Emt 2012

From leaving the Old World to colonizing the New World:

A role of epithelial-mesenchymal transitions
in carcinogenic progression

“By prevailing over all obstacles and distractions,
one may unfailingly arrive at his chosen goal or destination.”

Kay Wiebrands
November 2010

A role of epithelial-mesenchymal transitions in carcinogenic progression
A Master’s thesis by Kay WiebrandsCancer Genomics and Developmental Biology, Utrecht University, the Netherlands
Supervision: Evelyne Beerling, MSc
Jacco van Rheenen, PhD
Department of Cancer Biophysics
Hubrecht Institute, Utrecht, the Netherlands
November 2010

A role of epithelial-mesenchymal transitions in carcinogenic
progression
The epithelial-mesenchymal transition plays an important role in several developmentalprocesses,
tissue repair, but is also associated with fibrosis and cancer. During tumorigenic progression, EMT
pathways are used by cancer cells to gain a migratory and invasive phenotype, enabling these cells
to metastasize. This increased migratory potential relies on major changes in, for example, cell
adhesion molecule (CAM) expression and cytoskeletal reorganization. In this thesis, Idiscuss the
most important transcription factors during EMT, the effects these genes exert at the cellular level,
and how these transcription factor aid carcinogenic progression during the different steps of
metastasis. Studying the changing cell states during EMT and the responsible signaling pathways
during these processes will enhance our understanding of the metastatic cascade and lead tobetter
targeted therapies.
Introduction
“Omnis cellula e cellula”, Rudolf Virchow stated in
1863 in his book ‘Cellular Pathology’. Virchow
postulated his controversial idea that every cell
arises from another cell while he was studying
cancer and was subsequently seen as founder of
cellular pathology. Starting with the zygote,
proliferation is required to form all tissues and
organs in theadult body. Furthermore, as can be
seen by the ultimate diversity of tissues in a mature
organism, cells can assume different fates. This
process, known as differentiation, provides cells
with their distinct identities and specialized
functions. Initially, it was thought that differentiation
is a one-way process, and that terminally
differentiated cells, i.e. cells of the epithelium, areunable to lose their individuality and differentiate
towards a cell type of another lineage. However,
more recent studies have shown that cells of the
epithelium can actually dedifferentiate towards a
mesenchymal state, enabling the cells to migrate
and form new structures at a distant site. This
epithelial-mesenchymal transition (EMT) is a crucial
biological process during embryonicdevelopment
and wound healing. Next to these physiological
events, EMT pathways are also activated during
pathologies. Cancer cells can go through EMT to
detach from the primary tumor, migrate towards the
vasculature, get transported through the body by
the blood circulation, and settle at a distant site
where metastatic foci can be formed.
This thesis provides a short overview on the role
of EMTduring development and wound healing, but
is focused mainly on EMT during the different steps
of the metastatic cascade. I will discuss the key
transcription factors associated with cancer
progression and the effects of these factors on the
expression of different cell adhesion molecules

(CAMs) and the cytoskeleton, which are key
molecules in this process.
EMT in development and tissueregeneration
EMT involves the formation of a motile
mesenchymal cell from an immobile epithelial
predecessor (Figure 1). In literature three different
subtypes of EMT are recognized. Although EMT
per definition results in the formation of migratory
mesenchymal cells, the three subtypes all
represent a specific biological event (Zeisberg and
Neilson, 2009). The earliest EMT (type 1 EMT) in...