Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis /orthodontic courses by Indian dental academy

JOURNAL CLUB
Epithelial-Mesenchymal Transition:
At the Crossroads of Development and
Tumor Metastasis
INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indiandentalacademy.com

REFERENCES
• Epithelial-Mesenchymal Transition in tumor
microenvironment, Jing et al. Cell & Bioscience
2011, 1:29.
• Epithelial-mesenchymal signalling regulating tooth
morphogenesis, Irma Thesleff, Journal of Cell
Science 116, 1647-1648, 2003
• Epithelial-mesenchymal transitions: the importance
of changing cell state in development and disease, J.
Clin. Invest. 119:1438–1449 (2009).www.indiandentalacademy.com

• Genetics and tooth anomalies - an update, Oral &
Maxillofacial Pathology Journal, Vol. 4, Jan, 2013.
• Reiterative signaling and patterning during
mammalian tooth morphogenesis, Mechanisms of
Development 92 (2000) 19-29.
• Oral Anatomy, Histology and Embryology – 4th
Edition, Berkovitz.
• Textbook of Oral Anatomy & Histology - 4th Edition,
Tencate.

OVERVIEW OF EPITHELIAL-
MESENCHYMAL TRANSITION
• There are mainly two cell types -epithelial and
mesenchymal.
• Epithelial cells are adherent cells that form coherent
layers.
• Apico-basal polarity,
• Characteristic basally localized basement membrane
that separates the epithelium from other tissues.

• Mesenchymal cells are non-polarized and lack
intercellular junctions, such that they can move as
individual cells throughout the extracellular matrix.
• The epithelial and mesenchymal cell phenotypes are
not irreversible, and during embryonic development,
cells can convert between the epithelial and
mesenchymal states.

INTRODUCTION
• Epithelial-mesenchymal transition (EMT) and its
converse, mesenchymal-epithelial transition (MET),
are concepts first defined by Elizabeth Hay, 40 years
ago.
• EMT is a process, whereby epithelial cell layers lose
polarity and cell-cell contacts and undergo a
dramatic remodeling of cytoskeleton. ( Thiery, 2002)

3 major changes in cellular phenotype in
EMT
1. Morphological changes from a cobblestone-like
monolayer of epithelial cells with an apical-basal
polarity to dispersed, spindle-shaped mesenchymal
cells with migratory protrusions.

2. Changes of differentiation markers from cell-cell
junction proteins and cytokeratin intermediate
filaments to vimentin filaments and fibronectin.
3. Functional changes associated with the
conversion of stationary cells to motile cells that
can invade through ECM.

• The epithelial-mesenchymal transition is a highly
conserved cellular program that allows polarized,
immotile epithelial cells to convert to motile
mesenchymal cells.
• This important process was initially recognized during
embryonic development and recently been implicated
in promoting carcinoma invasion and metastasis.

• In this review, the authors have summarized and
compared major signaling pathways that
regulate the epithelial-mesenchymal transitions
during both development and tumor metastasis.

EMT IN DEVELOPMENT
• During development, the EMT program has been
observed to underlie a variety of tissue
remodeling events, including mesoderm
formation, neural crest development, secondary
palate formation.

Mesoderm Formation
• The earliest example of an EMT program
participating in embryogenesis is the formation of
mesoderm from the primitive ectoderm.
• The induction of mesoderm begins in a specific
area of the primitive ectoderm, termed the
primitive streak.

• The first event in mesoderm formation is the
invagination of the epithelial cells.
• This step is characterized by drastic morphological
changes in a small population of epithelial cells.

• Subsequently, these cells undergo mesenchymal
differentiation and migrate along the narrow
extracellular space underneath the ectoderm.
• The newly gained ability for such ectoderm-derived
cells to migrate along and through ECM marks the
completion of the EMT program during gastrulation.

Neural Crest Formation
• The neural crest develops at the
boundary between the neural plate
and the epidermal ectoderm.
• The presumptive neural crest cells
proceed to lose N-cadherin-
mediated cell-cell adhesion while
becoming excluded from the
neural epithelium. www.indiandentalacademy.com

• Upregulate genes required for mesenchymal
phenotype and migratory ability.
• High levels of fibronectin and hyaluronan
appear in the presumptive neural crest area
before the onset of migration.

Secondary Palate Formation
• Development of the secondary
palate requires fusion of the
palatal shelves at the midline.
• As the shelves approach one
another from opposite sides of
the developing oral cavity,
epithelial cells covering the tip
of each shelf intercalate and
form the medial epithelial seam.

• Soon after fusion, these medial epithelial cells
undergo an EMT and are integrated into the
mesenchymal compartment of the palate, thereby
completing the program of palatogenesis.

Epithelial-Mesenchymal Interactions During
Tooth Development
Initiation of Tooth Development
• Epithelium is the instructive component of
epithelial-mesenchymal interaction.
I arch epithelium + I arch mesenchyme Tooth germs
II arch epithelium + I or II arch mesenchyme No

• The potential for first arch epithelium to initiate tooth
development only exists in the very early stages of
odontogenesis.
• Thereafter, when first arch mesenchyme is combined
with second arch epithelium, tooth germs are formed.
• This suggests that, after initiation by the oral epithelium,
the ‘control’ of tooth development passes to the
mesenchyme.

Mechanisms responsible for specifying the tooth
forming zones in the oral region and for
controlling tooth number
• The expression of Pitx2 is restricted to dental
epithelium.
• Shh gene expression is restricted to the dental
epithelium at sites of tooth development and appears
to be involved in epithelial-mesenchymal
interactions.

• Wnt helps maintain boundaries between tooth-
forming areas and non-tooth forming regions.
• Pax9 and Msx1 genes appear to be required to
enable the tooth germ to progress beyond the bud
stage.

Mechanisms responsible for specifying tooth type
and tooth shape
Which of the two components is more important
for inducing morphogenesis and histogenesis –
the enamel organ or the dental papilla ?

• Culturing dental papilla mesenchyme with
epithelium from the developing foot pad – normal
tooth development.
• Incisor enamel organ is combined with a molar
papilla, the resulting tooth is a molariform and
vice versa.

• The results indicated that, at the cap stage of
tooth development, the principal organizer is
the dental papilla, in terms of both
morphogenesis and histogenesis.

Epithelial-mesenchymal signalling regulating
tooth morphogenesis
• Tooth morphogenesis is an advancing process that is
regulated by sequential and reciprocal interactions
between the epithelial and mesenchymal tissues.
• During which the simple oral ectoderm thickens,
buds, grows and folds to form the complex shape of
the tooth crown.

• During tooth initiation the ectoderm (white) thickens
and forms a placode that buds to the underlying
neural-crest derived mesenchyme (yellow).

• The epithelium signals to the mesenchyme, which
then condenses around the epithelial bud.
• During subsequent morphogenesis the epithelium
folds and grows to surround the dental papilla
mesenchyme (cap stage).

• The final shape of the tooth crown becomes fixed
during the bell stage, when the hard tissue forming
cells of the tooth (odontoblasts and amelobasts)
differentiate at the interface of the epithelium and
mesenchyme and deposit the dentin and enamel
matrices, respectively.

• The signal molecules of several conserved families
mediate cell communication during tooth
development.
• Most of them belong to the transforming growth
factor β (TGFβ), fibroblast growth factor (FGF),
Hedgehog and Wnt families.

• The signals mostly regulate interactions between the
ectoderm and mesenchyme, they also mediate
communication within one tissue layer.
• The genes regulated by the different signals include
transcription factors and signal receptors that regulate
the competence of the cells to respond to the next
signals, and thereby continue the communication
between cells and tissues.

Molecular regulation of tooth development from
initiation to crown morphogenesis

Molecular Regulation of EMT
• A number of distinct signaling pathways that
regulate EMT.
• The extracellular signals responsible for inducing
EMTs and the key transcriptional factors that
respond these signals.
• Such transcription factors function as master
regulators of the EMT programs.

TGF- β Signaling
• Members of the transforming growth factor- β (TGF- β)
superfamily have been implicated as major induction
signals of EMT during almost all of the morphogenetic
events.
• Primary inducer of EMT.

• TGF- β receptors are localized at tight junctions and
directly interact with two important regulators of
epithelial cell polarity and tight-junction assembly,
Par6 and Occludin.
• Phosphorylation of Par6 by TGF- β receptor leads
to a loss of tight junctions and apical-basal
polarity.

The Wnt Signal
• The Wnt pathway is implicated in the initiation and
maintenance of mesoderm formation and neural
crest formation.
• The role of Wnt signaling in heart valve induction is
also well documented.

The Notch Pathway
• Notch signalling has also been implicated in
modulating the EMT program during embryogenesis.
• Notch signalling regulates cranial neural crest cells
indirectly through its effect on expression of BMP
family members.

• Notch signalling is not sufficient and needs to be
co-ordinated with additional signalling inputs in
order to promote an EMT.

Signals from Tyrosine Kinase Receptors
• In addition to TGF-β, several other tyrosine kinase
receptors, including FGF, IGF, EGF family
members, and more recently PDGF, also play critical
roles in regulating EMT-like morphogenetic events
that occur during development.

Transcriptional Regulation
• During the execution of the EMT program, many
genes involved in cell adhesion, mesenchymal
differentiation, cell migration, and invasion are
transcriptionally altered.
• The best-studied transcriptional modulation during
EMT is that involving the E-cadherin gene promoter.

• The functional loss of E-cadherin in an epithelial
cell has been considered a hallmark of EMT.
• Detailed analyses of the human E-cadherin promoter
have identified E-box elements that are responsible
for its transcriptional repression.

• The zinc-finger transcription factor Snail was
found to directly bind to the E-boxes of the E-
cadherin promoter and to repress transcription
of this gene (Batlle et al., Cano et al., 2000).

• Several additional zinc-finger transcription factors
have been found to be capable of repressing E-
cadherin transcription, thereby causing the dissolution
of cell-cell adhesion that occurs during EMT, these
include Slug and two members of the ZEB family of
transcription factors, ZEB1 (dEF1) and ZEB2
(SIP1).

• Recently, E47 and Twist1, widely expressed
bHLH transcription factors, have been shown to
repress E-cadherin transcription directly by
binding to E-boxes in the E-cadherin promoter.

• Like Twist1, two additional embryonic
transcription factors, FOXC2 and Goosecoid have
also been demonstrated to induce EMTs in certain
epithelial cells, while they seem to lack the ability
to directly bind to the E-cadherin promoter.

EMT in Carcinoma Progression and
Metastasis
• In order for carcinoma cells to break away from
neighboring cells to invade adjacent cell layers, these
tumor cells must lose cell-cell adhesion and acquire
motility.
• Loss of E-cadherin has been associated with
carcinoma progression and poor prognosis in various
human tumors.

Molecular Network of Signaling Pathways and Transcription Factors that Regulate the
EMT Program in Carcinoma Cells

Future Perspectives
• Currently, the EMT program is only loosely defined by
certain cell morphological changes, changes of
differentiation markers from epithelial to mesenchymal
patterns, and the functional changes required for cells to
migrate and invade through ECM.
• As such, a clear molecular definition of the EMT
program during both development and tumor metastasis
is still elusive.

• Loss of E-cadherin may be the only consistently
reported molecular change occurring during the
various EMTs.
• Since loss of E-cadherin alone in normal epithelial
cells results in cell death rather than EMT, it appears
that the core EMT molecular program includes more
than E-cadherin repression.

• Identification of the molecular signature of the EMT may
be aided by the recent genomic analyses of the EMT
program occurring in embryogenesis and tumor
progression.
• Such a specific molecular signature of the EMT
program would create the framework for elucidation of
the complete signaling network that regulates the EMT
program.

Shortcomings
• Epithelial mesenchymal interaction during tooth
development has not been included.
• Anomalies due to disturbances in epithelial
mesenchymal interaction- not mentioned.

THANK YOU !!

Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis /orthodontic courses by Indian dental academy

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