Deleted in Colorectal Cancer
Encyclopedia
Deleted in Colorectal Carcinoma, also known as DCC, is a protein
which in humans is encoded by the DCC gene
. DCC has long been implicated in colorectal cancer
. While the official, full name of this gene is Deleted in Colorectal Carcinoma, it is almost universally called Deleted in Colorectal Cancer. The protein product of DCC is a single transmembrane receptor also known as DCC, and it has the same interchangeable name.
Since it was first discovered in a colorectal cancer study in 1990, DCC has been the focus of a significant amount of research. DCC held a controversial place as a tumour suppressor gene for many years, and is well known as an axon guidance
receptor that responds to netrin-1.
More recently DCC has been characterized as a dependence receptor, and theories have been put forward that have revived interest in DCCs candidacy as a tumour suppressor gene, as it may be a ligand-dependent suppressor that is frequently epigenetically silenced.
Soon after the protein product was confirmed, DCC knockout mice were created. As DCC-/- mutations are rapidly fatal due to a lack of nervous system development, DCC+/- mice were assessed for increased tumour development over two years, and no increase in tumour predisposition was detected.
The discovery of a specific function for DCC that seemed to have little to do with cell cycle control, the low somatic mutation rate and the absence of cancer predisposition in DCC heterozygotes were fairly discouraging evidence for DCC's putative tumour suppressor status. This caused focus to shift to DCC's role in axon guidance for a time, until one study implicated DCC in regulation of cell death. As the 18q chromosomal deletions were never resolved to be related solely to another gene, DCC was rapidly reaccepted as a candidate. Recent research into the mechanisms of DCC signaling and in-vitro studies of DCC modifications have solidified DCC's tumour suppressor position, and have begun to integrate DCCs divergent functions as both an axon guidance molecule and a tumour suppressor into a single concept.
DCC has extracellular binding sites for both netrin-1 and heparin
. Heparin sulphate is believed to also be present during neural growth as a type of co-factor for axon guidance
. Intracellularly, DCC has been shown to have a caspase-3 proteolysis site at Asp 1290.
DCC and neogenin, two of the netrin-1 receptors, have recently been shown to have sites for tyrosine phosphorylation (at Y1420 on DCC) and are likely interacting with Src family kinases
in regulating responses to netrin-1.
, and are relatively inactive when no ligand is present. A number of receptors have been found that do not fit into this conceptual mould, and DCC is one of them. These receptors are active both with ligand bound and unbound, but the signals transmitted are different when the receptors are ligand bound. Collectively, this type of receptor is known as a dependence receptor because the unbound pathway is usually apoptotic, meaning that cell survival depends on ligand presence. Other receptors also show this functional profile, including p75NTR, the androgen receptor
, RET
, several integrins and Patched
.
While not the first dependence receptor pair discovered, DCC and netrin-1 are an often quoted example of a dependence receptor system. When DCC is present on the membrane and bound to netrin-1, signals are conveyed that can lead to proliferation
and cell migration
. In the absence of netrin-1, DCC signaling has been shown to induce apoptosis
. Only in the absence of the DCC receptor is there an absence of downstream signaling. There are therefore three possible signaling states for dependence receptors: on (ligand-bound, migration and proliferation), off (ligand-unbound, apoptosis inducing) and absent (lack of signal).
. A gradient of netrin-1 is produced from the floor plate, which allows orientation of the extending axons, aiding the development of the dorsal-ventral axis of the brain and spinal column. A variety of receptors are present on the axon surface which either repel or attract axons to the midline. When membrane DCC is stimulated by netrin-1, it promotes axon progression towards the midline.
There are several other molecules also involved in the guidance of axons to and across the midline. The slit proteins have repulsive functions, as opposed to netrins, and are mediated by the transmembrane protein Robo. Axonal growth cones that are attracted to the midline by netrin/DCC signaling eventually cross the floor plate. When this occurs they lose responsiveness to netrin and become repulsed by slit/Robo signaling. This is accomplished by the formation of a DCC-Robo complex, which inhibits attractive netrin/DCC signals while allowing slit/Robo signals. Netrin also has other receptors, the UNC5 family. The UNC5 receptors have repellant migratory responses to netrin binding, and have similar effects to the slit/Robo system.
The intracellular signaling responses to netrin-1 are not yet well understood, even in neurobiology studies. Several phosphorylation events have been established, as have the involvement of several src family kinases and small GTPases, but the sequence of events has not yet been determined. DCC is also required to be recruited to lipid rafts for axon outgrowth and apoptotic signaling.
DCC is developmentally regulated, being present in most fetal tissues of the body at higher levels than what is found in adult tissues. DCC and netrin have been found to be specifically involved in the secondary migration of neural crest cells into the pancreas and developing gut structures, and may prove to be vital to other areas during fetal growth.
(LOH) of DCC in region 18q21.
DCC in a receptor for netrin-1 and is currently believed by some to be a conditional tumour suppressor gene, meaning that it normally prevents cell growth when in the absence of netrin-1. DCC elimination is not believed to be a key genetic change in tumour formation, but one of many alterations that can promote existing tumour growth. DCC's possible role in migration of cancerous cells is in the process of being characterized.
While recent results make it fairly likely that DCC is involved in the biology of several cancers, the extent of its involvement and the details of how it works are still being studied.
, and induces apoptosis in a caspase-9
-dependent pathway. This domain does not correspond to a known caspase recruitment motif or death sequence domain, but is required to initiate apoptosis. It has been theorized that the domain acts as a scaffold to recruit and activate caspase-9 and caspase-3. This DCC apoptosis pathway is not dependent on either the mitochondrial apoptosis pathway or the death receptor/caspase-8 pathway. In the absence of ligand, DCC interacts with caspase-9 (likely via an unidentified adaptor protein) and promotes the assembly of a caspase-activating complex. This causes the activation of caspase-3 through caspase-9, and initiates apoptosis without the formation of an apoptosome
or cytochrome c
release. This implies that DCC regulates a novel pathway for caspase activation, and that it is one that is apoptosome-independent.
To put this into a biological systems context, some physiology is required. In the gastrointestinal tract, epithelial cells proliferate and die rapidly. The division of these cells occurs at the base of villi, and cells are pushed upwards by subsequent divisions to the tip where they enter apoptosis and shed off into the lumen. Netrin-1 is produced in the base of the villi, so a gradient of netrin is present that is weakest at the tip. In normal physiology, the presence of netrin-1 inhibits DCC-mediated cell death until the epithelial cell reaches the tip of the villus, where the now unbound DCC causes the cell to enter apoptosis. In a cancer state, the absence of DCC prevents the gradient from having an effect on the cell, making it more likely to continue to survive.
DCC's role as a tumour suppressor is tied to its dependence receptor characteristics. DCC induces cell death on epithelial cells when no netrin-1 is bound. Besides from loss of heterozygosity
of DCC, this mechanism of apoptosis can also be avoided in malignant processes by overexpression of netrin-1.
. When DCC is present and not activated by netrin it is proapoptotic, and represses tumour formation. When DCC is present and netrin-activated it promotes cell survival, acting as an oncoprotein. Netrin-activated DCC is known to activate the CDC42
-RAC1
and MAPK1
/3 pathways, both of which are activated in cancer and promote tumour development.
pathway, which is characterized by increases or decreases in the number of tandem repeats of simple DNA sequences. This type of instability is associated with some specific mutations, including genes involved with DNA mismatch repair
and surprisingly, transforming growth factor-beta. More recently, those in the field of colorectal cancer have acknowledged that cancer formation is far more complex, but cancer related genes still tend to be categorized as chromosomal or microsatellite instability genes.
DCC would fall into the chromosomal instability category. The chromosomal region of 18q has shown consistent LOH for nearly twenty years. Approximately 70% of primary colorectal cancers display LOH in this region, and the percentage increases when comparing early to advanced cancers. This increase in DCC loss in advanced cancer may indicate that DCC loss is more important to tumour progression than tumour formation. However, region 18q is not the location of DCC alone, and many studies are in conflict when reporting whether 18q LOH is attributable to DCC or other tumour suppressor candidates in the neighbouring areas. Many reviews refuse to comment on DCC due to its history of conflicting information, stating that more study is required.
Chromosome 18 LOH tends to occur in clusters. One major cluster is at 18q21, which agrees with the location of DCC. This cluster includes the marker D18S51, and is flanked by the D18S1109 and D18S68 loci. This segment spans 7.64cM, which is a relatively large section of DNA that could easily encompass more than one tumour suppressor gene.
A significant difference between DCC expression and 18q21 LOH was detected in 1997. Studies found that more tumours had reduced DCC expression than could be explained by LOH or MSI, indicating that another mechanism was at work. This observation was likely explained when epigenetic analysis was performed.
Epigenetic silencing of DCC by promoter hypermethylation has shown to be a significant factor in other cancer types. In head and neck squamous cell carcinoma, 77.3% of tumour samples presented DCC promoter hypermethylation versus 0.8% in non-cancerous saliva samples. Similar results have been seen in breast cancer, acute lymphoblastic leukemia, and several others.
A recent review of over two dozen 18q LOH-survival studies concluded that there was a significant amount of inconsistency between the data sets. They concluded that loss of 18q remains a marker for poor prognosis, and that DCC status has the potential to define a group of patients who may benefit from specific treatment regimes.
DCC is expressed at very low levels through most of the body but at higher levels in many areas of the brain, particularly in dopamine neurons. Recently it has been shown that a sensitizing treatment regimen of amphetamines causes markedly increased levels of DCC and UNC-5 expression on neuron cell bodies. This may indicate that netrin-1 receptors are involved in the lasting effects of exposure to stimulant drugs like amphetamine, and may have some therapeutic value in the field of drug tolerance.
with PTK2
, APPL1
, MAZ
, Caspase 3
, NTN1
and Androgen receptor
.
When the genetic abnormalities that occur in advanced colorectal cancer were first identified, one of the most frequent events was found to be loss of heterozygosity (LOH) of region 18q21. One of the first genes sequenced in this region was DCC, and it was subsequently analyzed for tumour suppressor activity. However, the lack of somatic DCC mutations made it seem likely that the nearby SMAD2 and SMAD4 genes were the reason for 18q21 LOH. The fact that DCC heterozygotes had no increased rates of cancer, even when crossed with mice carrying Apc
mutations, solidified this viewpoint. The finding that DCC was a receptor for netrin-1 involved in axon guidance initially moved research away from DCC in cancer. It was later realized that DCC may be involved in directing cell motility, which has direct implications for metastatic cancer.
The first direct evidence for DCC as a tumour suppressor gene was published in 1995. Researchers found that addition of DCC to an immortalized cell line suppressed tumorigenicity rather definitively. However no mechanism for this suppression was obvious, and it took several years to propose one.
Nearly ten years after DCC was discovered, studies were published that showed that DCC was involved in apoptosis. Instead of studying loss of DCC as was commonly done, the authors looked at human embryonic kidney cells transfected with DCC. They found an increase in apoptosis that corresponded to DCC expression, which was completely eliminated when netrin-1 was co-transfected or simply added to the media.
When it was understood that DCC apoptosis may also be overcome by netrin-1 overexpression, colorectal cancers were assessed for netrin-1 overexpression, and a small but significant percent of these cancers were found to vastly overexpress the molecule.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the DCC gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. DCC has long been implicated in colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. While the official, full name of this gene is Deleted in Colorectal Carcinoma, it is almost universally called Deleted in Colorectal Cancer. The protein product of DCC is a single transmembrane receptor also known as DCC, and it has the same interchangeable name.
Since it was first discovered in a colorectal cancer study in 1990, DCC has been the focus of a significant amount of research. DCC held a controversial place as a tumour suppressor gene for many years, and is well known as an axon guidance
Axon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...
receptor that responds to netrin-1.
More recently DCC has been characterized as a dependence receptor, and theories have been put forward that have revived interest in DCCs candidacy as a tumour suppressor gene, as it may be a ligand-dependent suppressor that is frequently epigenetically silenced.
Background
Early studies of colorectal tumours found that allelic deletions of segments of chromosome 18q occur in a very high percentage of colorectal cancers. DCC was initially cloned out of the region and put forth as a putative tumour suppressor gene, though nothing was known about its function at the time. The DCC gene was examined for the genetic changes found with most other tumour suppressor genes, but it was found to have a comparatively low frequency of somatic mutation. Several years later DCC was shown to encode a transmembrane receptor protein that mediated the effects of netrin-1 on axon outgrowth.Soon after the protein product was confirmed, DCC knockout mice were created. As DCC-/- mutations are rapidly fatal due to a lack of nervous system development, DCC+/- mice were assessed for increased tumour development over two years, and no increase in tumour predisposition was detected.
The discovery of a specific function for DCC that seemed to have little to do with cell cycle control, the low somatic mutation rate and the absence of cancer predisposition in DCC heterozygotes were fairly discouraging evidence for DCC's putative tumour suppressor status. This caused focus to shift to DCC's role in axon guidance for a time, until one study implicated DCC in regulation of cell death. As the 18q chromosomal deletions were never resolved to be related solely to another gene, DCC was rapidly reaccepted as a candidate. Recent research into the mechanisms of DCC signaling and in-vitro studies of DCC modifications have solidified DCC's tumour suppressor position, and have begun to integrate DCCs divergent functions as both an axon guidance molecule and a tumour suppressor into a single concept.
Structure
The DCC gene is located at 18q21.3, and has a total of 57 possible exons and 43 possible introns. This theoretically results in 13 correctly sliced, putatively good proteins. The typical DCC protein has one signal peptide motif and eleven domains, including multiple immunoglobulin-like domains, a transmembrane domain, and several fibronectin type 3 domains.DCC has extracellular binding sites for both netrin-1 and heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
. Heparin sulphate is believed to also be present during neural growth as a type of co-factor for axon guidance
Axon guidance
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach the correct targets...
. Intracellularly, DCC has been shown to have a caspase-3 proteolysis site at Asp 1290.
DCC and neogenin, two of the netrin-1 receptors, have recently been shown to have sites for tyrosine phosphorylation (at Y1420 on DCC) and are likely interacting with Src family kinases
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
in regulating responses to netrin-1.
DCC as a dependence receptor
Historically, cellular receptors have been thought to be activated when bound to their ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, and are relatively inactive when no ligand is present. A number of receptors have been found that do not fit into this conceptual mould, and DCC is one of them. These receptors are active both with ligand bound and unbound, but the signals transmitted are different when the receptors are ligand bound. Collectively, this type of receptor is known as a dependence receptor because the unbound pathway is usually apoptotic, meaning that cell survival depends on ligand presence. Other receptors also show this functional profile, including p75NTR, the androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
, RET
RET
- People :* Ret Chol , Southern Sudanese politician from Nasir County of the Upper Nile state- Engineering and computer science :* Remote Electrical Tilt * Renewable energy target* Renewable energy Technology...
, several integrins and Patched
Patched
Patched is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. The original mutations in the ptc gene were discovered in the fruit fly Drosophila melanogaster by 1995 Nobel Laureates Eric F...
.
While not the first dependence receptor pair discovered, DCC and netrin-1 are an often quoted example of a dependence receptor system. When DCC is present on the membrane and bound to netrin-1, signals are conveyed that can lead to proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
and cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
. In the absence of netrin-1, DCC signaling has been shown to induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Only in the absence of the DCC receptor is there an absence of downstream signaling. There are therefore three possible signaling states for dependence receptors: on (ligand-bound, migration and proliferation), off (ligand-unbound, apoptosis inducing) and absent (lack of signal).
Developmental and neurological roles
DCC's role in commissural axon outgrowth is perhaps its best characterized. In the developing spinal cord, commissural neurons located dorsally extend axons ventrally using a mechanism dependent on a ventral midline structure, the floor plateFloor plate
The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions...
. A gradient of netrin-1 is produced from the floor plate, which allows orientation of the extending axons, aiding the development of the dorsal-ventral axis of the brain and spinal column. A variety of receptors are present on the axon surface which either repel or attract axons to the midline. When membrane DCC is stimulated by netrin-1, it promotes axon progression towards the midline.
There are several other molecules also involved in the guidance of axons to and across the midline. The slit proteins have repulsive functions, as opposed to netrins, and are mediated by the transmembrane protein Robo. Axonal growth cones that are attracted to the midline by netrin/DCC signaling eventually cross the floor plate. When this occurs they lose responsiveness to netrin and become repulsed by slit/Robo signaling. This is accomplished by the formation of a DCC-Robo complex, which inhibits attractive netrin/DCC signals while allowing slit/Robo signals. Netrin also has other receptors, the UNC5 family. The UNC5 receptors have repellant migratory responses to netrin binding, and have similar effects to the slit/Robo system.
The intracellular signaling responses to netrin-1 are not yet well understood, even in neurobiology studies. Several phosphorylation events have been established, as have the involvement of several src family kinases and small GTPases, but the sequence of events has not yet been determined. DCC is also required to be recruited to lipid rafts for axon outgrowth and apoptotic signaling.
DCC is developmentally regulated, being present in most fetal tissues of the body at higher levels than what is found in adult tissues. DCC and netrin have been found to be specifically involved in the secondary migration of neural crest cells into the pancreas and developing gut structures, and may prove to be vital to other areas during fetal growth.
Role in cancer
One of the most frequent genetic abnormalities that occur in advanced colorectal cancer is loss of heterozygosityLoss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
(LOH) of DCC in region 18q21.
DCC in a receptor for netrin-1 and is currently believed by some to be a conditional tumour suppressor gene, meaning that it normally prevents cell growth when in the absence of netrin-1. DCC elimination is not believed to be a key genetic change in tumour formation, but one of many alterations that can promote existing tumour growth. DCC's possible role in migration of cancerous cells is in the process of being characterized.
While recent results make it fairly likely that DCC is involved in the biology of several cancers, the extent of its involvement and the details of how it works are still being studied.
Normal function in tumour suppression and apoptosis
When not bound to netrin-1, an intracellular domain of DCC is cleaved by a caspaseCaspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
, and induces apoptosis in a caspase-9
Caspase-9
Caspase-9 is an initiator caspase, encoded by the CASP9 gene.CASP9 orthologs have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts....
-dependent pathway. This domain does not correspond to a known caspase recruitment motif or death sequence domain, but is required to initiate apoptosis. It has been theorized that the domain acts as a scaffold to recruit and activate caspase-9 and caspase-3. This DCC apoptosis pathway is not dependent on either the mitochondrial apoptosis pathway or the death receptor/caspase-8 pathway. In the absence of ligand, DCC interacts with caspase-9 (likely via an unidentified adaptor protein) and promotes the assembly of a caspase-activating complex. This causes the activation of caspase-3 through caspase-9, and initiates apoptosis without the formation of an apoptosome
Apoptosome
The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...
or cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
release. This implies that DCC regulates a novel pathway for caspase activation, and that it is one that is apoptosome-independent.
To put this into a biological systems context, some physiology is required. In the gastrointestinal tract, epithelial cells proliferate and die rapidly. The division of these cells occurs at the base of villi, and cells are pushed upwards by subsequent divisions to the tip where they enter apoptosis and shed off into the lumen. Netrin-1 is produced in the base of the villi, so a gradient of netrin is present that is weakest at the tip. In normal physiology, the presence of netrin-1 inhibits DCC-mediated cell death until the epithelial cell reaches the tip of the villus, where the now unbound DCC causes the cell to enter apoptosis. In a cancer state, the absence of DCC prevents the gradient from having an effect on the cell, making it more likely to continue to survive.
DCC's role as a tumour suppressor is tied to its dependence receptor characteristics. DCC induces cell death on epithelial cells when no netrin-1 is bound. Besides from loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
of DCC, this mechanism of apoptosis can also be avoided in malignant processes by overexpression of netrin-1.
Is DCC also an oncogene?
DCC can be considered a conditional tumour suppressor gene as well as a conditional oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. When DCC is present and not activated by netrin it is proapoptotic, and represses tumour formation. When DCC is present and netrin-activated it promotes cell survival, acting as an oncoprotein. Netrin-activated DCC is known to activate the CDC42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
-RAC1
RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
and MAPK1
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...
/3 pathways, both of which are activated in cancer and promote tumour development.
Mechanism of deletion
It was originally believed that there were two major pathways in colorectal cancer formation. The first was a chromosomal instability pathway thought to be responsible for the ademona to carcinoma progression, which was characterized by loss of heterozygosity (LOH) on chromosome 5q, 17p and 18q. The second pathway was believed to be the microsatellite instabilityMicrosatellite instability
Microsatellites are repeated sequences of DNA. Although the length of these microsatellites is highly variable from person to person, each individual has microsatellites of a set length. These repeated sequences are common, and normal...
pathway, which is characterized by increases or decreases in the number of tandem repeats of simple DNA sequences. This type of instability is associated with some specific mutations, including genes involved with DNA mismatch repair
DNA mismatch repair
DNA mismatch repair is a system for recognizing and repairing erroneous insertion, deletion and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage....
and surprisingly, transforming growth factor-beta. More recently, those in the field of colorectal cancer have acknowledged that cancer formation is far more complex, but cancer related genes still tend to be categorized as chromosomal or microsatellite instability genes.
DCC would fall into the chromosomal instability category. The chromosomal region of 18q has shown consistent LOH for nearly twenty years. Approximately 70% of primary colorectal cancers display LOH in this region, and the percentage increases when comparing early to advanced cancers. This increase in DCC loss in advanced cancer may indicate that DCC loss is more important to tumour progression than tumour formation. However, region 18q is not the location of DCC alone, and many studies are in conflict when reporting whether 18q LOH is attributable to DCC or other tumour suppressor candidates in the neighbouring areas. Many reviews refuse to comment on DCC due to its history of conflicting information, stating that more study is required.
Chromosome 18 LOH tends to occur in clusters. One major cluster is at 18q21, which agrees with the location of DCC. This cluster includes the marker D18S51, and is flanked by the D18S1109 and D18S68 loci. This segment spans 7.64cM, which is a relatively large section of DNA that could easily encompass more than one tumour suppressor gene.
A significant difference between DCC expression and 18q21 LOH was detected in 1997. Studies found that more tumours had reduced DCC expression than could be explained by LOH or MSI, indicating that another mechanism was at work. This observation was likely explained when epigenetic analysis was performed.
Epigenetics
Loss of DCC in colorectal cancer primarily occurs via chromosomal instability, with only a small percent having epigenetic silencing involved.Epigenetic silencing of DCC by promoter hypermethylation has shown to be a significant factor in other cancer types. In head and neck squamous cell carcinoma, 77.3% of tumour samples presented DCC promoter hypermethylation versus 0.8% in non-cancerous saliva samples. Similar results have been seen in breast cancer, acute lymphoblastic leukemia, and several others.
Use in pharmacogenetics
DCC has found to be a useful prognostic marker for late stage colorectal carcinoma in some studies, but unhelpful in others. Currently the American Society of Clinical Oncology does not recommend using DCC as a marker due to insufficient classification data.A recent review of over two dozen 18q LOH-survival studies concluded that there was a significant amount of inconsistency between the data sets. They concluded that loss of 18q remains a marker for poor prognosis, and that DCC status has the potential to define a group of patients who may benefit from specific treatment regimes.
Metastasis
The increase in loss of heterozygosity percentages of chromosome 18q21 have long suggested that DCC may be involved in the progression of benign adenomas to malignant carcinomas. DCC has recently been found to suppress metastasis in an experimental environment, but a mechanism for this has not yet been proposed.Pharmacology
At this junction, DCC is not a pharmaceutical target. As DCC is not overexpressed in cancer and is present throughout the body, so it is not considered a good target for most types of cancer drugs.DCC is expressed at very low levels through most of the body but at higher levels in many areas of the brain, particularly in dopamine neurons. Recently it has been shown that a sensitizing treatment regimen of amphetamines causes markedly increased levels of DCC and UNC-5 expression on neuron cell bodies. This may indicate that netrin-1 receptors are involved in the lasting effects of exposure to stimulant drugs like amphetamine, and may have some therapeutic value in the field of drug tolerance.
Interactions
Deleted in Colorectal Cancer has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PTK2
PTK2
PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...
, APPL1
APPL1
DCC-interacting protein 13-alpha is a protein that in humans is encoded by the APPL1 gene.Mouse Mutant Alleles for Appl1 Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the Mutant Mouse Embryonic Stem Cell Clones...
, MAZ
MAZ (gene)
Myc-associated zinc finger protein is a protein that in humans is encoded by the MAZ gene.-Interactions:MAZ has been shown to interact with BPTF and Deleted in Colorectal Cancer.-Further reading:...
, Caspase 3
Caspase 3
Caspase 3 is a caspase protein that interacts with caspase 8 and caspase 9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available...
, NTN1
NTN1
Netrin-1 is a protein that in humans is encoded by the NTN1 gene.Netrin is included in a family of laminin-related secreted proteins. The function of this gene has not yet been defined; however, netrin is thought to be involved in axon guidance and cell migration during development...
and Androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
.
History of research
DCC's biological role in cancer has had a long, controversial history. Although DCC has been studied for many years, a significant amount of the data collected is contradictory and much of the focus has been on getting clear picture of the basics.When the genetic abnormalities that occur in advanced colorectal cancer were first identified, one of the most frequent events was found to be loss of heterozygosity (LOH) of region 18q21. One of the first genes sequenced in this region was DCC, and it was subsequently analyzed for tumour suppressor activity. However, the lack of somatic DCC mutations made it seem likely that the nearby SMAD2 and SMAD4 genes were the reason for 18q21 LOH. The fact that DCC heterozygotes had no increased rates of cancer, even when crossed with mice carrying Apc
Adenomatosis polyposis coli
Adenomatous polyposis coli also known as deleted in polyposis 2.5 is a protein that in humans is encoded by the APC gene. Mutations in the APC gene may result in colorectal cancer....
mutations, solidified this viewpoint. The finding that DCC was a receptor for netrin-1 involved in axon guidance initially moved research away from DCC in cancer. It was later realized that DCC may be involved in directing cell motility, which has direct implications for metastatic cancer.
The first direct evidence for DCC as a tumour suppressor gene was published in 1995. Researchers found that addition of DCC to an immortalized cell line suppressed tumorigenicity rather definitively. However no mechanism for this suppression was obvious, and it took several years to propose one.
Nearly ten years after DCC was discovered, studies were published that showed that DCC was involved in apoptosis. Instead of studying loss of DCC as was commonly done, the authors looked at human embryonic kidney cells transfected with DCC. They found an increase in apoptosis that corresponded to DCC expression, which was completely eliminated when netrin-1 was co-transfected or simply added to the media.
When it was understood that DCC apoptosis may also be overcome by netrin-1 overexpression, colorectal cancers were assessed for netrin-1 overexpression, and a small but significant percent of these cancers were found to vastly overexpress the molecule.
External links
- KEGG pathway for colorectal cancer
- KEGG pathway for axon guidance
- Frontiers in Bioscience Review - the DCC protein
- Brain Briefings website - article on axon guidance
- BC Cancer Agency - information on colorectal cancer