Epithelial-mesenchymal Transition - Role in Metastasis and Proliferation

Role in Metastasis and Proliferation

Initiation of metastasis 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 EMT. 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.