3 The Lack of Universal Markers and Some Misleading Concepts
In general terms, one process is considered to be well defined when
specific markers are described, and one drawback in the study of
EMT is the lack of universal specific markers. During EMT, epithelial genes (E) are downregulated and mesenchymal markers (M) are
activated. Their expression or better, that of the proteins they
encode, is used as markers of EMT. The problem is that, in many
studies, only one marker is used as representatives of the E or M
phenotype, E-cadherin, and vimentin, respectively. And it is a problem because E-cadherin and vimentin are not universal or exclusive
markers of the E and M states and also because the E and M
phenotypes are not static entities. At this point it is worth going
back to the actual term, EMT, the epithelial-to-mesenchymal transition and discuss some terms that can be misleading.
1. Transition versus binary transformation. The EMT is a transition, and it is not implemented as a binary decision. In agreement with that, the EMT community agreed already in 2003 at
the first meeting of the Epithelial-Mesenchymal transition
International Association, (TEMTIA), to use transition rather
than the original term transformation [9]. Transition implies
the sequential nature of the process and, although not that
evident at that time, the existence of intermediate states
(Fig. 1). Even though the latter is easy to understand, in the
field we have failed to convey this message of intermediate states,
leading to false expectations and misinterpretations, some of
which I will discuss below.
2. Cell behavior, not cell fate. During embryonic development, cell
behavior and fate occur in parallel, but they are independently
regulated. The EMT is a program for cell behavior, not fate.
When Snail, one of the most potent EMT-TFs was first identified in Drosophila, it was described as a mesodermal inducer
[10], but it was later found in the majority of vertebrate tissues
where cell delamination occurs in the developing embryo,
regardless of their embryonic origin [11]. As such, the role of
EMT-TFs is related to changes in cell shape and motility rather
than to specific cell fates, and this needs to be considered in all
physiological and pathological contexts.
3. Kinetics and hierarchy. In the search for EMT markers, temporal aspects and functional hierarchy are frequently not considered, and this can have an impact in the definition of the
process. We need to consider at least three hierarchical levels:
(1) the inducing signals (non-cell autonomous), (2) the
EMT-TFs as gene expression regulators (cell autonomous),
and (3) the final effectors: structural molecules and enzymes
that altogether include those involved in adhesion, cytoskeletal
Are You Interested or Afraid of Working on EMT?
21
In general terms, one process is considered to be well defined when
specific markers are described, and one drawback in the study of
EMT is the lack of universal specific markers. During EMT, epithelial genes (E) are downregulated and mesenchymal markers (M) are
activated. Their expression or better, that of the proteins they
encode, is used as markers of EMT. The problem is that, in many
studies, only one marker is used as representatives of the E or M
phenotype, E-cadherin, and vimentin, respectively. And it is a problem because E-cadherin and vimentin are not universal or exclusive
markers of the E and M states and also because the E and M
phenotypes are not static entities. At this point it is worth going
back to the actual term, EMT, the epithelial-to-mesenchymal transition and discuss some terms that can be misleading.
1. Transition versus binary transformation. The EMT is a transition, and it is not implemented as a binary decision. In agreement with that, the EMT community agreed already in 2003 at
the first meeting of the Epithelial-Mesenchymal transition
International Association, (TEMTIA), to use transition rather
than the original term transformation [9]. Transition implies
the sequential nature of the process and, although not that
evident at that time, the existence of intermediate states
(Fig. 1). Even though the latter is easy to understand, in the
field we have failed to convey this message of intermediate states,
leading to false expectations and misinterpretations, some of
which I will discuss below.
2. Cell behavior, not cell fate. During embryonic development, cell
behavior and fate occur in parallel, but they are independently
regulated. The EMT is a program for cell behavior, not fate.
When Snail, one of the most potent EMT-TFs was first identified in Drosophila, it was described as a mesodermal inducer
[10], but it was later found in the majority of vertebrate tissues
where cell delamination occurs in the developing embryo,
regardless of their embryonic origin [11]. As such, the role of
EMT-TFs is related to changes in cell shape and motility rather
than to specific cell fates, and this needs to be considered in all
physiological and pathological contexts.
3. Kinetics and hierarchy. In the search for EMT markers, temporal aspects and functional hierarchy are frequently not considered, and this can have an impact in the definition of the
process. We need to consider at least three hierarchical levels:
(1) the inducing signals (non-cell autonomous), (2) the
EMT-TFs as gene expression regulators (cell autonomous),
and (3) the final effectors: structural molecules and enzymes
that altogether include those involved in adhesion, cytoskeletal
Are You Interested or Afraid of Working on EMT?
21