Epithelial

to Mesenchymal Transition (EMT)

In order for cancer to metastasize, the cells at the primary tumour site must
be able to overcome the linkages holding the cells together and gain
migratory characteristics. This is possible due to a process called Epithelial to
mesenchymal transition (EMT) that enables a polarized, adherent epithelial
cell to undergo multiple biochemical changes and mutations in its DNA that
enables the cell to develop a mesenchymal cell phenotype. This allows the cell
to migrate away from its initial growth site and spread to distant regions of
the body via the blood.

Epithelial cells vs. Mesenchymal cells

Epithelial Cell Mesenchymal Cell
Differentiated cells which may have Spindle shaped cells
specific shapes and structures
depending on their funcstions
Derived from the ectoderm of a Derived from the mesoderm of a
trilaminar embryo trilaminar embryo
Cells are tightly connected to each Cells are highly mobile and are linked
other at junctions to each other at focal points
Normal cells line organs and vessels, Normal cells can differentiate into
providing protection connective tissue and provide support
Cells show apico-basal polarity No evidence of polarity seen in cells
Cancerous cells cannot secrete Cancerous cells can secrete
extracellular matrix components extracellular matrix components to
support proliferation


The Go vs Grow Hypothesis

A cancer cell may either proliferate (grow) or move (go). Proliferation is a
characteristic central to primary tumour cells whereas movement is central to
metastasizing cells. Within a single cell, this going and growing is separated in
space as well as in time. Cancer cells may switch between these 2 processes
but a more proliferative cell is less mobile; the converse holds true. However,
some cancer cells may also show a mixture of these 2 phenotypes.





Types of EMT

Based on the various functional consequences of EMTs, there are 3 broad
categories for the same:

Type 1 EMT: This type of EMT mostly aids the developmental process of a
fetus by giving rise to the endoderm and mesoderm of the trilaminar embryo.
Type 1 primary epithelial cells, called epiblasts, may undergo an EMT to form
mesenchymal cells that may differentiate into secondary epithelial cells by the
reverse process- a mesenchymal to epithelial transition (MET).

Type 2 EMT: This type of EMT is responsible for the triggering of inflammation
and fibrosis or healing of organs. Type 2 EMT is expressed over extended time
periods and may destroy an affected organ if the cause of inflammation is not
terminated.

Type 3 EMT: Differentiated secondary epithelial cells may form cancer cells
which undergo Type 3 EMT to enable the invasive and metastatic
characteristics of the cells.

The process of EMT in cancer cells

While EMT is a vital process for wound healing, embryonic development, and
organ fibrosis, it is also the initiative process for cancer metastasis. Pressures
in the tumour microenvironment, including hypoxemia or low oxygen levels
for the tumour cells, low concentrations of cytokines, chemokines as well as
other signaling molecules may cause the tumour cells to express a different
set of genes in their DNA which result in several characteristics conferred by
these cells:
• The cells become spindle shaped
• The cells lose their polarization and their junction points break down so
that they detach and break through the extracellular matrix with the aid of
ECM-degrading enzymes like Matrix metalloproteinase-2
• Downregulation of tumour suppressor proteins like E-Cadherin and
upregulation of metastatic proteins like N-Cadherin with the aid of
transcription factors belonging to the SNAIL, ZEB and TWIST families.
• Progressive loss of epithelial markers and gain of mesenchymal markers
• Cells can secrete extracellular matrix components
• Reorganization of cytoskeletal proteins like ZO proteins and claudins

As a result of some of these biochemical changes, the motility of the cancer
cells increases and they invade the local region containing normal body cells
before intravasating into the blood vessels.
Signaling pathways involved in EMT

1) The TGF-beta signaling pathway: TGF-beta is a signaling molecule which
plays a dual role- inducing programmed cell death in the early stages of
tumour growth and EMT, migration and invasion in the later stages. The
TFG-beta molecule binds to a receptor protein in the cell surface
membrane of the cancer cell that has a complementary shape to the
signaling molecule. This triggers a G-protein to activate a regulatory
protein called SMAD. This protein travels to the nucleus of the cancer cell,
where it aids the transcription of EMT-inducing target genes which results
in EMT.
2) The Wnt signaling pathway: The Wnt pathway operates in a similar way to
the TGF-beta pathway. Wnt, a signaling molecule, binds to a specific cell
surface receptor protein called FRIZZLED. This inactivates an enzyme called
Glycogen synthase kinase 3-beta (GSK3-beta) that is responsible for the
prevention of the stabilization of beta-catenin molecules. In the absence of
the GSK3-beta molecule, stable beta-catenin molecules travel to the
nucleus of the cancer cell, where they aid the transcription of EMT-
inducing target genes.

Although diligent research has been going on to find a successful remedy for
cancer metastasis, little is known about the mechanism of EMT in cancer cells.
Further research concerning how to break the signaling pathways involved in
EMT may spur the development of chemotherapeutic drugs that target the
cancer cells undergoing EMT. In the future, this may reduce the incidence of
cancer metastasis and allude to a solution to one of the most puzzling aspects
of cancer cell histology.