Carcinogenesis
From Wikipedia, the free encyclopedia
Carcinogenesis (meaning literally, the creation of cancer) is the process by which normal cells are transformed into cancer cells.
Contents |
[edit] 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.
[edit] 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.
[edit] Mechanisms of carcinogenesis
Cancer is, ultimately, a disease of genes. In order for cells to start dividing uncontrollably, genes which regulate cell growth must be damaged. Proto-oncogenes are genes which promote cell growth and mitosis, a process of cell division, and tumor suppressor genes discourage cell growth, or temporarily halts cell division from occurring in order to carry out DNA repair. Typically, a series of several mutations to these genes are required before a normal cell transforms into a cancer cell.
[edit] Proto-oncogenes
Proto-oncogenes, promote cell growth through a variety of ways. Many can produce hormones, a "chemical messenger" between cells which 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.
[edit] Tumor suppressor genes
Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally 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 which 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 passed on to daughter cells. Canonical tumor suppressors include the p53 gene, which is a transcription factor activated by many cellular stress including hypoxia and ultraviolet radiation damage.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.
[edit] 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, which was first hypothesised by the Knudson hypothesis. 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 increase as one gets older, because DNA damage forms a feedback loop.
Usually, oncogenes are dominant, as they contain gain-of-function mutations mutations, while mutated tumor suppressors are recessive, 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 need to 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, and this is 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 suppressers act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype. For instance, individuals who are heterozygous for p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rb mutations develop retinoblastoma. Similarly, mutations in the adenomatous polyposis coli gene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.
[edit] Role of genetic damage
Cancer is ultimately due to accumulation of genetic damage, which are fundamentally mutations in the DNA. Substances that cause these mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances 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.
[edit] 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, increasingly 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.
[edit] 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, as viruses only responsible for 15% of human cancers. 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.
[edit] Etiology
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. 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.
[edit] Cancer stem cells
A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell paradigm proposes that some or all cancers arise from transformation of adult stem cells. These cells persist as a subcomponent of the tumor and retain key stem cell properties. 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. It simply points to adult stem cells as the site where the process begins.
[edit] Non-mainstream theories
There are a number of theories of carcinogenesis and cancer treatment which 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 which have a logical basis within mainstream cancer biology, and from which conventionally testable hypotheses can be made.
[edit] References
- Knudson AG (2001). "Two genetic hits (more or less) to cancer". Nat Rev Cancer 1 (2): 157-62. PMID 11905807.
- Fearon ER, Vogelstein B (1990). "A genetic model for colorectal tumorigenesis". Cell 61 (5): 759-67. PMID 2188735.
- 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.
- Wicha MS, Liu S, Dontu G (2006). "Cancer stem cells: an old idea--a paradigm shift.". Cancer Res 66: 1883-90. PMID 16488983.
- The Basic Science of Oncology. Tannock IF, Hill RP et al (eds) 4th ed.2005 McGraw-Hill.
- Principles of Cancer Biology. Kleinsmith, LJ (2006). Pearson Benjamin Cummings.
