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From Wikipedia, the free encyclopedia

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Carcinogenesis (the creation of cancer), is the process by which normal cells are transformed into cancer cells.

Cell division is a physiological process that occurs in almost all tissues and under many circumstances. Under normal circumstances, 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 (only certain mutations can lead to cancer and the majority of potential mutations will have no bearing) 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 the evolution of those cells by natural selection in the body. 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 (metastasis) 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.[1] Only mutations in those certain types of genes which play vital roles in cell division, apoptosis (cell death), and DNA repair will cause a cell to lose control of its cell proliferation.


Mechanisms of carcinogenesis

Cancer is a genetic disease: In order for cells to start dividing uncontrollably, genes that regulate cell growth must be damaged. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. This concept is sometimes termed "oncoevolution."


Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes is responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the 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. It is important to note that a gene possessing a growth-promoting role may increase carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated[2]. This condition includes also the inactivation of specific tumor suppressor genes (see below). If the condition is not fulfilled, the cell may cease to grow and can proceed to die. This makes knowledge of the stage and type of cancer cell that grows under the control of a given oncogene crucial for the development of treatment strategies.

Tumor suppressor genes

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. In general, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from passing on to daughter cells. Canonical tumor suppressors include the p53 gene, which is a transcription factor activated by many cellular stresses including hypoxia and ultraviolet radiation damage.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway that activates it, switching it off. This can hinder DNA repair, so that DNA damage accumulates, including changes that lead to cancer.

Multiple mutations

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 and tumor suppressor genes, first hypothesised by the Knudson hypothesis.[3] 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, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop.

Usually, oncogenes are dominant alleles, as they contain gain-of-function mutations, whereas mutated tumor suppressors are recessive alleles, as they contain loss-of-function mutations. Each cell has two copies of a same gene, one from each parent, and, under most cases, gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation must happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional, called the dominant negative effect. This is observed in many p53 mutations.

Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals that are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and that are heterozygous for Rb mutations develop retinoblastoma. In similar fashion, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in the colon while young, whereas mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Non-mutagenic carcinogens

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 cell mitosis. Faster rates of mitosis increasingly leave less opportunities 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.

Role of viral infections

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but less so in humans. 12% of human cancers can be attributed to a viral infection.[4] The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely-transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements, in turn, cause over-expression of that proto-oncogene, which, in turn, induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming virus, which already carries the viral-oncogene.

How viruses are thought to cause cancer

Viruses that are known to cause cancer such as HPV (cervical cancer), Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA viruses. It is thought that when the virus infects a cell, it inserts a part of its own DNA near the cell growth genes, causing cell division. The group of changed cells that are formed from the first cell dividing all have the same viral DNA near the cell growth genes. The group of changed cells are now special because one of the normal controls on growth has been lost.

Depending on their location, cells can be damaged through radiation from sunshine, chemicals from cigarette smoke, and inflammation from bacterial infection or other viruses. Each cell has a chance of damage, a step on a path toward cancer. Cells often die if they are damaged, through failure of a vital process or the immune system; however, sometimes damage will knock out a single cancer gene. In an old person, there are thousands, tens of thousands or hundreds of thousands of knocked-out cells. The chance that any one would form a cancer is very low.

When the damage occurs in any area of changed cells, something different occurs. Each of the cells has the potential for growth. The changed cells will divide quicker when the area is damaged by physical, chemical, or viral agents. A vicious circle has been set up: Damaging the area will cause the changed cells to divide, causing a greater likelihood that they will suffer knock-outs.

This model of carcinogenesis is popular because it explains why cancers grow. It would be expected that cells that are damaged through radiation would die or at least be worse off because they have fewer genes working; viruses increase the number of genes working.

One concern is that we may end up with thousands of vaccines to prevent every virus that can change our cells. Viruses can have different effects on different parts of the body. It may be possible to prevent a number of different cancers by immunizing against one viral agent. It is likely that HPV, for instance, has a role in cancers of the mucous membranes of the mouth.


It is impossible to determine 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. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or 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.

Cancer stem cells

A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control[5]. Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells. The cancer stem cell hypothesis does not contradict earlier concepts of carcinogenesis.

Clonal evolution

While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment.[6] Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment.[7] Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution.[8] Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertarial and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulative group dynamics. OMG GIVE ME SOME EXAMPLES OF CARCINOGENS...

Non-mainstream theories

There are a number of theories of carcinogenesis and cancer treatment that fall outside the mainstream of scientific opinion, due to lack of scientific rationale, logic, or evidence base. These theories may be used to justify various alternative cancer treatments. They should be distinguished from those theories of carcinogenesis that have a logical basis within mainstream cancer biology, and from which conventionally-testable hypotheses can be made.

See also


  1. ^ Fearon ER, Vogelstein B (June 1990). "A genetic model for colorectal tumorigenesis". Cell 61 (5): 759–67. doi:10.1016/0092-8674(90)90186-I. PMID 2188735.  
  2. ^ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (April 2008). "The role of ATF-2 in oncogenesis". BioEssays 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191.  
  3. ^ Knudson AG (November 2001). "Two genetic hits (more or less) to cancer". Nature Reviews. Cancer 1 (2): 157–62. doi:10.1038/35101031. PMID 11905807.  
  4. ^ Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A (June 2007). "Viral infections as a cause of cancer (review)". Int. J. Oncol. 30 (6): 1521–8. PMID 17487374.  
  5. ^ Dalerba, P., R. W. Cho, and M. F. Clarke. 2007 Cancer stem cells: models and concepts. Annu. Rev. Med. 58:267-284
  6. ^ Nowell PC (October 1976). "The clonal evolution of tumor cell populations". Science (New York, N.Y.) 194 (4260): 23–8. doi:10.1126/science.959840. PMID 959840.  
  7. ^ Zhang W, Hanks AN, Boucher K et al. (January 2005). "UVB-induced apoptosis drives clonal expansion during skin tumor development". Carcinogenesis 26 (1): 249–57. doi:10.1093/carcin/bgh300. PMID 15498793.  
  8. ^ Merlo LM, Pepper JW, Reid BJ, Maley CC (December 2006). "Cancer as an evolutionary and ecological process". Nature Reviews. Cancer 6 (12): 924–35. doi:10.1038/nrc2013. PMID 17109012.  

Further reading

  • Dixon K, Kopras E (2004). "Genetic alterations and DNA repair in human carcinogenesis.". Semin Cancer Biol 14 (6): 441–8. doi:10.1016/j.semcancer.2004.06.007. PMID 15489137.  
  • Kleinsmith, Lewis J (2006). Principles of cancer biology. San Francisco: Pearson Benjamin Cummings. ISBN 978-0-8053-4003-7.  
  • Sarasin A (2003). "An overview of the mechanisms of mutagenesis and carcinogenesis.". Mutat Res 544 (2-3): 99–106. doi:10.1016/j.mrrev.2003.06.024. 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. doi:10.1146/annurev.publhealth.26.021304.144402. PMID 15760280.  
  • Tannock, Ian; Hill, Richard; Bristow, Robert; Harrington, Lea (2005). The basic science of oncology (4th ed.). New York: McGraw-Hill. ISBN 978-0-07-138774-3.  
  • Wicha MS, Liu S, Dontu G (2006). "Cancer stem cells: an old idea--a paradigm shift.". Cancer Res 66 (4): 1883–90. doi:10.1158/0008-5472.CAN-05-3153. PMID 16488983.  

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