Carcinogenesis

Image:Cancer requires multiple mutations from NIH.png Carcinogenesis (meaning literally, the creation of cancer) is the process by which normal cellsare transformed into cancer cells.

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. Mutationsin DNAthat lead to cancer disrupt these orderly processes by disrupting the programming regulating the processes.

Carcinogenesis is caused by this mutation of the geneticmaterialof normal cells, which upsets the normal balance between proliferation and cell death. This results in uncontrolled cell divisionand tumorformation. The uncontrolled and often rapid proliferation of cells can lead to benigntumors; some types of these may turn into malignanttumors (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 mutationis 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 repairwill 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 inhibitionis 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 metalloproteinasesthat can digest extracellular matrixmaterial.
• 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 selectiveadvantage 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 benigntumors. However, when enough mutations accumulate, the mutant cells will become a malignanttumor.

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-oncogenesare genes which promote cell growth and mitosis, a process of cell division, and tumor suppressor genesdiscourage cell growth, or temporarily halts cell division from occurring in order to carry out DNA repair. Typically, a series of several mutationsto these genes are required before a normal cell transforms into a cancer cell.

Proto-oncogenes

Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, a "chemical messenger" between cells which encourage mitosis, the effect of which depends on the signal transductionof the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptorsin cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcriptionof DNA in protein synthesis, which create the proteinsand enzymesis responsible for producing the products and biochemicalscells use and interact with.

Mutations in proto-oncogenes will modify their function. If their function is modified so that they become overexpressedand thus produce more proteins of which they are coded for, thus becoming overactive. When this happens, they become oncogenes, and thus cells have a higher chance to divide excessively and uncontrollably. Frustratingly, the chance of cancer cannot be reduced by removing proto-oncogenes from the genomeas they are critical for growth, repair and homeostasisof the body. It is only when they become mutated, that the signals for growth become excessive.

Tumor suppressor genes

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally tumor suppressors are transcription factorsthat are activated by cellular stressor 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 p53gene, which is a transcription factor activated by many cellular stress including hypoxiaand ultraviolet radiationdamage.

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.

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 hypothesisedby 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 feedbackloop.

Usually, oncogenes are dominant, as they contain gain of function 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 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 offspringcan 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 heterozygousfor p53 mutations are often victims of Li-Fraumeni syndrome, and those who are heterozygous for Rbmutations develop retinoblastoma. Similarly, mutations in the adenomatous polyposis coligene are linked to adenopolyposis colon cancer, with thousands of polyps in colon while young, while mutations in BRCA1and BRCA2lead to early onset of breast cancer.

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 smokingis associated with lung cancer. Prolonged exposure to radiation, particularly ultraviolet radiationfrom the sun, leads to melanomaand other skin malignancies. Breathing asbestosfibers is associated with mesothelioma. In more general terms, chemicals called mutagensand free radicalsare known to cause mutations. Other types of mutations can be caused by chronic inflammation, as neutrophil granulocytessecrete free radicals that damage DNA. Chromosomal translocations, such as the Philadelphia chromosome, are a special type of mutation that involve exchanges between different chromosomes.

Non-mutagenic carcinogens

Many mutagensare also carcinogens, but some carcinogens are not mutagens. Examples of carcinogens that are not mutagens include alcoholand 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 aneuploidyand may lead to cancer.

Role of viral infections

Furthermore, many cancers originate from a viralinfection; 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 a 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 promoteror 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.

Etiology

It is impossible to tell the initial cause for any specific cancer. However, with the help of molecular biologicaltechniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosisbased 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 apoptosisor programmed cell deathwhen damaged by therapy. Telomerasemutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vesselsto provide more nutrients, or to metastasize, spreading to other parts of the body.

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.

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See also

• Cancer
• Cancer research
• Carcinogen
• Mutagen
• Oncogene
• Tumor suppressor gene

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Carcinogenesis Wikipedia article Carcinogenesis.