Caretaker gene
Encyclopedia
Changes in the genome
that allow uncontrolled cell proliferation or cell immortality are responsible for cancer
. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein
grouped these cancer susceptibility genes into two classes: "caretakers" and "gatekeepers". In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa
, and Martin Nowak
; "landscaper" genes.
Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability
. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.
In contrast to caretaker genes, gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation
The third classification of genes, the landscapers, encode products that, when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation.
inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome
. Caretaker genes provide genome stability by preventing the accumulation of these mutations.
Factors that contribute to genome stabilization include proper cell-cycle checkpoints, DNA
repair pathways, and other actions that ensure cell survival following DNA damage. Specific DNA maintenance operations encoded by caretaker genes include nucleotide excision repair
, base excision repair
, non-homologous end joining
recombination pathways, mismatch repair pathways, and telomere
metabolism.
Upon mutation, caretaker genes lead to altered gene products that result in increased conversion of a normal cell to a cell of neoplasia
, a cell that; (1) divides more often than it should or (2) does not die when conditions warrant cell death. Thus, caretaker genes do not directly regulate cell proliferation. In genetic knock-out and rescue experiments, restoration of a caretaker gene from the mutated form to the wildtype version does not limit tumorigenesis. This is because caretaker genes only indirectly contribute to the pathway to cancer.
Inactivation of caretaker genes is environmentally equivalent to exposing the cell to mutagens incessantly. For example, a mutation in a caretaker gene coding for a DNA repair pathway that leads to the inability to properly repair DNA damage could allow uncontrolled cell growth. This is the result of mutations of other genes that accumulate unchecked as a result of faulty gene products encoded by the caretakers.
In addition to providing genomic stability, caretakers also provide chromosomal stability. Chromosomal instability resulting from dysfunctional caretaker genes is the most common form of genetic instability that leads to cancer in humans. In fact, it has been proposed that these caretaker genes are responsible for many hereditary predispositions to cancers.
In individuals predisposed to cancer via mutations in caretaker genes, a total of three subsequent somatic mutations are required to acquire the cancerous phenotype. Mutations must occur in the remaining normal caretaker allele in addition to both alleles of gatekeeper genes within that cell for the said cell to turn to neoplasia. Thus, the risk of cancer in these affected populations is much less when compared to cancer risk in families predisposed to cancer via the gatekeeper pathway.
and death. When tissue damage occurs, for example, products of gatekeeper genes ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes do not lead to on-going growth imbalances.
Mutations altering these genes lead to irregular growth regulation and differentiation. Each cell type has only one, or at least only very few, gatekeeper genes. If a person is predisposed to cancer, they have inherited a mutation in one of two copies of a gatekeeper gene. Mutation of the alternate allele leads to progression to neoplasia.
Historically, the term gatekeeper gene was first coined in association with the APC gene, a tumor suppressor that is consistently found to mutated in colorectal tumors. Gatekeeper genes are in fact specific to the tissues in which they reside .
The probability that mutations occur in other genes increases when DNA repair pathway mechanisms are damaged as a result of mutations in caretaker genes. Thus, the probability that a mutation will take place in a gatekeeper gene increases when the caretaker gene has been mutated.
Apoptosis
, or induced cell suicide, usually serves as a mechanism to prevent excessive cellular growth. Gatekeeper genes regulate apoptosis. However, in instances where tissue growth or regrowth is warranted, these signals must be inactivated or net tissue regeneration would be impossible. Thus, mutations in growth-controlling genes would lead to the characteristics of uncontrolled cellular proliferation, neoplasia
, while in a parallel cell that had no mutations in the gatekeeper function, simple cell death would ensue.
Landscaper genes encode gene products that control the microenvironment in which cells grow. Growth of cells depends both on cell-to-cell interactions and cell-to-extracellular matrix
(ECM) interactions. Mechanisms of control via regulation of extracellular matrix proteins, cellular surface markers, cellular adhesion molecules, and growth factors have been proposed.
Cells communicate with each other via the ECM through both direct contact and through signaling molecules. Stromal cell abnormalities arising from gene products coded by faulty landscaper genes could induce abnormal cell growth on the epithelium
, leading to cancer
of that tissue.
Biochemical cascades consisting of signaling proteins occur in the ECM and play an important role to the regulation of many aspects of cell life. Landscaper genes encode products that determine the composition of the membranes in which cells live. For example, large molecular weight glycoproteins and proteoglycans have been found to in association with signaling and structural roles. There exist proteolytic molecules in the ECM that are essential for clearing unwanted molecules, such as growth factors, cell adhesion molecules, and others from the space surrounding cells. It is proposed that landscaper genes control the mechanisms by which these factors are properly cleared. Different characteristics of these membranes lead to different cellular effects, such as differing rates of cell proliferation or differentiation. If, for example, the ECM is disrupted, incoming cells, such as those of the immune system, can overload the area and release chemical signals that induce abnormal cell proliferation. These conditions lead to an environment conducive to tumor
growth and the cancerous phenotype.
A specific purpose of caretaker genes has been outlined in chromosomal duplication. Caretakers have been identified as crucial to encoding products that maintain the telomeres. It is believed that degradation of telomeres, the ends of chromosomes, through repeated cell cycle divisions, is a main component of cellular aging and death.
It has been suggested that gatekeeper genes confer beneficial anti-cancer affects but may provide deleterious affects that increase aging. This is because young organisms experiencing times of rapid growth necessitate significant anti-cancer mechanisms. As the organism ages, however, these formerly beneficial pathways become deleterious by inducing apoptosis in cells of renewable tissues, causing degeneration of the structure. Studies have shown an increased expression of pro-apoptotic genes in age-related pathologies. This is because the products of gatekeeper genes are directly involved in coding for cellular growth and proliferation.
It is interesting to note, however, that dysfunctional caretaker genes does not always lead to a cancerous phenotype. For example, defects in nucleotide excision repair pathways are associated with premature aging phenotypes in diseases such as Xeroderma pigmentosum
and Trichothiodystrophy. These patients exhibit brittle hair, nails, scaly skin, and hearing loss – characteristics associated with simple human aging. This is important because the nucleotide excision repair pathway is a mechanism thought to be encoded by a caretaker gene. Geneticists studying these premature-aging syndromes propose that caretaker genes that determine cell fate also play a significant role in aging .
Similarly, gatekeeper genes have been identified as having a role in aging disorders that exhibit mutations in such genes without an increased susceptibility to cancer. Experiments with mice that have increased gatekeeper function in the p53
gene show reduced cancer incidence (due to the protective activities of products encoded by p53
) but a faster rate of aging.
Cellular senescence
, also encoded by a gatekeeper gene, is arrest of the cell cycle in the G1 phase. Qualitative differences have been found between senescent cells and normal cells, including differential expression of cytokines and other factors associated with inflammation. It is believe that this may contribute, in part, to cellular aging.
In sum, although mechanisms encoded by gatekeeper and caretaker genes to protect individuals from cancer early in life, namely induction of apoptosis or senescence, later in life these functions may promote the aging phenotype.
s in gatekeeper genes could, to an extent, offer a sort of selective advantage to the individual in which the change occurs. This is because cells with these mutations are able to replicate at a faster rate than nearby cells. This is known as "increased somatic fitness". Caretaker genes, on the other hand, confer selective disadvantage because the result is inherently decreased cellular success. However, increased somatic fitness could also arise from a mutation in a caretaker gene if mutations in tumor suppressor genes increase the net reproductive rate of the cell.
Although mutations in gatekeeper genes may lead to the same result as those of caretaker genes, namely cancer, the transcripts that gatekeeper genes encode are significantly different from those encoded by caretaker genes.
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death. In cases of tissue damage, for example, gatekeeper genes would ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes would not lead to on-going growth imbalances.
Whether or not mutations in these genes confer beneficial or deleterious effects to the animal depends partially on the environmental context in which these changes occur, a context encoded by the landscaper genes. For example, tissues of the skin and colon reside in compartments of cells that rarely mix with one another. These tissues are replenished by stem cells. Mutations that occur within these cell lineages remain confined to the compartment in which they reside, increasing the future risk of cancer. This is also protective, however, because the cancer will remain confined to that specific area, rather than invading the rest of the body, a phenomenon known as metastasis
.
In areas of the body compartmentalized into small subsets of cells, mutations that lead to cancer most often begin with caretaker genes. On the other hand, cancer progression in non-compartmentalized or large cell populations may be a result of initial mutations in gatekeepers.
These delineations offer a suggestion why different types of tissue within the body progress to cancer by differing mechanisms.
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
that allow uncontrolled cell proliferation or cell immortality are responsible for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein
Bert Vogelstein
Bert Vogelstein is a Howard Hughes Medical Institute investigator at The Johns Hopkins University. He clarified the role of the gene p53, which repairs DNA in dividing cells and destroys the cell if its DNA cannot be repaired. Damaged p53 is responsible for half of all cancers...
grouped these cancer susceptibility genes into two classes: "caretakers" and "gatekeepers". In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa
Yoh Iwasa
Yoh Iwasa is a Japanese Mathematical Biologist who is considered the leading mathematical biologist in Japan.His work includes the evolution of costly mate prefereces and the evolutionary dynamics of cancer. Notable papers include:...
, and Martin Nowak
Martin Nowak
Martin A. Nowak is Professor of Biology and Mathematics and Director of the Program for Evolutionary Dynamics at Harvard University.-Career:Martin Nowak studied biochemistry and mathematics at the University of Vienna, and earned his Ph. D. in 1989, working with Peter Schuster on quasi-species...
; "landscaper" genes.
Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability
Genome instability
Usually, all cells in an individual in a given species show a constant number of chromosomes, which constitute what is known as the karyotype defining this species , although some species present a very high karyotypic variability.Sometimes, in a species with a stable karyotype, random variations...
. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.
In contrast to caretaker genes, gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation
The third classification of genes, the landscapers, encode products that, when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation.
Pathways to Cancer via the Caretakers
The process of DNA replicationDNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. Caretaker genes provide genome stability by preventing the accumulation of these mutations.
Factors that contribute to genome stabilization include proper cell-cycle checkpoints, DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
repair pathways, and other actions that ensure cell survival following DNA damage. Specific DNA maintenance operations encoded by caretaker genes include nucleotide excision repair
Nucleotide excision repair
Nucleotide excision repair is a DNA repair mechanism. DNA constantly requires repair due to damage that can occur to bases from a vast variety of sources including chemicals, radiation and other mutagens...
, base excision repair
Base excision repair
In biochemistry and genetics, base excision repair is a cellular mechanism that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky...
, non-homologous end joining
Non-homologous end joining
Non-homologous end joining is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homologous recombination, which requires a homologous sequence to guide...
recombination pathways, mismatch repair pathways, and telomere
Telomere
A telomere is a region of repetitive DNA sequences at the end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos "end" and merοs "part"...
metabolism.
Upon mutation, caretaker genes lead to altered gene products that result in increased conversion of a normal cell to a cell of neoplasia
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
, a cell that; (1) divides more often than it should or (2) does not die when conditions warrant cell death. Thus, caretaker genes do not directly regulate cell proliferation. In genetic knock-out and rescue experiments, restoration of a caretaker gene from the mutated form to the wildtype version does not limit tumorigenesis. This is because caretaker genes only indirectly contribute to the pathway to cancer.
Inactivation of caretaker genes is environmentally equivalent to exposing the cell to mutagens incessantly. For example, a mutation in a caretaker gene coding for a DNA repair pathway that leads to the inability to properly repair DNA damage could allow uncontrolled cell growth. This is the result of mutations of other genes that accumulate unchecked as a result of faulty gene products encoded by the caretakers.
In addition to providing genomic stability, caretakers also provide chromosomal stability. Chromosomal instability resulting from dysfunctional caretaker genes is the most common form of genetic instability that leads to cancer in humans. In fact, it has been proposed that these caretaker genes are responsible for many hereditary predispositions to cancers.
In individuals predisposed to cancer via mutations in caretaker genes, a total of three subsequent somatic mutations are required to acquire the cancerous phenotype. Mutations must occur in the remaining normal caretaker allele in addition to both alleles of gatekeeper genes within that cell for the said cell to turn to neoplasia. Thus, the risk of cancer in these affected populations is much less when compared to cancer risk in families predisposed to cancer via the gatekeeper pathway.
Pathways to cancer via the Gatekeepers
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell divisionCell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and death. When tissue damage occurs, for example, products of gatekeeper genes ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes do not lead to on-going growth imbalances.
Mutations altering these genes lead to irregular growth regulation and differentiation. Each cell type has only one, or at least only very few, gatekeeper genes. If a person is predisposed to cancer, they have inherited a mutation in one of two copies of a gatekeeper gene. Mutation of the alternate allele leads to progression to neoplasia.
Historically, the term gatekeeper gene was first coined in association with the APC gene, a tumor suppressor that is consistently found to mutated in colorectal tumors. Gatekeeper genes are in fact specific to the tissues in which they reside .
The probability that mutations occur in other genes increases when DNA repair pathway mechanisms are damaged as a result of mutations in caretaker genes. Thus, the probability that a mutation will take place in a gatekeeper gene increases when the caretaker gene has been mutated.
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...
, or induced cell suicide, usually serves as a mechanism to prevent excessive cellular growth. Gatekeeper genes regulate apoptosis. However, in instances where tissue growth or regrowth is warranted, these signals must be inactivated or net tissue regeneration would be impossible. Thus, mutations in growth-controlling genes would lead to the characteristics of uncontrolled cellular proliferation, neoplasia
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
, while in a parallel cell that had no mutations in the gatekeeper function, simple cell death would ensue.
Pathways to cancer via the Landscapers
A third group of genes in which mutations lead to a significant susceptibility to cancer is the class of landscaper genes. Products encoded by landscaper genes contribute to the neoplastic growth of cells by fostering stromal environments conducive to unregulated cell proliferation.Landscaper genes encode gene products that control the microenvironment in which cells grow. Growth of cells depends both on cell-to-cell interactions and cell-to-extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM) interactions. Mechanisms of control via regulation of extracellular matrix proteins, cellular surface markers, cellular adhesion molecules, and growth factors have been proposed.
Cells communicate with each other via the ECM through both direct contact and through signaling molecules. Stromal cell abnormalities arising from gene products coded by faulty landscaper genes could induce abnormal cell growth on the epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
, leading to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
of that tissue.
Biochemical cascades consisting of signaling proteins occur in the ECM and play an important role to the regulation of many aspects of cell life. Landscaper genes encode products that determine the composition of the membranes in which cells live. For example, large molecular weight glycoproteins and proteoglycans have been found to in association with signaling and structural roles. There exist proteolytic molecules in the ECM that are essential for clearing unwanted molecules, such as growth factors, cell adhesion molecules, and others from the space surrounding cells. It is proposed that landscaper genes control the mechanisms by which these factors are properly cleared. Different characteristics of these membranes lead to different cellular effects, such as differing rates of cell proliferation or differentiation. If, for example, the ECM is disrupted, incoming cells, such as those of the immune system, can overload the area and release chemical signals that induce abnormal cell proliferation. These conditions lead to an environment conducive to tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
growth and the cancerous phenotype.
Gatekeepers, Caretakers, and Cellular Aging
Because mechanisms that control the accumulation of damage through the lifetime of a cell is essential to longevity, it is logical that caretaker and gatekeeper genes play a significant role in cellular aging. Increased activity of caretaker genes postpones aging, increasing lifespan. This is because of the regulatory function associated with caretaker genes in maintaining the stability of the genome. The actions of caretaker genes contribute to increasing lifespan of the cell.A specific purpose of caretaker genes has been outlined in chromosomal duplication. Caretakers have been identified as crucial to encoding products that maintain the telomeres. It is believed that degradation of telomeres, the ends of chromosomes, through repeated cell cycle divisions, is a main component of cellular aging and death.
It has been suggested that gatekeeper genes confer beneficial anti-cancer affects but may provide deleterious affects that increase aging. This is because young organisms experiencing times of rapid growth necessitate significant anti-cancer mechanisms. As the organism ages, however, these formerly beneficial pathways become deleterious by inducing apoptosis in cells of renewable tissues, causing degeneration of the structure. Studies have shown an increased expression of pro-apoptotic genes in age-related pathologies. This is because the products of gatekeeper genes are directly involved in coding for cellular growth and proliferation.
It is interesting to note, however, that dysfunctional caretaker genes does not always lead to a cancerous phenotype. For example, defects in nucleotide excision repair pathways are associated with premature aging phenotypes in diseases such as Xeroderma pigmentosum
Xeroderma pigmentosum
Xeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. In extreme cases, all exposure to sunlight must be forbidden, no matter how small. Multiple basal cell carcinomas and other skin...
and Trichothiodystrophy. These patients exhibit brittle hair, nails, scaly skin, and hearing loss – characteristics associated with simple human aging. This is important because the nucleotide excision repair pathway is a mechanism thought to be encoded by a caretaker gene. Geneticists studying these premature-aging syndromes propose that caretaker genes that determine cell fate also play a significant role in aging .
Similarly, gatekeeper genes have been identified as having a role in aging disorders that exhibit mutations in such genes without an increased susceptibility to cancer. Experiments with mice that have increased gatekeeper function in the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
gene show reduced cancer incidence (due to the protective activities of products encoded by p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
) but a faster rate of aging.
Cellular senescence
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
, also encoded by a gatekeeper gene, is arrest of the cell cycle in the G1 phase. Qualitative differences have been found between senescent cells and normal cells, including differential expression of cytokines and other factors associated with inflammation. It is believe that this may contribute, in part, to cellular aging.
In sum, although mechanisms encoded by gatekeeper and caretaker genes to protect individuals from cancer early in life, namely induction of apoptosis or senescence, later in life these functions may promote the aging phenotype.
Mutations in context
It has been proposed that mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in gatekeeper genes could, to an extent, offer a sort of selective advantage to the individual in which the change occurs. This is because cells with these mutations are able to replicate at a faster rate than nearby cells. This is known as "increased somatic fitness". Caretaker genes, on the other hand, confer selective disadvantage because the result is inherently decreased cellular success. However, increased somatic fitness could also arise from a mutation in a caretaker gene if mutations in tumor suppressor genes increase the net reproductive rate of the cell.
Although mutations in gatekeeper genes may lead to the same result as those of caretaker genes, namely cancer, the transcripts that gatekeeper genes encode are significantly different from those encoded by caretaker genes.
In many cases, gatekeeper genes encode a system of checks and balances that monitor cell division and death. In cases of tissue damage, for example, gatekeeper genes would ensure that balance of cell growth over cellular death remains in check. In the presence of competent gatekeeper genes, mutations of other genes would not lead to on-going growth imbalances.
Whether or not mutations in these genes confer beneficial or deleterious effects to the animal depends partially on the environmental context in which these changes occur, a context encoded by the landscaper genes. For example, tissues of the skin and colon reside in compartments of cells that rarely mix with one another. These tissues are replenished by stem cells. Mutations that occur within these cell lineages remain confined to the compartment in which they reside, increasing the future risk of cancer. This is also protective, however, because the cancer will remain confined to that specific area, rather than invading the rest of the body, a phenomenon known as metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
In areas of the body compartmentalized into small subsets of cells, mutations that lead to cancer most often begin with caretaker genes. On the other hand, cancer progression in non-compartmentalized or large cell populations may be a result of initial mutations in gatekeepers.
These delineations offer a suggestion why different types of tissue within the body progress to cancer by differing mechanisms.