Carcinogenesis
From Freepedia
Carcinogenesis (meaning literally, the creation of cancer) is the process by which normal cells are transformed into cancer cells.
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Introduction
Cell division (proliferation) is a physiological process that occurs in almost all tissues and under many circumstances. Normally homeostasis, the balance between proliferation and programmed cell death, usually in the form of apoptosis, is maintained by tightly regulating both processes to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes.
Carcinogenesis is caused by this mutation of the genetic material of normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell division and tumor formation. The uncontrolled and often rapid proliferation of cells can lead to benign tumors; some types of these may turn into malignant tumors (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they compress vital structures or are physiologically active (for instance, producing a hormone). Malignant tumors can invade other organs, spread to distant locations (metastasize) and become life threatening.
More than one mutation is necessary for carcinogenesis. In fact, a series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. Only mutations in those certain types of genes which play vital roles in cell division, cell death, and DNA repair will cause a cell to lose control of its proliferation.
Properties of malignant cells
Cells capable of forming malignant tumors exhibit many properties which distinguish them from the cells of healthy tissue.
- They are resistant to apoptosis ("programmed" cell death).
- They have an uncontrolled ability to divide (or, they are immortal), and they often divide at an increased rate.
- These cells are self-sufficient with respect to growth factors.
- They are insensitive to antigrowth factors, and contact inhibition is suppressed.
- These cells may exhibit altered differentiation.
More aggressive malignant cells may also show additional abilities.
- They have the ability to invade neighboring tissues, usually through the secretion of metalloproteinases that can digest extracellular matrix material.
- They can form new tumors (metastases) at distant sites.
- They secrete chemical signals that stimulate the growth of new blood vessels (angiogenesis).
Nearly all cancers originate from a single cell, but a cell that degenerates into a tumor cell does not usually acquire all these properties at once. With each carcinogenic mutation, a cell gains a slight selective advantage over its neighbors, resulting in a process known as clonal evolution. This leads to an increased chance that the descendents of the original mutant cell will acquire extra mutations, giving them even more selective advantage. Cells which acquire only some of the mutations necessary to become malignant are thought to be the source of benign tumors. However, when enough mutations accumulate, the mutant cells will become a malignant tumor.
Mechanisms of carcinogenesis
Cancer is, ultimately, a disease of genes. Typically, a series of several mutations is required before a normal cell transforms into a cancer cell. The process involves both proto-oncogenes and tumor suppressor genes.
Proto-oncogenes are involved in signal transduction by coding for a chemical "messenger", produced when a cell undergoes protein synthesis. These messengers send signals based on the amount of them present to the cell or other cells, telling them to undergo mitosis in order divide and reproduce. When mutated, they become oncogenes and overexpress the signals to divide, giving cells a higher chance to divide excessively. The chance of cancer cannot be reduced by removing proto-oncogenes from the human genome as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive.
Tumor suppressor genes code for chemical messengers that command cells to slow or stop mitosis in order to allow DNA repair. This is done by special enzymes which detect any mutation or damage to DNA, such that the mistake is not carried on to the next generation. Tumor suppressor genes are usually triggered by signals that DNA damage has occurred. In addition, they can code for the enzymes themselves that repair DNA, or code for signals that activate such enzymes. However, a mutation can damage the tumor suppressor gene itself or the signal pathway which activates it, "switching it off". The invariable consequence is that DNA repair is hindered or inhibited by every such event. Damage is originally checked by the tumor suppressor genes, but accumulates and becomes more rampant as more tumor suppressor genes succumb to mutation. With repair functions disabled, this inevitably leads to cancer.
In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control (the Knudson or 1-2-hit hypothesis) and tumor suppressor genes. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it and cell growth quickly spirals out of control.
Accumulated damage is generally theorised by most cancer researchers to build up exponentially later in life. Originally at youth defenses against DNA damage are strong, but as more mutations to tumor suppressor genes occur, the rate of damage accumulation rises, causing exponential accumulation, a "death spiral" of sorts. This is further supported by the fact that the chance of acquiring cancer increases exponentially with age, rather than linearly. The average accumulated damage sampled from cancer cells tend to be immense - nearly all of the chromosomes have been mutated in some way, such as four copies of the same chromosome, trisomy, monosomy, or even completely missing chromosomes in the cell.
Mutations can have various causes. Particular causes have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiation from the sun, leads to melanoma and other skin malignancies. Breathing asbestos fibers is associated with mesothelioma. In more general terms, chemicals called mutagens and free radicals are known to cause mutations. Other types of mutations can be caused by chronic inflammation, as neutrophil granulocytes secrete free radicals that damage DNA. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcohol and estrogen. These are thought to promote cancers through their stimulating effect on the rate of cellular mitosis. Faster rates of mitosis increasingly leave less window space for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes, which leads to aneuploidy and may lead to cancer.
Mutations can also be inherited. Inheriting certain mutations in the BRCA1 gene, a tumor suppressor gene, renders a woman much more likely to develop breast cancer and ovarian cancer. Mutations in the Rb1 gene predispose to retinoblastoma, and those in the APC gene lead to colon cancer.
Some types of viruses can cause mutations. They play a role in about 15% of all cancers. Tumor viruses, such as some retroviruses, herpesviruses and papillomaviruses, usually carry an oncogene, or a gene inhibits normal tumor suppression in their genome.
It is impossible to tell the initial cause for any specific cancer. However, with the help of molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene, a tumor suppressor gene also known as "the guardian of the genome". This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis (programmed cell death) when damaged by therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.
References
- Dixon K, Kopras E (2004). Genetic alterations and DNA repair in human carcinogenesis.. Semin Cancer Biol 14 (6): 441-8. PMID 15489137
- Sarasin A (2003). An overview of the mechanisms of mutagenesis and carcinogenesis.. Mutat Res 544 (2-3): 99-106. PMID 14644312
- Schottenfeld D, Beebe-Dimmer JL (2005). Advances in cancer epidemiology: understanding causal mechanisms and the evidence for implementing interventions.. Annu Rev Public Health 26: 37-60. PMID 15760280
- Stoika RS, Panchuk RR, Stoika BR (2004). [The similarities and the differences of embryogenesis and carcinogenesis]. Ontogenez 35 (2): 85-90. PMID 15124348
