In a cell with normal control regulation (non-cancerous), genes produce proteins that provide regulated cell division. Cancer is the disease caused by cells that have lost their ability to control their regulation. The abnormal proteins allowing the non-regulated cancerous state are produced by genes known as oncogenes. The normal gene from which the oncogene evolved is called a protooncogene.
The word oncogene comes from the Greek term oncos, which means tumor. Oncogenes were originally discovered in certain types of animal viruses that were capable of inducing tumors in the animals they infected. These viral oncogenes, called v-onc, were later found in human tumors, although most human cancers do not appear to be caused by viruses. Since their original discovery, hundreds of oncogenes have been found, but only a small number of them are known to affect humans. Although different oncogenes have different functions, they are all somehow involved in the process of transformation (change) of normal cells to cancerous cells.
The transformation of normal cells into cancerous cells
The process by which normal cells are transformed into cancerous cells is a complex, multi-step process involving a breakdown in the normal cell cycle. Normally, a somatic cell goes through a growth cycle in which it produces new cells. The two main stages of this cycle are interphase (genetic material in the cell duplicates) and mitosis (the cell divides to produce two other identical cells). The process of cell division is necessary for the growth of tissues and organs of the body and for the replacement of damaged cells. Normal cells have a limited life span and only go through the cell cycle a limited number of times.
Different cell types are produced by the regulation of which genes in a given cell are allowed to be expressed. One way cancer is caused, is by de-regulation of those genes related to control of the cell cycle; the development of oncogenes. If the oncogene is present in a skin cell, the patient will have skin cancer; in a breast cell, breast cancer will result, and so on.
Cells that loose control of their cell cycle and replicate out of control are called cancer cells. Cancer cells undergo many cell divisions often at a quicker rate than normal cells and do not have a limited life span. This allows them to eventually overwhelm the body with a large number of abnormal cells and eventually affect the functioning of the normal cells.
A cell becomes cancerous only after changes occur in a number of genes that are involved in the regulation of its cell cycle. A change in a regulatory gene can cause it to stop producing a normal regulatory protein or can produce an abnormal protein which does not regulate the cell in a normal manner. When changes occur in one regulatory gene this often causes changes in other regulatory genes. Cancers in different types of cells can be caused by changes in different types of regulatory genes.
Proto-oncogenes and tumor-suppressor genes are the two most common genes involved in regulating the cell cycle. Proto-oncogenes and tumor-suppressor genes have different functions in the cell cycle. Tumor-suppressor genes produce proteins that are involved in prevention of uncontrolled cell growth and division. Since two of each type of gene are inherited two of each type of tumor-suppressor gene are inherited. Both tumor suppressor genes of a pair need to be changed in order for the protein produced to stop functioning as a tumor suppressor. Mutated tumor-suppressor genes therefore act in an autosomal recessive manner.
Proto-oncogenes produce proteins that are largely involved in stimulating the growth and division of cells in a controlled manner. Each proto-oncogene produces a different protein that has a unique role in regulating the cell cycles of particular types of cells. We inherit two of each type of proto-oncogene. A change in only one protooncogene of a pair converts it into an oncogene. The
Classes of proto-oncogene
There are five major classes of proto-oncogene/oncogenes: (1) growth factors, (2) growth factor receptors, (3) signal transducers (4) transcription factors, and (5) programmed cell death regulators.
GROWTH FACTORS Some proto-oncogenes produce proteins, called growth factors, which indirectly stimulate growth of the cell by activating receptors on the surface of the cell. Different growth factors activate different receptors, found on different cells of the body. Mutations in growth factor proto-oncogene result in oncogenes that promote uncontrolled growth in cells for which they have a receptor. For example, platelet-derived growth factor (PDGF) is a proto-oncogene that helps to promote wound healing by stimulating the growth of cells around a wound. PDGF can be mutated into an oncogene called vsis (PDGFB) which is often present in connective-tissue tumors.
GROWTH FACTOR RECEPTORS Growth factor receptors are found on the surface of cells and are activated by growth factors. Growth factors send signals to the center of the cell (nucleus) and stimulate cells that are at rest to enter the cell cycle. Different cells have different growth factors receptors. Mutations in a proto-oncogene that are growth factor receptors can result in oncogenes that produce receptors that do not require growth factors to stimulate cell growth. Overstimulation of cells to enter the cell cycle can result and promote uncontrolled cell growth. Most proto-oncogene growth factor receptors are called tyrosine kinases and are very involved in controlling cell shape and growth. One example of a tyrosine kinase is called GDFNR. The RET (rearranged during transfection) oncogene is a mutated form of GDFNR and is commonly found in cancerous thyroid cells.
SIGNAL TRANSDUCERS Signal transducers are proteins that relay cell cycle stimulation signals, from growth factor receptors to proteins in the nucleus of the cell. The transfer of signals to the nucleus is a stepwise process that involves a large number of proto-oncogenes and is often called the signal transduction cascade. Mutations in proto-oncogene involved in this cascade can cause unregulated activity, which can result in abnormal cell proliferation. Signal transducer oncogenes are the largest class of oncogenes. The RAS family is a group of 50 related signal transducer oncogenes that are found in approximately 20% of tumors.
TRANSCRIPTION FACTORS Transcription factors are proteins found in the nucleus of the cell which ultimately receive the signals from the growth factor receptors. Transcription factors directly control the expression of genes that are involved in the growth and proliferation of cells. Transcription factors produced by oncogenes typically do not require growth factor receptor stimulation and thus can result in uncontrolled cell proliferation. Transcription factor proto-oncogenes are often changed into oncogenes by chromosomal translocations in leukemias, lymphomas, and solid tumors. C-myc is a common transcription factor oncogene that results from a chromosomal translocation and is often found in leukemias and lymphomas.
PROGRAMMED CELL DEATH REGULATORS Normal cells have a predetermined life span and different genes regulate their growth and death. Cells that have been damaged or have an abnormal cell cycle may develop into cancer cells. Usually these cells are destroyed through a process called programmed cell death (apoptosis). Cells that have developed into cancer cells, however, do not undergo apoptosis. Mutated proto-oncogenes may inhibit the death of abnormal cells, which can lead to the formation and spread of cancer. The bcl-2 oncogene, for example, inhibits cell death in cancerous cells of the immune system.
Mechanisms of transformation of proto-oncogene into oncogenes
It is not known in most cases what triggers a particular proto-oncogene to change into an oncogene. There appear to be environmental triggers such as exposure to toxic chemicals. There also appear to be genetic triggers since changes in other genes in a particular cell can trigger changes in proto-oncogenes.
The mechanisms through which proto-oncogenes are changed into oncogenes are, however, better understood. Proto-oncogenes are transformed into oncogenes through: 1) mutation 2) chromosomal translocation, and 3) gene amplification.
A tiny change, called a mutation, in a proto-oncogene can convert it into an oncogene. The mutation results in an oncogene that produces a protein with an abnormal structure. These mutations often make the protein resistant to regulation and cause uncontrolled and continuous activity of the protein. The RAS family of oncogenes, found in approximately 20% of tumors, are examples of oncogenes caused by mutations.
Chromosomal translocations, which result from errors in mitosis, have also been implicated in the transformation of proto-oncogenes into oncogenes. Chromosomal translocations result in the transfer of a
In other cases, the translocation results in the fusion of a proto-oncogene with another gene. The resulting oncogene produces an unregulated protein that is involved in stimulating uncontrolled cell proliferation. The first discovered fusion oncogene resulted from a Philadelphia chromosome translocation. This type of translocation is found in the leukemia cells of greater than 95% of patients with a chronic form of leukemia. The Philadelphia chromosome translocation results in the fusion of the c-abl proto-oncogene, normally found on chromosome 9 to the bcr gene found on chromosome 22. The fused gene produces an unregulated transcription factor protein that has a different structure than the normal protein. It is not
Some oncogenes result when multiple copies of a proto-oncogene are created (gene amplification). Gene amplification often results in hundreds of copies of a gene, which results in increased production of proteins and increased cell growth. Multiple copies of proto-oncogenes are found in many tumors. Sometimes amplified genes form separate chromosomes called double minute chromosomes and sometimes they are found within normal chromosomes.
In most cases, oncogenes result from changes in proto-oncogenes in select somatic cells and are not passed on to future generations. People with an inherited oncogene, however, do exist. They possess one changed proto-oncogene (oncogene) and one unchanged protooncogene in all of their somatic cells. The somatic cells have two of each chromosome and therefore two of each gene since one of each type of chromosome is inherited from the mother in the egg cell and one of each is inherited from the father in the sperm cell. The egg and sperm cells have undergone a number of divisions in their cell cycle and therefore only contain one of each type of chromosome and one of each type of gene. A person with an inherited oncogene has a changed proto-oncogene in approximately 50% of their egg or sperm cells and an unchanged proto-oncogene in the other 50% of their egg or sperm cells and therefore has a 50% chance of passing this oncogene on to their children.
A person only has to inherit a change in one protooncogene of a pair to have an increased risk of cancer. This is called autosomal dominant inheritance. Not all people with an inherited oncogene develop cancer, since mutations in other genes that regulate the cell cycle need to occur in a cell for it to be transformed into a cancerous cell. The presence of an oncogene in a cell does, however, make it more likely that changes will occur in other regulatory genes. The degree of cancer risk depends on the type of oncogene inherited as well as other genetic factors and environmental exposures. The type of cancers that are likely to develop depend on the type of oncogene that has been inherited.
Multiple endocrine neoplasia type II (MENII) is one example of a condition caused by an inherited oncogene. People with MENII have usually inherited the RET oncogene. They have approximately a 70% chance of developing thyroid cancer, a 50% chance of developing a tumor of the adrenal glands (pheochromocytoma) and about a 5-10% chance of developing symptomatic parathyroid disease.
Oncogenes as targets for cancer treatment
The discovery of oncogenes approximately 20 years ago has played an important role in developing an understanding of cancer. Oncogenes promise to play an even greater role in the development of improved cancer therapies since oncogenes may be important targets for drugs that are used for the treatment of cancer. The goal of these therapies is to selectively destroy cancer cells while leaving normal cells intact. Many anti-cancer therapies currently under development are designed to interfere with oncogenic signal transducer proteins, which relay the signals involved in triggering the abnormal growth of tumor cells. Other therapies hope to trigger specific oncogenes to cause programmed cell death in cancer cells. Whatever the mechanism by which they operate, it is hoped that these experimental therapies will offer a great improvement over current cancer treatments.
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Lisa Maria Andres, MS, CGC