The uncontrolled proliferation of cancer cells, combined with their ability to metastasize to distant sites, makes cancer a potentially life-threatening disease.
Many chemicals can cause cancer, often after metabolic activation in the liver.
Carcinogens are the cancer causing agents. 2-naphthylamine is a potent carcinogen that causes bladder cancer in industrial workers. When it is inhaled or ingested by animals, it passes through the liver and is metabolized into other chemicals that are the actual causes of cancer. Placing 2- naphthylamine directly in an animal's bladder bypasses this metabolic activation and so cancer does not arise.
Many carcinogens share this need for metabolic activation before they can cause cancer. Substances exhibiting such behavior are more accurately called precarcinogens, a term applied to any chemical that is capable of causing cancer only after it has been metabolically activated. Members of liver cytochrome P450 enzyme family activate these procarcinogens. They catalyze the oxidation of ingested foreign chemicals, such as drugs and pollutants, to make the molecules less toxic and easier to excrete from the body.
DNA Mutations triggered by chemical carcinogens lead to cancer.
Carcinogenic chemicals inflict DNA damage in several ways, including binding to DNA and disrupting normal base-pairing; generating crosslinks between the two strands of the double helix; creating chemical linkages between adjacent bases; hydroxylating or removing individual DNA bases; and causing breaks in one or both DNA strands. In some cases, the mutational role of specific chemicals in causing cancer has been linked to effects on specific genes. For example, the polycyclic aromatic hydrocarbons found in tobacco smoke preferentially bind to specific regions of the p53 gene and trigger unique mutations in which the base T is substituted to base G.
Ames Test for identifying potential carcinogens.
The Ames Test is based on the rationale that most carcinogens are mutagens. The ability of chemicals to induce mutations is measured in bacteria that cannot synthesize the amino acid histidine. When placed in a growth medium lacking histidine, the only bacteria that can grow are those that have acquired a mutation allowing them to make histidine. The number of bacterial colonies that grow is therefore related to the mutagenic potency of the substance being tested. Chemicals studied with the Ames test are first incubated with the liver homogenate because many chemicals become carcinogenic only after they have undergone biochemical modifications in the liver.
Cancer arises through a multistep process involving initiation, promotion and tumor progression.
During initiation, normal cells are converted to a precancerous state, and promotion then stimulates the altered cells to divide and form tumors. Promotion is a gradual process requiring prolonged or repeated exposure to a promoting agent.
When a cell with an initiating mutation is exposed to a promoting agent (or natural growth regulator) that causes the initiated cell to proliferate, the number of mutant cell increases. As proliferation continues, natural selection tends to favor cells exhibiting enhanced growth rate and invasive properties, eventually leading to the formation of a malignant tumor.
Initiation and promotion are followed by a third stage, known as tumor progression. During this, tumor cells properties gradually change over time as cells acquire more aberrant traits and become increasingly aggressive. Tumor progression is made possible by a combination of DNA mutations and epigenetic changes that don't require mutation, accompanied by natural selection of those cells that acquire advantageous properties through these mechanisms.
Main stages in Cancer development : Cancer arises by a multistep process involving (1) an initiation event based on DNA mutation, (2) a promotion stage in which the initiated cell is stimulated to proliferate, and (3) tumor progression, in which mutations and changes in gene expression create variant cells exhibiting enhanced growth rates or other aggressive properties that give certain cells a selective advantage. Such cells tend to outgrow their companions and become the predominant cell population in the tumor. During tumor progression, repeated cycles of this selection process create a population of cells whose properties gradually change over time.
Ionizing and Ultraviolet radiation also cause DNA mutations that lead to cancer.
X-rays and related forms of radiation emitted by radioactive elements are called ionizing radiation because they remove electrons from molecules, thereby generating highly reactive ions that create various types of DNA damage, including single- and double-stranded breaks. Ultraviolet radiation (UV) is another type of radiation that causes cancer by damaging DNA. UV radiation is absorbed mainly by the skin, where it imparts enough energy to trigger pyrimidine dimer formation. If the damage is not repaired, distortion of the double helix causes improper base pairing during DNA replication. For example, CC = TT mutation (conversion of two adjacent cytosine to thymine) is a unique product of UV exposure and can be used as a distinctive "signature" to identify mutations caused by sunlight.
Viruses and other infectious agents trigger the development of some cancers.
A virus that causes cancer is called oncogenic virus. Denis Burkitt, a British surgeon noted large outbreaks of lymphocytic cancers of the neck and jaw. Because of this, it is known as Burkitt lymphoma, which is transmitted by an infectious agent. Epstein- Barr virus (EBV) can play a role in Burkitt lymphoma : (1) EBV DNA and proteins are often found in tumor cells obtained from patients with Burkitt lymphoma but not in normal cells from the same individuals, (2) adding EBV to normal human lymphocytes in culture causes cells to acquire some of the properties of cancer cells. (3) injecting EBV into monkeys causes lymphomas to arise.
In addition to EBV, several other viruses have been linked to human cancers. Among these are the hepatitis B and hepatitis C viruses, which trigger some liver cancers; human T-cell lymphotropic virus-I (HTLV-I), which causes adult T-cell leukemia and lymphomas; and the sexually transmitted human papillomavirus (HPV), which is associated with uterine cervical cancer. Moreover, chronic infection with the bacterium Helicobacter pylori is a common cause of stomach ulcers, this can also trigger stomach cancer. Flatworm infections have been linked to a small number of bladder and bile duct cancers.
The mechanisms of action by these infectious agents can be grouped into two categories:
(1) These agent causes tissue destruction and chronic inflammation. Under these conditions, cells of the immune system infiltrate the tissue and attempt to kill the infectious agent. The mechanism used by immune cells to fight infections often produce mutagenic chemicals such as oxygen free radicals. The net result is an increased likelihood that cancer-causing mutations will arise when cells proliferate to repair the damaged tissue.
(2) The other mechanism used by infectious agents to cause cancer is based on the ability of certain viruses to stimulate the proliferation of infected cells. Some viruses trigger the cell proliferation through the direct action of viral genes, whereas other viruses alter the behavior of host cell genes.
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