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Cancer is the second most common cause of death in the United States. However, it is a very simple group of diseases in concept: the uncontrolled division of cells. When the division of cells becomes so rapid that the products are not fully functional, it becomes deadly. Most forms of cancer are caused by either the failure of tumor suppressor genes or the development of oncogenes. Tumor suppressor genes are the normal genes which slow down the division of cells. They repair the mistakes in DNA of cells and program the death of cells through apoptosis. Oncogenes, however, are the opposite of suppressor genes. When proto-oncogenes, the healthy cells which determine how often a cell should divide, turn into oncogenes, they no longer provide the correct information for how often the cell should divide. Usually, the cell is permanently activated, producing many unfinished or otherwise impaired cells. Tumor suppressor genes can be compared to the brake pedal in a car - it prevents the car from going too fast. A faulty suppressor gene would prevent the "car" from stopping. On the contrary, proto-oncogenes are like the gas pedal in a car. Oncogenes can then be represented by the gas pedal being stuck down. Body tissue begins to swell in both situations, creating a tumor. An important difference between oncogenes and tumor suppressor genes is that cancer develops when they are activated and inactivated, respectively.
The two different cancer-causing genes both play a role during the cell cycle. In the cell cycle, the cell goes through a series of steps through which it will eventually split into two different cells. While oncogenes make the host cell rush through the cycle, skipping important checks, faulty tumor suppressor genes allow cells to indefinitely reproduce. The cell cycle begins with the gap 1 (G1) phase, which mostly consists of the cell resting. Late in G1, cells get ready to enter DNA replication in the S phase. The S phase is then followed by the gap 2 (G2) phase. After G2, mitosis, or the division of cells occur, followed by the next G1. A cell's journey through the cell cycle is regulated by cyclin-dependent kinase (CDK) proteins. The CDK check points are biochemical pathways that coordinate the exact timing of cell cycle transitions. From G1 to S, the cell is regulated by cyclins D1, 2, and 3, cyclin E, and cyclin A. The B-type cyclins regulate the G2 to M transition phases. The CDK inhibitors are split into two groups based on their structural and functional properties. The INK4 proteins function during the middle of the S phase in proliferating cells. Both p15 and p16 show a high frequency of gene deletions, and p16 gene mutations are found in various human tumors and cell lines, suggesting that these genes may function as tumor suppressors. The second group of, the Cip/Kip family, inhibit kinase activities of the preactivated G1 cyclins. Overexpression of the Kip proteins leads to cell cycle arrest. Abnormalities of the TP53 gene (which codes for the p53 protein) have been found in more than half of human cancers. However, a few cancer syndromes are caused by inherited mutations of proto-oncogenes that cause the oncogene to be activated. For example, multiple endocrine neoplasia type 2 is caused by a mutation in the gene RET, developing the uncommon medullary thyroid cancer. It also causes other tumors, including pheochromocytoma and nerve tumors. Cancer-causing mutations involving both tumor suppressor genes and oncogenes are usually acquired, not inherited. Acquired changes in many tumor suppressor genes contribute to the development of sporadic (non-inherited) cancers. Oncogenes are generally activated by chromosome rearrangements, gene duplication, or mutation.
Most human cancers are caused by of a complex blend of genetic and environmental factors. While some forms of cancer are clearly related to certain environmental factors, these factors act on a genetic substrate that may be either susceptible or resistant to the development of cancer. It is well known that lung cancer is much more common in smokers than in nonsmokers. However, lung cancer develops 30 times more frequently among smokers with high levels of aryl hydrocarbon hydroxylase, an enzyme that metabolizes tobacco smoke's benzo(a)pyrene into highly carcinogenic chemicals, than among other smokers. Here, tobacco smoke interacts with the genetically determined enzyme to facilitate the growth of a tumor. Environmental factors in the development of cancers can be chemical, physical, or biological substances. Cancer from environmental factors develop in three stages. The first stage is initiation, in which is a specific alteration in the DNA is made, usually by inducing oncogenes. Many chemical carcinogens are capable of mutating the cell, which can result in activation of the transforming potential of an oncogene. Promotion, the second phase, involves the reversible stimulation of expansion of the cell. Promoters are often incapable of causing cancers on their own, but significantly enhance the development of cancers by initiating agents. Because promotion is thought to be reversible, it is a target for prevention. The final phase of carcinogenesis is progression. It is characterized by invasiveness, transformation, and growth advantage of the tumor.
In 1775, it was noted that chimney sweeps, who had abundant exposure to coal tar, had a high chance of receiving scrotal cancer. Over 140 years later, the precise cause was found to be benzo(a)pyrene. Chemical compounds capable of inducing cancer include polycyclic hydrocarbons, aromatic amines, and alkylating agents. Many chemical carcinogens are actually inactive until activated by the body's metabolism, such as the microsomal enzymes that, ironically, evolved to detoxify compounds. Nearly all chemical carcinogens interact directly with DNA, forming adducts that can result in errors in the base sequence when replicating. Tobacco, the most important environmental carcinogen, accounts for an increasing number of deaths each year from cancer as well as heart and respiratory diseases. Disturbingly, evidence shows that nonsmokers who inhale exhaled smoke are also at risk for smoking-associated cancers.
Another form of environmental carcinogens are physical carcinogens. The three major physical carcinogens are ionizing radiation, ultraviolet radiation, and foreign bodies. Ionizing radiation can originate from many sources and can occur in many forms, but the two major categories are electromagnetic radiation, from x-rays and gamma rays, and particle radiation. Electromagnetic radiation is weakly ionizing and has a low linear-energy-transfer value, but particle radiation is densely ionizing and has a high linear-energy-transfer value, causing more damage. The major physical features that determine the risk of cancer are linear-energy-transfer value, dose, dose rate, and fractionation. Radiation may induce cancers at any site. More than 80% of radiation exposure is from natural sources such as cosmic rays, terrestrial gamma rays, and radon. It is known that radiation can induce mutations in DNA and can activate oncogenes, but the precise mechanism of radiation-induced carcinogenesis is unclear. Ultraviolet radiation, mainly from the Sun, is carcinogenic to skin. The incidence of skin cancers other than melanoma is much higher in southern latitudes and on sites exposed to the Sun, and the incidence of melanoma may also be augmented. The UVB portion (280-320 nanometers) of the ultraviolet spectrum is most damaging to tissues. Ultraviolet radiation brings about alterations in the normal sequence of bases in DNA. Individuals with red hair and with certain genetic conditions, such as xeroderma pigmentosum, are less able to repair ultraviolet-induced damage and are more susceptible to Sun-induced skin cancers than the general population. Protection against ultraviolet radiation is offered by the ozone layer of the atmosphere and by pigmentation of the skin. Foreign bodies are only an occasional cause of tumors. In animal models, the composition of the foreign body is less important than its size and shape. The same materials are more carcinogenic if they are fibrous than if they are powdered, porous, or perforated. The malignant transformation is probably related to a derangement during the connective tissue reaction to the foreign body. The foreign body that is most carcinogenic in humans is asbestos, a natural mineral fiber that is inhaled and is associated with lung cancer. Other potentially carcinogenic fibers include synthetic vitreous and crystalline fibers.
Although viral carcinogenesis is widespread in nature, examples in humans are not numerous, and knowledge of oncogenes has relied on the prevalence of tumors induced by retroviruses in animals; but the precise mechanism of carcinogenesis is not yet clear. There are four documented oncogenic virus types in humans: the hepadnavirus family (specifically hepatitis B virus), the herpesvirus family (specifically Epstein-Barr virus), some papilloma viruses, and the human retrovirus family (specifically HTLV-I). Chronic bacterial infections may lead to cancers in certain sites. For example, Helicobacter pylori gastritis can lead to gastric mucosa-associated lymphatic tissue lymphoma and to gastric adenocarcinoma. Infections with certain parasites can also lead to carcinogenesis, like foreign bodies. An example is bilharzial squamous-cell bladder cancer, which follows chronic bladder infection with Schistosoma haematobium. Hormones may also be considered biological carcinogens. Estrogens can cause endometrial cancer. The synthetic estrogen diethylstilbestrol (DES), administered to women in the 1950s to prevent spontaneous abortion, was found to result in clear-cell carcinoma of the vagina in some of their female offspring between the ages of 15 and 30.