Beruflich Dokumente
Kultur Dokumente
Neophytou
1309539
Professor Viant
The
Biology
of
the
Cancer
Stem
Cell
Model
and
Potential
Therapeutic
Targets
Introduction
Malignant
tumours
arise
from
uncontrolled
cellular
growth,
they
are
better
known
as
cancer.
The
driving
force
behind
tumour
growth
has
long
been
the
subject
of
debate,
one
theory
which
is
gaining
much
reputation
as
a
result
of
experimental
evidence
is
the
cancer
stem
cell
model.
This
model
depicts
a
specific
subpopulation
of
cancer
cells
as
having
similar
properties
to
healthy
stem
cells,
the
most
important
being
the
ability
of
self-renewal
and
the
production
of
more
differentiated
cells.
Cancer
stem
cells
14
(CSCs)
are
what
initiate
tumourigenesis
and
may
be
the
cause
of
metastasis
and
relapse
in
sufferers
of
cancer.
This
essay
focuses
on
the
biological
mechanisms
of
CSCs
and
how
targeting
these
cells
may
prove
to
be
the
source
of
more
prolific
cancer
treatment.
Evidence
for
Cancer
Stem
Cell
Existence
The
identification
of
cells
with
tumourigenic
potential
through
specific
biomarker
expression
in
multiple
cancer
types
has
provided
evidence
for
the
CSC
model
and
exposed
prospective
therapeutic
targets,
the
following
are
a
few
examples
of
tumours
where
CSCs
have
been
identified
and
extracted.
Acute
Myeloid
Lymphoma
The
theory
of
CSCs
was
not
supported
by
experimental
evidence
until
1997
where
cells
thought
to
be
CSCs
were
identified
and
extracted
from
human
acute
myeloid
lymphoma
(AML)
and
shown
to
drive
AML
after
xenotransplantation
into
NOD/SCID
mice.
The
identification
of
CSCs
was
achieved
by
classifying
cells
by
their
cell
surface
receptors,
specifically
the
CD34
and
CD38
cell
markers.
These
biomarkers
were
chosen
due
to
+
-
haemopoetic
stem
cells
(HSCs)
expressing
a
CD34
CD38
phenotype,
as
HSCs
are
the
most
likely
target
for
the
site
of
malignant
transformation
in
AML
it
was
hypothesised
CSCs
from
AML
would
have
the
same
phenotype.
It
was
+
-
shown
that
xenotransplantation
of
CD34
CD38
AML
cells
initiated
tumourigenesis
in
the
NOD/SCID
mice.
Only
+
-
CD34
CD38 AML
cells
had
tumourigenic
capabilities,
therefore
proving
a
single
sub-population
was
responsible
for
driving
tumour
growth.
This
CSC
subpopulation
represented
only
one
cell
for
every
five-hundred
AML
cells,
this
1
suggested
CSCs
only
constitute
for
a
minute
fraction
of
the
total
cancer
cell
population.
However,
as
will
be
explained
later,
this
is
not
always
the
case.
Andreas Neophytou
1309539
Professor Viant
Brain
Tumour
Brain
tumour
cultures
from
fourteen
patients
were
exposed
to
conditions
which
allow
the
identification
and
extraction
of
normal
neural
stem
cells,
as
neurospheres,
in
order
to
detect
brain
tumour
stem
cells
(BTSCs).
Neurospheres
were
formed
by
a
minor
part
of
the
tumour
population
in
the
cultures.
The
biomarker
CD133,
expressed
by
neural
stem
cells
and
HSCs,
was
shown
to
be
present
on
BTSCs
thus
allowing
their
isolation
and
extraction.
The
BTSC
neurosphere
structures
were
allowed
to
grow
in
conditions
used
to
culture
healthy
neurospheres
for
one
week,
this
resulted
in
the
formation
of
cells
that
are
more
differentiated
than
BTSCs
and
+
express
a
phenotype
similar
to
that
of
the
original
tumour.
In
order
to
ensure
only
CD133 cells
had
tumourigenic
+
-
+
-
capabilities
both
CD133 and
CD133 cells
were
cultured,
only
CD133 cells
exhibited
tumourigenesis
whilst
CD133
cells
showed
no
such
potential.
This
therefore
proved
only
a
subpopulation
of
brain
tumours
expressed
tumour
5
initiating
capabilities
as
defined
by
the
CSC
model.
Breast
Cancer
The
principles
used
to
isolate
AML
CSCs
were
applied
to
breast
cancer
cells
in
order
to
determine
whether
CSCs
were
also
present
in
breast
cancers.
Biomarkers
CD44
and
CD24
were
used
in
order
to
classify
which
cells
were
tumourigenic,
this
is
due
to
the
heterogeneity
of
breast
cancer
cells
with
respect
to
these
biomarkers.
Breast
+
-
cancer
cells
that
were
xenotransplanted
into
NOD/SCID
mice
and
expressed
a
CD44
CD24
phenotype
resulted
in
-
+
tumour
formation,
whereas
CD44
CD24
cells
had
no
tumourigenic
potential.
Analysis
of
the
tumour
formed
by
21
the
xenotransplanted
cells
revealed
it
expressed
a
phenotype
similar
to
that
of
the
original
tumour.
The
identification
and
extraction
of
CSCs
from
other
cancers,
including
melanoma,
prostate,
colon,
pancreatic
and
many
others,
by
their
specific
cell-surface
biomarker
phenotype
has
proven
the
existence
of
CSCs
and
has
allowed
insight
into
their
potential
origin
and
biological
processes.
The
heterogeneity
of
cancer
cells
has
facilitated
the
identification
and
extraction
of
CSCs
as
they
express
a
different
phenotype
to
that
of
non-stem
cancer
cells.
Figure
2:
The
adjacent
table
shows
currently
discovered
cell
surface
biomarker
expression
that
is
specific
to
CSCs
from
various
cancer
types.
Source:
http://www.allthingsstemcell.co
m/wp-
content/uploads/2009/07/Cancer
StemCellMarkers2.jpg
Despite
this
research
providing
the
evidence
that
CSCs
exist
their
origin
is
still
the
subject
of
debate.
As
they
possess
the
ability
of
self-renewal
and
have
differentiative
capabilities,
normal
stem
cells
are
the
obvious
target
for
the
site
of
the
malignant
transformations
which
lead
to
the
production
of
CSCs.
As
pathways
that
regulate
self-
renewal
are
also
involved
in
tumourigenesis,
such
as
the
Wnt/-catenin
signalling
pathway,
this
connection
between
stem
cells
and
cancer
made
sense
as
less
mutations
would
be
needed
to
maintain
the
capability
of
self-
renewal
compared
to
ectopic
activation.
Also
this
self-renewal
capability
means
stem
cells
remain
in
the
body
much
longer
when
compared
to
more
differentiated
cells,
therefore
the
probability
of
a
series
of
mutations
leading
to
malignant
transformation
is
much
greater
in
stem
cells
when
compared
to
other
cells.
Evidence
supports
+
-
this
as
CSCs
isolated
from
AML
express
a
CD34
CD38
phenotype
identical
to
that
of
HSCs,
this
therefore
suggests
1
HSCs
and
not
progenitor
cells
to
be
the
site
of
malignant
transformation
in
AML.
Andreas Neophytou
1309539
Professor Viant
Andreas Neophytou
1309539
Professor Viant
Andreas
Neophytou
1309539
Professor Viant
Andreas Neophytou
1309539
Professor Viant
EMT
in
CSCs
is
initiated
by
dysregulation
of
various
signalling
pathways,
transforming
growth
factor-
(TGF-)
seems
to
play
a
vital
role
in
the
initiation
of
EMT.
TGF-
is
initially
involved
in
the
prevention
of
tumourigenesis
however
as
the
tumour
progresses
it
gains
resistance
to
the
anti-growth
effects
of
TGF-.
As
the
tumour
gains
resistance
to
TGF-
it
simultaneously
over
expresses
the
cytokine.
High
TGF-
levels
are
often
associated
with
4
greater
potential
for
a
metastatic
tumour
to
form
and
the
unlikelihood
of
survival.
TGF-
has
been
shown
to
induce
EMT
in
cancer
cells
by
activating
Smad
proteins,
which
regulates
the
transcription
of
specific
genes,
thus
altering
the
synthesis
of
certain
protein
and
cytokines.
Smad
proteins
form
complexes
with
EMT
associated
transcription
factors,
such
as
Snail1,
Zeb1/2
and
-catenin,
in
order
to
stimulate
mesenchymal
genes
and
inactivate
epithelial
genes.
This
is
well
exhibited
by
the
binding
of
Smads
to
Snail1,
resulting
in
E-cadherin
10
inhibition
and
a
loss
of
cell-cell
adhesion;
thus
promoting
mesenchymal
transformation
of
CSCs.
NF-B
is
also
thought
induce
EMT
through
interaction
with
Ras
proteins,
and
its
removal
results
in
the
initiation
of
2
mesenchymal-epithelial
transition
(MET).
NF-B
activation
has
been
shown
to
be
induced
by
TGF--activated
23
kinase
1,
therefore
suggesting
a
TGF-/NF-B
pathway
may
be
key
in
EMT.
Nevertheless
NF-B
is
vital
for
EMT
2
initiation
and
its
inhibition
will
result
in
impaired
metastatic
capabilities
of
the
tumour.
Andreas Neophytou
1309539
Professor Viant
The
ability
to
reprogramme
fibroblasts
into
neurons
and
hepatocytes
by
inducing
and
repressing
the
expression
of
certain
transcription
factors
has
proven
cells
have
the
ability
to
transdifferentiate.
For
metastasis
to
successfully
occur
CSCs
must
travel
to
the
metastatic
site,
therefore
they
must
also
experience
and
survive
multiple
and
varying
17
microenvironments.
As
the
genetic
material
in
cancer
cells
is
much
more
prone
to
mutation
when
compared
to
normal
cells
it
is
likely
CSCs
have
the
ability
to
alter
their
epigenetics
and
are
able
to
transdifferentiate.
If
CSCs
are
able
to
transdifferentiate
it
would
increase
their
chance
of
survival
during
the
initiation
of
metastasis,
due
to
the
18
ability
to
adapt
to
the
various
micro-environments
and
differing
conditions
they
will
be
exposed
to.
Figure
6:
Glioblastoma
stem
cells
(GSCs)
have
been
shown
to
generate
pericytes
in
order
to
increase
blood
and
oxygen
transport
to
the
tumour
micro-environment,
therefore
showing
CSCs
have
transdifferentiative
capabilities.
Pericytes
presence
in
the
tumour
micro-environment
has
been
shown
to
correlate
with
resistance
to
various
cancer
therapies.
Methods
of
removing
pericytes
from
a
tumour
in
an
attempt
to
reduce
this
resistance
have
proven
successful
and
has
resulted
in
tumour
deterioration
at
the
initial
8
site.
However
due
to
the
sudden
induction
of
a
hypoxic
micro-environment
by
removing
pericytes,
EMT
is
initiated
at
an
elevated
rate
14
resulting
in
metastasis.
Source:
http://origin-ars.els-
cdn.com/content/image/1-s2.0-
S0092867413002109-fx1.jpg
Figure
7:
Induction
of
hypoxia
has
also
been
linked
to
the
overexpression
of
the
Met
receptor
protein
and
increased
synthesis
of
hepatocyte
growth
factors.
Activation
of
Met
receptors
by
hepatocyte
growth
factors
results
increased
cellular
mobility
and
increased
invasive
capabilities.
Therefore
the
ability
for
hypoxia
to
initiate
EMT
in
CSCs
may
be
partly
due
to
the
increased
expression
of
Met
receptors
and
its
over-activation.
The
adjacent
image
shows
the
effects
of
Met
inhibition
on
metastasis.
NG2-tk+GCV
mice,
which
have
impaired
pericyte
synthesis,
were
shown
to
over-express
Met
and
undergo
lung
metastasis.
However
inhibition
of
Met
in
NG2-tk+GCV
mice
showed
almost
14
complete
suppression
of
metastasis.
Source:
http://origin-ars.els-
cdn.com/content/image/1-s2.0-
S1535610811004478-gr5.jpg
The
induction
of
EMT
in
CSCs
combined
with
their
potential
to
transdifferentiate
and
tumourigenic
capabilities
strongly
suggests
they
are
the
cause
of
metastatic
cancers.
This
information
can
therefore
be
utilised
to
design
therapies
directed
at
preventing
EMT
or
inducing
MET
in
order
to
decrease
the
invasive
potential
of
tumours.
Andreas Neophytou
1309539
Professor Viant
Andreas Neophytou
1309539
Professor Viant
Conclusion
The
discovery
of
CSCs
has
given
us
greater
knowledge
into
how
a
tumour
develops
and
thus
may
shed
light
on
new,
more
successful
ways
to
treat
cancer.
However,
CSCs
are
resistant
to
current
cancer
therapies
which
attack
the
bulk
of
the
tumour
which
is
mostly
made
up
of
non-stem
cancer
cells.
Therefore
even
if
the
bulk
of
the
tumour
is
removed
patients
will
still
be
vulnerable
to
a
relapse
as
only
a
single
CSC
is
required
to
survive
in
order
to
re-
initiate
tumourigenesis.
Therapies
should
be
and
are
being
designed
in
order
to
specifically
target
and
destroy
CSCs
therefore
removing
cells
with
self-renewal
capabilities
and
so
reducing
the
likelihood
of
any
form
of
relapse.
However
due
to
the
plasticity
of
cancer
cells
it
is
possible
that
solely
targeting
CSCs
may
prove
to
be
ineffective,
instead
a
combination
of
current
cancer
therapies
and
CSC
targeting
therapies
should
be
used
to
ensure
successful
treatment.
Targeting
CSCs
will
also
reduce
the
occurrence
of
a
metastatic
tumour,
however
ways
of
blocking
EMT
in
CSCs
must
also
be
discovered
in
order
to
further
reduce
the
risk
of
metastasis.
Overall
the
discovery
and
understanding
of
how
CSCs
function
should
prove
to
be
extremely
important
in
future
cancer
therapies.
References
1. Bonnet, D. & Dick, J.E., 1997. Human acute myeloid leukemia is organized as a hierarchy
that originates from a primitive hematopoietic cell. Nature Medicine, 3(7), pp.730737.
2. Huber, M.A. et al., 2004. NF-kappaB is essential for epithelial-mesenchymal transition
and metastasis in a model of breast cancer progression. The Journal of clinical
Andreas Neophytou
1309539
Professor Viant
11. Gupta, P.B., Chaffer, C.L. & Weinberg, R.A., 2009. Cancer stem cells: mirage or
reality? Nature Medicine, 15(9), pp.10101012.
12. Larue, L. & Bellacosa, A., 2005. Epithelial-mesenchymal transition in development and
cancer: role of phosphatidylinositol 3 kinase/AKT pathways. Oncogene, 24(50),
pp.74437454.
13. Lobo, N.A. et al., 2007. The biology of cancer stem cells. Annual review of cell and
Andreas Neophytou
1309539
Professor Viant