However, a decade later, the term transition was preferred over
transformation to reflect the dynamics, the complexity, and the
plasticity of this mechanism. Indeed, cells were described in various
stages of EMT co-expressing markers of epithelial and mesenchymal states or neither. For a historical perspective on the field of
EMT we recommend the review by Angela Nieto in Annual
Reviews of Cell and Developmental Biology published in 2011 [3].
EMT can be initiated by various signaling pathways, including
the Bone Morphogenetic Protein (BMP), Wnt, Fibroblast Growth
Factor (FGF), Notch and hypoxia pathways, which induce the
expression of transcription factors from the Twist, Snail, SoxE,
FoxD, Ets, and Zeb families. These transcription factors modulate
the expression of the proteins involved in cell–cell junctions (type I
and type II cadherins) to reduce cell–cell junction strength and
promote the loss of apicobasal polarity. They also induce the expression of cell-matrix adhesion proteins (e.g., Integrins), extracellular
matrix components (e.g., Fibronectin, Collagen, Vitronectin, Laminin) and remodeling factors (e.g., ADAMs, MMPs) as well as
cytoskeleton proteins and regulators (e.g., Keratins, Vimentin,
small GTPases) necessary for front-back polarity and motility. In
the 1990s, a parallel was drawn between tumor progression/metastasis and EMT, identifying common actors and signaling pathways
(reviewed in [4, 5]). It was suggested that cancer cells were hijacking the embryonic EMT programs. Therefore, a better understanding of the molecular mechanisms regulating EMT was believed to
be of primary importance to understand tumor progression.
During the development of vertebrate embryos, EMT is essential for the delamination and long-distance migration of neural
crest (NC) cells, a transient multipotent population of cells that
arises at the neural plate border and gives rise to a wide variety of
derivatives [6]. Over the years, NC cells became a well establish
model for physiological EMT, delamination and migration
mechanisms, notably for its accessibility and ease of manipulation
both in vivo and ex vivo.
In particular, Xenopus NC development recapitulates the main
step of EMT and long-distance migration observed in most epithelial cancers. Xenopus NC cells can be defined as the cell population
initiating the expressing of a repertoire of EMT transcription factors (Twist1, Snail1/2, Ets1, Zeb2) at the border of the neural
plate, at the end of neurulation. Expression of these genes is controlled by the BMP, Wnt, FGF, Notch and hypoxia pathways [7–
9]. Xenopus NC cells then undergo a typical case of cadherin
switching, going from E-cadherin-dependent cell–cell junctions
to N-cadherin ones [10]. This switch is associated with a change
of cell polarity from apicobasal to front-rear, and is directly linked
to the acquisition of motility and dispersion, by endowing NC cells
with the ability to perform contact-inhibition of locomotion
[10]. Importantly, EMT in Xenopus NC cells is also linked with
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Nade ` ge Gouignard et al.
transformation to reflect the dynamics, the complexity, and the
plasticity of this mechanism. Indeed, cells were described in various
stages of EMT co-expressing markers of epithelial and mesenchymal states or neither. For a historical perspective on the field of
EMT we recommend the review by Angela Nieto in Annual
Reviews of Cell and Developmental Biology published in 2011 [3].
EMT can be initiated by various signaling pathways, including
the Bone Morphogenetic Protein (BMP), Wnt, Fibroblast Growth
Factor (FGF), Notch and hypoxia pathways, which induce the
expression of transcription factors from the Twist, Snail, SoxE,
FoxD, Ets, and Zeb families. These transcription factors modulate
the expression of the proteins involved in cell–cell junctions (type I
and type II cadherins) to reduce cell–cell junction strength and
promote the loss of apicobasal polarity. They also induce the expression of cell-matrix adhesion proteins (e.g., Integrins), extracellular
matrix components (e.g., Fibronectin, Collagen, Vitronectin, Laminin) and remodeling factors (e.g., ADAMs, MMPs) as well as
cytoskeleton proteins and regulators (e.g., Keratins, Vimentin,
small GTPases) necessary for front-back polarity and motility. In
the 1990s, a parallel was drawn between tumor progression/metastasis and EMT, identifying common actors and signaling pathways
(reviewed in [4, 5]). It was suggested that cancer cells were hijacking the embryonic EMT programs. Therefore, a better understanding of the molecular mechanisms regulating EMT was believed to
be of primary importance to understand tumor progression.
During the development of vertebrate embryos, EMT is essential for the delamination and long-distance migration of neural
crest (NC) cells, a transient multipotent population of cells that
arises at the neural plate border and gives rise to a wide variety of
derivatives [6]. Over the years, NC cells became a well establish
model for physiological EMT, delamination and migration
mechanisms, notably for its accessibility and ease of manipulation
both in vivo and ex vivo.
In particular, Xenopus NC development recapitulates the main
step of EMT and long-distance migration observed in most epithelial cancers. Xenopus NC cells can be defined as the cell population
initiating the expressing of a repertoire of EMT transcription factors (Twist1, Snail1/2, Ets1, Zeb2) at the border of the neural
plate, at the end of neurulation. Expression of these genes is controlled by the BMP, Wnt, FGF, Notch and hypoxia pathways [7–
9]. Xenopus NC cells then undergo a typical case of cadherin
switching, going from E-cadherin-dependent cell–cell junctions
to N-cadherin ones [10]. This switch is associated with a change
of cell polarity from apicobasal to front-rear, and is directly linked
to the acquisition of motility and dispersion, by endowing NC cells
with the ability to perform contact-inhibition of locomotion
[10]. Importantly, EMT in Xenopus NC cells is also linked with
258
Nade ` ge Gouignard et al.