having a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.
p53 Tumor Suppressor Protein Triggers Cell Suicide
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One particular tumor suppressor gene codes for a protein called "p53" that can trigger cell suicide (apoptosis). In cells that have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cell from growing out of control.
A third type of genes implicated in cancer are called "DNA repair genes." DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division. Mutations in DNA repair genes can lead to a failure in repair, which in turn allows subsequent mutations to accumulate. People with a condition called xeroderma pigmentosum have an inherited defect in a DNA repair gene. As a result, they cannot effectively repair the DNA damage that normally occurs when skin cells are exposed to sunlight, and so they exhibit an abnormally high incidence of skin cancer. Certain forms of hereditary colon cancer also involve defects in DNA repair.
Cancer Tends to Involve Multiple Mutations
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Cancer may begin because of the accumulation of mutations involving oncogenes, tumor suppressor genes, and DNA repair genes. For example, colon cancer can begin with a defect in a tumor suppressor gene that allows excessive cell proliferation. The proliferating cells then tend to acquire additional mutations involving DNA repair genes, other tumor suppressor genes, and many other growth-related genes. Over time, the accumulated damage can yield a highly malignant, metastatic tumor. In other words, creating a cancer cell requires that the brakes on cell growth (tumor suppressor genes) be released at the same time that the accelerators for cell growth (oncogenes) are being activated.
While the prime suspects for cancer-linked mutations are the oncogenes, tumor suppressor genes, and DNA repair genes, cancer conspires even beyond these. Mutations also are seen in the genes that activate and deactivate carcinogens, and in those that govern the cell cycle, cell senescence (or "aging"), cell suicide (apoptosis), cell signaling, and cell differentiation. And still other mutations develop that enable cancer to invade and metastasize to other parts of the body.
Cancer Tends to Corrupt Surrounding Environment
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In addition to all the molecular changes that occur within a cancer cell, the environment around the tumor changes dramatically as well. The cancer cell loses receptors that would normally respond to neighboring cells that call for growth to stop. Instead, tumors amplify their own supply of growth signals. They also flood their neighbors with other signals called cytokines and enzymes called proteases. This action destroys both the basement membrane and surrounding matrix, which lies between the tumor and its path to metastasis--a blood vessel or duct of the lymphatic system.
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