Epithelial-mesenchymal transition
Encyclopedia
Epithelial-mesenchymal transition or transformation (EMT) is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin
expression, and increased cell mobility. EMT may be essential for numerous developmental processes including mesoderm formation and neural tube
formation.
pathways (peptide growth factors, Src, Ras, Ets, integrin, Wnt/beta-catenin and Notch) may induce EMT. In particular, Ras-MAPK has been shown to activate two related transcription factor
s known as Snail
and Slug
. Both of these proteins are transcriptional repressors of E-cadherin and their expression induces EMT. Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT.
Twist
, another transcription factor, has also been shown to possibly induce EMT, and is also implicated in the regulation of metastasis
. Expression of FOXC2
, an important player during embryonic development has been shown to induce EMT and regulate metastasis
. Moreover, expression of FOXC2
is induced when epithelial cells undergo EMT by Snail
, Twist
, Goosecoid, and TGF-beta 1.
EMT may be induced by type I collagen, mediated by integrin α1β2. As cells assume a more mesenchymal phenotype, expression of molecules such as osteopontin and type 1 collagen are increased.
involves invasion, which has many phenotypic similarities to EMT, including a loss of cell-cell adhesion mediated by E-cadherin repression and an increase in cell mobility. Loss of certain genes (e.g. Hedgehog family) has been shown to activate integrin, Wnt, and possibly other signaling pathways, leading to alterations in cell-cell adhesion.
EMT is a characteristic feature of cells undergoing proliferation. Cells expanding in-vitro, like beta cells- and epithelial phenotype, of the pancreas, assume mesenchymal phenotype. Similarly cultured hepatocytes and kidney tubular epithelial cells undergo dedifferentiation in a process similar to an EMT event. In-vivo (via KO or under cancer-inducing scenarios), EMT has been shown to occur in proliferating cells (e.g. stomach epithelium) when pathways known to be involved with EMT are altered.
Nicotine may contribute to EMThttp://www.ncbi.nlm.nih.gov/pubmed?term=Nicotine%20induces%20cell%20proliferation%2C%20invasion%20and%20epithelial-mesenchymal%20transition%20in%20a%20variety%20of%20human%20cancer%20cell%20lines. Molecular factors that participate in EMT-related processes include also Hedgehog, nuclear factor-kappaB and Activating Transcription Factor 2.
The concept of Epithelial-Mesenchymal Transition (EMT) was also demonstrated to be useful in generation of endocrine progenitor cells from human pancreatic islets. However, there has been significant debate in understanding the proliferative potential of "terminally" differentiated cells, such as the insulin-producing β-cells. The entire debate started after the initial presentation of EMT in cadaveric human islets. These investigators proposed that human islet-derived progenitor cells (hIPCs) are better precursors since β-cell progeny in these hIPCs inherit epigenetic marks that define an active insulin promoter region. Although similar observations in single cells obtained from human islets were also reported shortly after this initial presentation, the entire concept was strongly opposed by a series of articles. These researchers used genetic lineage tracing system to label β-cells and convincingly demonstrate that labelled (mouse) cells do not exist in the expanded (proliferating) cultures. Two of these articles noted that labelled β-cells de-differentiate to a mesenchymal-like phenotype in vitro, but fail to proliferate. Overall, these articles, suggested that (mouse) β-cells do not proliferate /undergo epithelial-mesenchymal transition (EMT) in vitro. Since previous studies in human islets lacked lineage-tracing analysis, these findings from irreversibly tagged beta cells in mice were extrapolated to human islets. It became a consensus that terminally differentiated islet β-cells do not proliferate in vitro and the mesenchymal population seen in vitro was proposed to arise from rapid proliferation of pre-existing mesenchymal cells. However, the group of Shimon Efrat, used a dual lentiviral system to irreversibly label human β-cells in vitro, demonstrating that adult human islet β-cells undergo EMT and proliferate in vitro. Following this publication, the group of Anandwardhan Hardikar published data confirming these findings in human fetal pancreatic insulin-producing cells. These authors used multiple approaches, including immunostaining and FISH, single cell PCR, clonal expansion analysis, assessment of heritable marks of insulin-promoter region and thymidine-analog based lineage tracing analysis to demonstrate proliferation of human fetal insulin-producing cells. Furthermore, the same group also demonstrated that members of the miR-30 family of microRNAs (a class of non-codingRNAs) are involved in regulation of EMT in human islets, mainly due to the genomic (intronic) location of members of this family. These studies from the group of Efrat and Hardikar now confirm that human pancreatic insulin-producing cells proliferate and undergo EMT in vitro.
These groups have also indicated that mesenchymal cells derived from pancreatic islets can undergo reverse EMT or mesenchymal-epithelial transition
(MET)to generate islet-like cell aggregates. Although such islet-like aggregates show very low levels of insulin, the concept of generating progenitors from insulin-producing cells by EMT may help in generation of lineage-committed islet progenitor cells. Such cells may have potential for replacement therapy in diabetes.
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
expression, and increased cell mobility. EMT may be essential for numerous developmental processes including mesoderm formation and neural tube
Neural tube
In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord...
formation.
Induction
Several oncogenicOncogene
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...
pathways (peptide growth factors, Src, Ras, Ets, integrin, Wnt/beta-catenin and Notch) may induce EMT. In particular, Ras-MAPK has been shown to activate two related transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s known as Snail
SNAI1
Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene.-Interactions:SNAI1 has been shown to interact with CTDSPL, CTDSP1 and CTDSP2.-Further reading:...
and Slug
SNAI2
Zinc finger protein SNAI2 is a protein that in humans is encoded by the SNAI2 gene.-Further reading:...
. Both of these proteins are transcriptional repressors of E-cadherin and their expression induces EMT. Recently, activation of the phosphatidylinositol 3' kinase (PI3K)/AKT axis is emerging as a central feature of EMT.
Twist
Twist transcription factor
Twist transcription factor is a basic-helix-loop-helix transcription factor associated with Saethre-Chotzen syndrome.-Interactions:Twist transcription factor has been shown to interact with EP300, TCF3 and PCAF.-External links:*...
, another transcription factor, has also been shown to possibly induce EMT, and is also implicated in the regulation of 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...
. Expression of FOXC2
FOXC2
Forkhead box protein C2 also known as forkhead-related protein FKHL14 , transcription factor FKH-14, or mesenchyme fork head protein 1 is a protein that in humans is encoded by the FOXC2 gene...
, an important player during embryonic development has been shown to induce EMT and regulate 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...
. Moreover, expression of FOXC2
FOXC2
Forkhead box protein C2 also known as forkhead-related protein FKHL14 , transcription factor FKH-14, or mesenchyme fork head protein 1 is a protein that in humans is encoded by the FOXC2 gene...
is induced when epithelial cells undergo EMT by Snail
SNAI1
Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene.-Interactions:SNAI1 has been shown to interact with CTDSPL, CTDSP1 and CTDSP2.-Further reading:...
, Twist
Twist transcription factor
Twist transcription factor is a basic-helix-loop-helix transcription factor associated with Saethre-Chotzen syndrome.-Interactions:Twist transcription factor has been shown to interact with EP300, TCF3 and PCAF.-External links:*...
, Goosecoid, and TGF-beta 1.
EMT may be induced by type I collagen, mediated by integrin α1β2. As cells assume a more mesenchymal phenotype, expression of molecules such as osteopontin and type 1 collagen are increased.
Role in metastasis and proliferation
Initiation of metastasisMetastasis
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...
involves invasion, which has many phenotypic similarities to EMT, including a loss of cell-cell adhesion mediated by E-cadherin repression and an increase in cell mobility. Loss of certain genes (e.g. Hedgehog family) has been shown to activate integrin, Wnt, and possibly other signaling pathways, leading to alterations in cell-cell adhesion.
EMT is a characteristic feature of cells undergoing proliferation. Cells expanding in-vitro, like beta cells- and epithelial phenotype, of the pancreas, assume mesenchymal phenotype. Similarly cultured hepatocytes and kidney tubular epithelial cells undergo dedifferentiation in a process similar to an EMT event. In-vivo (via KO or under cancer-inducing scenarios), EMT has been shown to occur in proliferating cells (e.g. stomach epithelium) when pathways known to be involved with EMT are altered.
Nicotine may contribute to EMThttp://www.ncbi.nlm.nih.gov/pubmed?term=Nicotine%20induces%20cell%20proliferation%2C%20invasion%20and%20epithelial-mesenchymal%20transition%20in%20a%20variety%20of%20human%20cancer%20cell%20lines. Molecular factors that participate in EMT-related processes include also Hedgehog, nuclear factor-kappaB and Activating Transcription Factor 2.
The concept of Epithelial-Mesenchymal Transition (EMT) was also demonstrated to be useful in generation of endocrine progenitor cells from human pancreatic islets. However, there has been significant debate in understanding the proliferative potential of "terminally" differentiated cells, such as the insulin-producing β-cells. The entire debate started after the initial presentation of EMT in cadaveric human islets. These investigators proposed that human islet-derived progenitor cells (hIPCs) are better precursors since β-cell progeny in these hIPCs inherit epigenetic marks that define an active insulin promoter region. Although similar observations in single cells obtained from human islets were also reported shortly after this initial presentation, the entire concept was strongly opposed by a series of articles. These researchers used genetic lineage tracing system to label β-cells and convincingly demonstrate that labelled (mouse) cells do not exist in the expanded (proliferating) cultures. Two of these articles noted that labelled β-cells de-differentiate to a mesenchymal-like phenotype in vitro, but fail to proliferate. Overall, these articles, suggested that (mouse) β-cells do not proliferate /undergo epithelial-mesenchymal transition (EMT) in vitro. Since previous studies in human islets lacked lineage-tracing analysis, these findings from irreversibly tagged beta cells in mice were extrapolated to human islets. It became a consensus that terminally differentiated islet β-cells do not proliferate in vitro and the mesenchymal population seen in vitro was proposed to arise from rapid proliferation of pre-existing mesenchymal cells. However, the group of Shimon Efrat, used a dual lentiviral system to irreversibly label human β-cells in vitro, demonstrating that adult human islet β-cells undergo EMT and proliferate in vitro. Following this publication, the group of Anandwardhan Hardikar published data confirming these findings in human fetal pancreatic insulin-producing cells. These authors used multiple approaches, including immunostaining and FISH, single cell PCR, clonal expansion analysis, assessment of heritable marks of insulin-promoter region and thymidine-analog based lineage tracing analysis to demonstrate proliferation of human fetal insulin-producing cells. Furthermore, the same group also demonstrated that members of the miR-30 family of microRNAs (a class of non-codingRNAs) are involved in regulation of EMT in human islets, mainly due to the genomic (intronic) location of members of this family. These studies from the group of Efrat and Hardikar now confirm that human pancreatic insulin-producing cells proliferate and undergo EMT in vitro.
These groups have also indicated that mesenchymal cells derived from pancreatic islets can undergo reverse EMT or mesenchymal-epithelial transition
Mesenchymal-epithelial transition
A mesenchymal-epithelial transition is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial-mesenchymal transition...
(MET)to generate islet-like cell aggregates. Although such islet-like aggregates show very low levels of insulin, the concept of generating progenitors from insulin-producing cells by EMT may help in generation of lineage-committed islet progenitor cells. Such cells may have potential for replacement therapy in diabetes.
See also
- Mesenchymal-epithelial transitionMesenchymal-epithelial transitionA mesenchymal-epithelial transition is a reversible biological process that involves the transition from motile, multipolar or spindle-shaped mesenchymal cells to planar arrays of polarized cells called epithelia. MET is the reverse process of epithelial-mesenchymal transition...
- Discovery and development of small molecule c-Met inhibitorsDiscovery and development of small molecule c-Met inhibitorsThe c-Met tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis and angiogenesis.c-Met is a receptor tyrosine kinase, which can cause a wide variety of different cancers, such as renal, gastric and small cell lung carcinomas, central nervous system tumours, as well as...