Desmoplastic stromal cells modulate tumour cell behaviour in pancreatic cancer
Abstract
Pancreatic
ductal
adenocarcinoma
(PDAC)
is
characterised
by
an
intense
desmoplastic
stromal
response
that
can
comprise
60
to
80%
of
tumour
volume
and
has
been
implicated
to
be
a
factor
in
promoting
tumour
invasiveness
and
the
poor
prognosis
associated
with
this
cancer
type.
It
is
now
well
established
that
pancreatic
stellate
cells,
which
are
vitamin
A
storing
cells
found
in
the
periacinar
spaces
of
the
stroma
in
the
normal
gland,
are
primarily
responsible
for
this
desmoplastic
reaction.
Studying
the
interaction
between
stellate
cells
and
cancer
cells
could
provide
for
a
better
understanding
of
the
disease
process.
During
the
evolution
of
PDAC,
the
stromal
proportion
increases
from
4%
in
the
normal
gland
to
up
to
80%.
We
hypothesised
that
there
is
an
optimal
proportion
of
stellate
cells
and
cancer
cells
that
modulates
tumour
behaviour
and
we
attempted
to
dissect
out
this
probable
‘tipping
point’
for
stromal
composition
upon
cancer
cell
behaviour
using
a
well-‐established
in
vitro
organotypic
culture
model
of
pancreatic
cancer.
The
cancer
cell-‐stromal
cell
interaction
led
to
extra-‐cellular
matrix
contraction
and
stiffening;
and
an
increase
in
cancer
cell
number.
The
stromal
stellate
cells
conferred
a
pro-‐survival
and
pro-‐
invasive
effect
on
cancer
cells
which
was
most
pronounced
at
a
stellate
cell
proportion
of
0.66-‐0.83.
The
expression
of
key
molecules
involved
in
EMT
and
metastasis
such
as
E-‐Cadherin
and
β-‐catenin
showed
a
reduction
and
this
was
found
to
be
most
significant
again
at
a
stellate
cell
proportion
of
0.66-‐0.83.
Stellate
cells
altered
the
genetic
profile
of
cancer
cells
leading
to
differential
expression
of
genes
involved
in
key
cellular
pathways
such
as
cell-‐cycle
and
proliferation,
cell
movement
and
death,
cell-‐cell
signalling,
and
inflammatory
response.
qRT-‐PCR
confirmed
the
differential
expression
of
the
top
differentially
expressed
genes
and
protein
validation
by
immunofluorescence
staining
using
PIGR
as
a
candidate
molecule
confirmed
the
experimental
findings
in
human
PDAC
specimens.This
study
demonstrates
that
the
progressive
accumulation
of
desmoplastic
stromal
cells
has
a
tumour
progressive
(pro-‐survival,
pro-‐invasive)
effect
on
cancer
cells
in
addition
to
stiffening
(contraction)
of
the
extracellular
matrix
(maximum
effect
when
the
stromal
cell
proportion
is
60-‐
80%).
This
is
mediated
through
a
number
of
signalling
cascades
and
molecular
targets.
Dampening
this
tumour-‐promoting
interaction
between
cancer
and
stromal
cells
by
‘multi-‐targeting’
agents
may
allow
traditional
chemo-‐
and/or
radiotherapy
to
be
effective.
Authors
Kadaba, RaghunandanCollections
- Theses [3834]
