Clonal Interactions in Barrett’s Carcinogenesis.
Abstract
Introduction:
Barrett’s
oesophagus
(BO)
is
a
metaplastic
premalignant
disease
which
can
undergo
a
metaplasia-‐dysplasia-‐adenocarcinoma
pathway.
It
represents
an
example
of
field
cancerization
by
which
an
area
occupied
by
BO
can
undergo
molecular
and
genetic
changes
associated
with
carcinogenesis
without
being
phenotypically
cancerous.
Previous
work
suggested
that
non-‐cancerous
BO
contains
a
monoclonal
population.
More
recent
work
demonstrated
that
premalignant
Barrett’s
fields
are
polyclonal
suggesting
that
clonal
interactions
may
be
important
in
carcinogenesis.
It
is
the
aim
of
this
thesis
to
further
investigate
clonal
interactions
in
BO
by
understanding
the
effects
of
therapy
in
altering
the
relationships
of
clonal
populations
in
BO,
by
assessing
the
relationship
of
clonal
populations
in
dysplasia
as
compared
with
the
associated
cancer,
and
by
attempting
to
elucidate
a
potential
molecular
mechanism
of
clonal
interactions.
Results:
The
overall
results
can
be
summarised
as
follows:
1.Premalignant
clonal
populations
are
well
mixed
allowing
for
clonal
interactions.
However,
the
adenocarcinoma
associated
with
high
grade
dysplasia
is
monoclonal
and
derived
from
clonal
populations
found
in
the
dysplasia,
indicating
possible
clonal
interactions
during
carcinogenesis.
2.
Patients
with
persistent
disease
after
endoscopy
retain
the
same
clonal
populations.
However,
the
clonal
populations
of
recurrent
disease
changes
such
that
new
clonal
populations
arise
or
may
benefit
from
the
extinction
of
others.
3.
These
clonal
populations
may
be
derived
from
deep
submucosal
glands
or
may
be
found
in
phenotypically
normal
squamous
epithelium
indicating
a
common
stem
cell
origin.
4.
A
possible
mechanism
of
clonal
interaction
may
be
the
senescence
associated
secretory
phenotype:
senescence
is
abundant
in
BO
and
can
cause
proliferation
in
neighbouring
cells
in
vitro.
Conclusion:
This
thesis
has
investigated
the
implications
of
clonal
interactions
in
BO.
The
demonstration
of
temporal
clonal
heterogeneity
as
a
result
of
endoscopic
therapy,
as
well
as
spatial
clonal
heterogeneity
possibly
resulting
in
carcinogenesis,
asks
for
a
mechanistic
explanation
of
clonal
interactions.
The
consequences
of
senescence
may
well
provide
one
such
mechanism.
Authors
Zeki, Sebastian SimonCollections
- Theses [4352]