representation of the full epithelial (E) and the full mesenchymal (M) states, usually represented on one hand by a beautiful
intestinal epithelial cell with microvilli and on the other hand
by a fibroblast; black and white, without the richness of the gray
shades, and biology is all about richness. In the vast majority of
EMT processes, both in physiology and pathology, in development and in cancer, EMT phenotypes are intermediate, just
meaning that they do not correspond to the pure E or pure M
states as they appear in textbooks and reviews (Fig. 1). One
paradigmatic example is that observed during the progression
of renal fibrosis, where damaged epithelial cells undergo a
partial EMT. This EMT program does not include the activation of invasive properties; cells downregulate markers of epithelial character, gain mesenchymal markers, activate the
EMT-TFs and cannot work as renal epithelial cells. However,
they do not delaminate from the renal tubules. Interestingly,
these damaged cells release signals to promote both fibrogenesis and inflammation, the two hallmarks of fibrotic disease
progression in a paracrine manner [12, 13]. Thus, in summary,
and valid for all EMT contexts, we should not expect to observe
individual migratory cells to invoke the activation of an EMT
program.
5. E-Cadherin loss versus E-Cadherin downregulation. Another
misleading message is that we have classically described the
EMT as a process where E-cadherin is lost. As a matter of
fact, in the vast majority of cases, if not all, E-Cadherin expression decreases during EMT, but cells maintain some degree of
expression. Thus, cells are formally kept in an “E-cadherin
positive state,” which should not be considered as a failure to
undergo EMT. The maintenance of certain E-cadherin level is
important to establish cell-cell contacts that are albeit frequently
transient, help collective migration of both embryonic and cancer
cells and, importantly, colonization [14–18]. Conversely, it is
worth noting that E-cadherin loss is not equivalent to an EMT,
as it does not imply changes in mesenchymal markers and
importantly, is not associated to crucial subprograms that are
frequently accompanying EMT, including the activation of
survival signaling cascades (see below). As such, E-cadherin
loss in epithelial cells frequently leads to cell death, which
would not happen when E-cadherin is downregulated in the
course of an EMT, due to the concomitant acquired survival
properties. This is in agreement with recent findings [18] and
old observations suggesting that the formation of cadherinmediated clusters helps survival of cancer cells in the
circulation [19].
6. EMT does not need to be massive. Another confounding issue has
been the difficulty in finding cells with EMT features in many
Are You Interested or Afraid of Working on EMT?
23
intestinal epithelial cell with microvilli and on the other hand
by a fibroblast; black and white, without the richness of the gray
shades, and biology is all about richness. In the vast majority of
EMT processes, both in physiology and pathology, in development and in cancer, EMT phenotypes are intermediate, just
meaning that they do not correspond to the pure E or pure M
states as they appear in textbooks and reviews (Fig. 1). One
paradigmatic example is that observed during the progression
of renal fibrosis, where damaged epithelial cells undergo a
partial EMT. This EMT program does not include the activation of invasive properties; cells downregulate markers of epithelial character, gain mesenchymal markers, activate the
EMT-TFs and cannot work as renal epithelial cells. However,
they do not delaminate from the renal tubules. Interestingly,
these damaged cells release signals to promote both fibrogenesis and inflammation, the two hallmarks of fibrotic disease
progression in a paracrine manner [12, 13]. Thus, in summary,
and valid for all EMT contexts, we should not expect to observe
individual migratory cells to invoke the activation of an EMT
program.
5. E-Cadherin loss versus E-Cadherin downregulation. Another
misleading message is that we have classically described the
EMT as a process where E-cadherin is lost. As a matter of
fact, in the vast majority of cases, if not all, E-Cadherin expression decreases during EMT, but cells maintain some degree of
expression. Thus, cells are formally kept in an “E-cadherin
positive state,” which should not be considered as a failure to
undergo EMT. The maintenance of certain E-cadherin level is
important to establish cell-cell contacts that are albeit frequently
transient, help collective migration of both embryonic and cancer
cells and, importantly, colonization [14–18]. Conversely, it is
worth noting that E-cadherin loss is not equivalent to an EMT,
as it does not imply changes in mesenchymal markers and
importantly, is not associated to crucial subprograms that are
frequently accompanying EMT, including the activation of
survival signaling cascades (see below). As such, E-cadherin
loss in epithelial cells frequently leads to cell death, which
would not happen when E-cadherin is downregulated in the
course of an EMT, due to the concomitant acquired survival
properties. This is in agreement with recent findings [18] and
old observations suggesting that the formation of cadherinmediated clusters helps survival of cancer cells in the
circulation [19].
6. EMT does not need to be massive. Another confounding issue has
been the difficulty in finding cells with EMT features in many
Are You Interested or Afraid of Working on EMT?
23