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There are a renewed interest metabolic alterations and its impact on cancer development and progression. The metabolism of cancer cells is reprogrammed in order to support their rapid proliferation. Elevated fatty acid synthesis is one of the most important aberrations in cancer cell metabolism, and is required both for carcinogenesis and cancer cell survival. We have previously shown that cancer cells explore metabolic pathways especially autophagy and particularly enhanced glycolysis and suppressed oxidative phosphorylation to promote treatment resistance. To support cell proliferation in cancer, lipid metabolism and biosynthetic activities is required and often up-regulated. Here we bring lipid metabolic pathways into focus and summarized details that suggest a new perspective for improving chemotherapeutic responses in cancer treatment, and indicate the need to design more inclusive molecular targeting for a better treatment response.
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Lipidmetabolismandcancerprogression:The
missingtargetinmetastaticcancertreatment
ArticleinJournalofappliedbiomedicine·October2014
DOI:10.1016/j.jab.2014.09.004
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UniversityofSaskatchewan
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FederalUniversityNdufuAlikeIkwo
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Review
Article
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment
Maxwell
Omabe
a,b,
*,
Martin
Ezeani
b
,
Kenneth
Nwobini
Omabe
c
a
Department
of
Oncology,
Cancer
Research
Division,
University
of
Saskatchewan,
Saskatoon,
Canada
b
Molecular
Cancer
Biology
Research
Group,
Molecular
Pathology
and
Immunology
Division,
Department
of
Medical
Laboratory
Sciences,
School
of
Biomedical
Science,
Faculty
of
Health
Science,
Ebonyi
State
University,
Nigeria
c
Department
of
Pathology
and
Molecular
Medicine,
University
of
Leicester,
United
Kingdom
Introduction
The
earliest
report
of
Otto
Warburg
about
100
years
ago
that
cancer
cells
exhibited
dysregulated
metabolism
compared
with
normal
cells,
lead
to
a
hypothesis
that
molecular
oxygen
defects
in
cells
results
in
a
slow
adaptation
to
enhanced
aerobic
glycolysis
and
may
constitute
a
metabolic
switch
that
caused
cancer
(Warburg,
1956).
The
enhanced
aerobic
glycoly-
sis
exhibited
by
some
cancer
cells
provides
them
with
a
characteristic
signature
and
results
in
increased
dependence
on
glucose
(Omabe
et
al.,
2013).
Thus,
Warburg
effect
is
a
distinctive
feature
of
many
human
and
animal
tumors
(Omabe
et
al.,
2013).
In
majority
of
cancers,
glucose
is
converted
mostly
to
lactate
(Fig.
1),
and,
therefore,
only
2
moles
of
ATP
per
1
mole
of
glucose
are
synthesized,
which
is
therefore
insufcient
for
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
17
July
2014
Received
in
revised
form
17
September
2014
Accepted
19
September
2014
Available
online
xxx
Keywords:
Adipocytes
Fatty
acid
synthase
Breast
cancer
Prostate
cancer
Palmitate
Glycolysis
Inammation
Cytokines
Oxidative
phosphorylation
Tumorigenesis
a
b
s
t
r
a
c
t
There
is
a
renewed
interest
in
metabolism
alterations
and
its
impact
on
cancer
development
and
progression.
The
metabolism
of
cancer
cells
is
reprogrammed
in
order
to
support
their
rapid
proliferation.
Elevated
fatty
acid
synthesis
is
one
of
the
most
important
aberrations
in
cancer
cell
metabolism,
and
is
required
both
for
carcinogenesis
and
cancer
cell
survival.
We
have
previously
shown
that
cancer
cells
explore
metabolic
pathways
especially
autophagy
and
particularly
enhanced
glycolysis
and
suppressed
oxidative
phosphorylation
to
promote
treatment
resistance.
To
support
cell
proliferation
in
cancer,
lipid
metabolism
and
biosyn-
thetic
activities
is
required
and
often
up-regulated.
Here
we
bring
lipid
metabolic
pathways
into
focus
and
summarized
details
that
suggest
a
new
perspective
for
improving
chemo-
therapeutic
responses
in
cancer
treatment,
and
indicate
the
need
to
design
more
inclusive
molecular
targeting
for
a
better
treatment
response.
#
2014
Faculty
of
Health
and
Social
Studies,
University
of
South
Bohemia
in
Ceske
Budejovice.
Published
by
Elsevier
Urban
&
Partner
Sp.
z
o.o.
All
rights
reserved.
*Corresponding
author
at:
Department
of
Oncology,
Cancer
Research
Division,
University
of
Saskatchewan,
Saskatoon,
Canada.
E-mail
address:
Maswello2002@yahoo.com
(M.
Omabe).
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
Available
online
at
www.sciencedirect.com
ScienceDirect
journal
homepage:
http://www.elsevier.com/locate/jab
1214-021X/$
see
front
matter
#
2014
Faculty
of
Health
and
Social
Studies,
University
of
South
Bohemia
in
Ceske
Budejovice.
Published
by
Elsevier
Urban
&
Partner
Sp.
z
o.o.
All
rights
reserved.
http://dx.doi.org/10.1016/j.jab.2014.09.004
cancer
cells
to
cope
with
its
energy
requirements.
However,
in
most
non-cancer
cells,
the
mitochondria
produce
CO
2
and
H
2
O
from
glucose,
and
38
moles
of
ATP
are
synthesized
per
1
mole
of
glucose
from
the
oxidative
metabolism
under
aerobic
conditions
(Omabe
et
al.,
2013).
From
glucose
metabolism
to
fatty
acid
biosynthesis
Full
detail
of
glucose
metabolism
can
be
found
in
appropriate
textbook
of
Biochemistry.
The
understanding
of
metabolism
forms
a
unique
component
of
practice
for
Chemical
Patholo-
gist.
In
brief,
following
cellular
uptake
by
glucose
transporters,
glucose
is
phosphorylated
by
hexokinases
to
glucose-6-
phosphate
(Figs.
1
and
2).
Most
of
glucose-6-phosphate
enters
the
glycolytic
pathway
to
generate
pyruvate
and
ATP.
Pyruvate
is
converted
to
acetyl
coenzyme
A
(CoA),
and
enters
the
citric
acid
cycle
in
the
mitochondria
(Omabe
et
al.,
2013).
Depending
on
the
oxygen
availability
citrate
can
be
fully
oxidized
to
generate
ATP
by
oxidative
phosphorylation,
or
it
can
be
transported
to
the
cytoplasm
where
it
is
converted
back
to
acetyl-CoA
(the
requisite
building
block
for
fatty
acid
(FA)
synthesis)
by
ATP
citrate
lyase
(ACLY).
Under
anaerobic
conditions
pyruvate
can
also
be
used
as
an
electron
acceptor,
resulting
in
the
lactate
dehydrogenase
(LDH)-catalyzed
pro-
duction
of
lactate,
which
is
secreted
from
the
cell.
A
portion
of
the
acetyl-CoA
is
carboxylated
to
malonyl-CoA
by
acetyl-CoA
carboxylase
(ACACA),
the
primary
rate-limiting
enzyme
and
site
of
pathway
regulation.
Fatty
acid
synthase
(FASN),
the
main
biosynthetic
enzyme,
performs
the
condensation
of
acetyl-CoA
and
malonyl-CoA
to
produce
the
16-carbon
saturated
FA
palmitate
and
other
saturated
long-chain
FAs,
which
is
dependent
on
NADPH
as
a
reducing
equivalent.
NADPH
(which
is
essential
for
FA
synthesis)
is
provided
in
a
reaction
catalyzed
by
malic
enzyme,
or
can
be
acquired
through
the
pentose
phosphate
pathway.
Saturated
long-
chain
FAs
can
be
further
modied
by
elongases
or
desaturases
to
form
more
complex
FAs,
which
are
used
for
the
synthesis
of
various
cellular
lipids
such
as
phospholipids,
triglycerides
and
cholesterol
esters,
or
for
the
acylation
of
proteins.
Elevated
activities
of
citrate
synthase
(CS)
and
ACLY
are
observed
in
some
malignancies,
hence,
inhibition
of
ACLY
is
known
to
lead
to
cessation
of
tumor
growth
(Schlichtholz
et
al.,
2005;
Vazquez-Martin
et
al.,
2009).
This
is
because
cell
proliferation
requires
a
constant
supply
of
lipids
and
lipid
precursors
to
fuel
membrane
biogenesis
and
protein
modication.
In
this
review,
we
searched
a
number
of
available
literatures
through
Med-
line,
pub
med,
Google
scholar
and
EMBO
search
engine
using
key
words
like
cancer
metabolism,
fatty
acid,
cytokines
and
metastasis.
This
work
therefore
highlights
a
synthesis,
and
focused
on
the
role
of
adipocytes
derived
molecules
and
lipid
metabolism
in
cancer
progression,
and
underscored
current
understanding
toward
exploring
this
physiologic
phenomena
Fig.
1
Malignant
cells
exhibit
a
profound
imbalance
toward
anabolic
metabolism.
Cancer
cells
take
up
high
amounts
of
glucose
(Glu;
underpinning
the
Warburg
effect)
and
glutamine
(Gln)
and
divert
them
to
the
phosphate
pentose
pathway
and
lipid
biosynthesis,
respectively.
Coupled
to
an
increased
uptake
of
glycine
(Gly)
and
serine
(Ser),
which
are
required
for
protein
synthesis
and
sustain
anaplerotic
reactions
that
replenish
Krebs
cycle
intermediates,
this
generates
sufficient
building
blocks
(that
is,
nucleic
acids,
proteins
and
membranes)
for
proliferation.
Source:
Adapted
from
Galluzzi
et
al.
(2013).
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x2
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
in
designing
and
developing
next
generation
treatment
target
for
cancer
control.
Details
discussed
in
this
review
suggest
that
lipid
metabo-
lism
and
indeed
adipocyte
derived
products
may
important
molecular
target
for
better
cancer
treatment.
Hypoxia
controls
the
metabolic
switch
The
switch
of
cellular
metabolism
from
mitochondrial
respiration
to
anaerobic
glycolysis
is
a
recognized
hallmark
of
cancer
cells
and
associated
with
tumor
malignancy
(Lu
et
al.,
2008;
Omabe
et
al.,
2013).
However,
the
mechanism
of
this
metabolic
switch
remains
largely
unknown.
Interest-
ingly,
some
tumors
display
a
diminished
ux
of
glucose
carbon
through
PDH-catalyzed
reaction,
due
to
increased
PDHK
(pyruvate
dehydrogenase
kinase)
activity,
under
the
inuence
either
hypoxia
or
oncogenic
factors.
In
fact
Lu
et
al.
(2008)
showed
that
hypoxia-inducible
factor-1
(HIF-1)
in-
duced
pyruvate
dehydrogenase
kinase-3
(PDK3)
expression
leading
to
inhibition
of
mitochondrial
respiration
and
increased
lactic
acid
accumulation
and
drugs
resistance.
Whereas
knocking
down
PDK3
inhibited
hypoxia-induced
cytoplasmic
glycolysis
and
cell
survival
(Lu
et
al.,
2008).
These
suggests
that
increased
PDK3
expression
due
to
elevated
HIF-1alpha
in
cancer
cells
may
play
critical
roles
in
metabolic
switch
during
cancer
progression
and
chemo
resistance
in
cancer
therapy
and
points
to
a
possible
use
of
carbon
source
other
than
glucose,
to
ll
up
its
increasing
lipid
requirement.
Data
from
a
western
blot
analysis
demonstrated
that
PDK3
was
markedly
increased
in
colon
cancer
compared
to
cells
in
adjacent
normal
tissues,
and
that
PDK3
expression
was
positively
correlated
HIF-1a,
a
known
cause
of
treatment
failures
and
cancer
progression
(Omabe
et
al.,
2011).
Therefore,
the
implication
of
hypoxia
mediated
mitochondrial
dysfunction
has
been
shown
to
be
a
loss
of
ability
to
trigger
apoptosis,
and
a
gain
in
survival
advantage
and
mutagenic
damage
to
DNA
(Omabe
and
Odii,
2013).
Fig.
2
illustrating
elevated
fatty-acid
metabolism
with
growth
factor
signaling
in
cancer
in
cancer
cells
play
essential
roles
including
tumor-related
FASN
overexpression.
FASN
and
ACLY,
PI3K
are
all
SREBP
-1c
regulated
in
cancer
cells.
Hypoxic
tumor
microenvironment,
as
well
as
multiple
other
factors
are
involved
in
FASN
overexpression
and
elevated
lipogenesis
in
cancer.
ACLY,
ATP
citrate
lyase;
ACC,
acetyl-CoA
carboxylase;
FASN,
fatty-acid
synthase;
ACS,
acyl-CoA
synthetase;
EGFR,
epidermal
growth
factor
receptor;
ER,
estrogen
receptor;
AR,
androgen
receptor;
PR,
progesterone
receptor;
PI3K,
phosphatidylinositol-3-kinase;
MAPK,
mitogen-activated
protein
kinase;
SREBP-1c,
sterol
regulatory
element-binding
protein
1c;
USP2a,
ubiquitin-specific
protease-2a.
Source:
Adapted
from
Mashima
et
al.
(2009).
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x
3
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
Oncometabolites
mediate
hypoxia
responses
The
oncogenic
roles
of
2-hydroxyglutarate
((R)-2HG),
succinate
and
fumarate
have
been
reported
(Adam
et
al.,
2014).
While
(R)-2HG
is
a
product
of
gain-of-function
mutations
in
the
cytosolic
and
mitochondrial
isoforms
of
isocitrate
dehydroge-
nase
(IDH),
succinate
and
fumarate
are
intermediates
of
the
Krebs
cycle.
Loss-of-function
mutations
in
the
tumor-sup-
pressor
genes
succinate
dehydrogenase
(SDH)
and
fumarate
hydratase
(FH)
cause
intracellular
accumulation
of
succinate
and
fumarate,
respectively
(Adam
et
al.,
2014).
These
three
oncometabolites
(R)-2HG,
succinate
and
fumarate
are
suf-
ciently
similar
in
structure
to
2-oxogluratate
(2OG)
and
inhibit
a
range
of
2OG-dependent
deoxygenates,
including
hypoxia-
inducible
factor
(HIF)
prolyl
hydroxylases
(PHDs),
histone
lysine
demethylases
(KDMs)
and
the
ten-eleven
translocation
(TET)
family
of
5-methylcytosine
(5mC)
hydroxylases,
leading
to
HIF-mediated
hypoxia
responses
and
alterations
in
gene
expression
through
global
epigenetic
remodeling
(Omabe
et
al.,
2011;
Adam
et
al.,
2014);
that
may
contribute
to
malignant
transformation.
In
addition,
the
(R)-2HG
alone
has
been
shown
in
some
settings
to
act
as
a
co-substrate
for
PHD2
in
the
prolyl
hydroxylation
of
HIF1a,
leading
to
cellular
transformation
as
a
result
of
reduced
HIF
expression,
while
fumarate
can
irreversibly
modify
cysteine
residues
in
proteins
via
succination,
leading
to
transcription
of
genes
involved
in
antioxidant
response
(Adam
et
al.,
2014).
Fumarate
accumula-
tion
may
also
impact
on
cytosolic
pathways
potentially
hampering
the
urea
and
purine
nucleotide
cycles
(Adam
et
al.,
2014).
The
adipocytes
and
adipose-derived
proteins
Fatty
acid
synthase
(FASN)
reaction
constitutes
the
last
step
in
palmitate
synthesis.
Fatty
acids
produced
by
FASN
are
in
excess
of
cell
requirements,
and
are
stored
in
the
adipocytes.
Increasing
mass
of
adipocytes
in
an
individual
results
in
obesity.
The
increasing
prevalence
of
obesity
is
of
great
concern
for
public
health
as
it
is
known
to
be
a
major
contributor
to
the
global
burden
of
disease.
The
prevalence
of
overweight,
dened
as
a
body
mass
index
(BMI,
weight/
height)
of
2529
kg/m
2
,
and
obesity,
BMI
30
kg/m
2
,
has
been
rapidly
increasing
during
recent
decades
in
both
developed
and
developing
countries.
In
the
US
and
Europe,
obesity
affects
approximately
1525%
of
men
and
1035%
of
women.
There
are
two
types
of
adipose
tissues,
white
adipose
tissue
(WAT)
and
brown
adipose
tissue
(BAT).
Adipose
tissue
is
composed
of
various
cell
types:
lipid-laden
mature
adipocytes
and
the
remaining
stoma
vascular
fraction
(SVF)
that
includes
blood
cells,
endothelial
cells,
and
macrophages
(Weisberg
et
al.,
2003).
In
fact,
adipose
tissue
is
an
important
endocrine
organ
that
secretes
many
biologically
active
substances,
such
as
leptin,
adiponectin,
tumor
necrosis
factor
a
(TNF-a),
and
monocyte
chemo
attractant
protein
1
(MCP-1),
which
are
collectively
termed
adipocytokines
(Weisberg
et
al.,
2003).
The
physiologic
role
of
these
adipose-derived
proteins
are
not
fully
understood,
while
some
cytokines
have
both
immunomodulatory
func-
tions
and
act
as
systemic
or
auto-/paracrine
regulators
of
metabolism,
others
such
as
leptin
and
adiponectin
are
regulators
of
both
metabolism
and
inammation
(Juge-
Aubry
et
al.,
2005)
(see
Fig.
3).
Adipocyte
derived
factors
and
cancer
progression
In
ovarian
cancer,
Nieman
et
al.
(2011)
demonstrated
that
primary
human
omental
adipocytes
promoted
homing,
migration
and
invasion
of
ovarian
cancer
cells,
and
that
adipokines
including
interleukin-8
(IL-8)
mediate
these
activities.
In
fact,
adipocyte-ovarian
cancer
cell
coculture
resulted
in
direct
transfer
of
lipids
from
adipocytes
to
ovarian
cancer
cells
and
promoted
in
vitro
and
in
vivo
tumor
growth
(Nieman
et
al.,
2011).
Furthermore,
mechanistic
studies
from
in
vitro
experiments
showed
that
coculture
induced
lipolysis
in
adipocytes
and
b-oxidation
in
cancer
cells,
suggesting
that
adipocytes
act
as
an
energy
source
for
the
cancer
cells
(Nieman
et
al.,
2011).
A
protein
array
identied
upregulation
of
fatty
acid-binding
protein
4
(FABP4,
also
known
as
aP2)
in
omental
metastases
as
compared
to
primary
ovarian
tumors,
and
that
FABP4
expression
was
detected
in
ovarian
cancer
cells
at
the
adipocyte-tumor
cell
interface,
and
FABP4
deciency
substantially
impaired
metastatic
tumor
growth
in
mice,
indicating
that
adipocytes
derived
factors
including
FABP4
has
a
key
role
in
ovarian
cancer
metastasis
(Nieman
et
al.,
2011).
These
data
indicate
adipocytes
provide
fatty
acids
for
rapid
tumor
growth,
identifying
lipid
metabolism
and
transport
as
new
targets
for
the
treatment
of
cancers
where
adipocytes
are
a
major
component
of
the
microenvi-
ronment.
In
breast
cancer,
evidence
from
two-dimensional
cocul-
ture
experiments
showed
that
murine
and
human
tumor
cells
cocultivated
with
mature
adipocytes
exhibit
increased
invasive
capacities
in
vitro
and
in
vivo,
using
an
original
(Dirat
et
al.,
2011)
the
authors
also
demonstrated
that
adipocytes
cultivated
with
cancer
cells
exhibit
an
altered
phenotype
in
terms
of
delipidation
and
decreased
adipocyte
markers
associated
with
the
occurrence
of
an
activated
state
charac-
terized
by
over
expression
of
proteases,
including
matrix
metalloproteinase-11,
and
proinammatory
cytokines
[in-
terleukin
(IL)-6,
IL-1b]
(Dirat
et
al.,
2011).
In
fact
Dirat
and
Colleagues
in
2011
claried
using
both
in
vitro
and
in
vivo
evidence
that
(i)
invasive
cancer
cells
dramatically
impact
surrounding
adipocytes;
(ii)
peritumoral
adipocytes
exhibit
a
modied
phenotype
and
specic
biological
features
sufcient
to
be
named
cancer-associated
adipocytes
(CAA);
and
(iii)
CAAs
modify
the
cancer
cell
characteristics/phenotype
leading
to
a
more
aggressive
behavior.
Thus
strongly
pointing
that
that
adipocytes
participate
in
a
highly
complex
vicious
cycle
orchestrated
by
cancer
cells
to
promote
tumor
progres-
sion
that
might
be
amplied
in
obese
patients,
indicating
that
novel
therapy
designed
toward
targeting
adipocytes
derived
factors
may
become
the
next
generation
cancer
treatment
and
chemoprevention.
This
is
supported
by
a
number
of
published
studies
in
the
literature.
For
instance,
repro-
grammed
adipocytes
have
been
shown
to
provide
growth
factors
and
fuel
to
cancer
cells,
promoting
metastasis,
and
sustaining
uncontrolled
growth
(Ribeiro
et
al.,
2012).
Ribeiro
et
al.
(2012)
have
shown
that
peri-prostatic
(PP)
adipose
tissue
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x4
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
explants
from
overweight/obese
prostate
cancer
patients
had
signicantly
elevated
matrix
metalloproteinases
9
MMP9
activity,
which
is
correlated
with
disease
progression
and
metastasis
(Ribeiro
et
al.,
2012).
When
PC-3
cells
were
stimulated
with
condition
medium
from
PP
adipose
tissue
explants,
increased
proliferative
and
migratory
capacities
resulted
on
the
other
hand,
when
LNCaP
cells
are
stimulated
with
PP
explants
condition
medium
enhanced
cancer
cell
motility
resulted
(Ribeiro
et
al.,
2012).
Put
together,
these
studies
concluded
that
PP
adipose
tissue
may
play
an
important
role
by
releasing
cytokines
and
growth
factors,
such
as
interleukin-6
and
matrix
metalloproteinases,
that
may
promote
tumor
cell
proliferation
and
migration.
These
interactions
may
have
a
key-role
in
determining
prostate
cancer
aggressiveness
and
progression.
Thus,
it
appears
therefore
that
cross-talk’’
mechanism
may
exist
between
adipose
tissue
and
cancer
cells
that
may
ultimately
result
in
more
aggressive
prostate
cancer
and
promote
disease
progression,
especially
in
obese
patients.
Oncophospholipid;
resources
for
cell
lipid
membrane
biosynthesis
Fatty
acid
synthesis
is
energetically
expensive,
requiring
ATP,
NADPH
and
redirection
of
acetyl-CoA
from
oxidative
path-
ways,
where
it
would
produce
ATP,
to
lipogenesis.
It
is
not
clear
if
cancer
cells
prefer
using
fatty
acid
produced
endogenously
through
FASN
or
exogenously.
Endogenous
fatty
acid
resources
It
is
generally
accepted
that
many
types
of
tumor
including
breast
cancer
cells
endogenously
synthesize
95%
of
fatty
acids
Fig.
3
Molecular
mechanism
underlying
adipocyte,
macrophages
interaction
and
inflammation
and
cancer.
increased
metabolic
stresses
such
as
hypoxia,
and
oxidative
stress
and
down-regulation
of
MKP-1
are
involved
in
the
induction
of
inflammatory
changes
in
adipocytes
during
the
course
of
adipocyte
hypertrophy.
T
lymphocytes,
and
macrophages,
infiltrate
into
obese
adipose
tissue
(ii)
and
thus,
enhance
the
inflammatory
changes
through
the
crosstalk
with
parenchymal
adipocytes
(iii).
For
example,
the
macrophage-derived
TNF-a
induces
the
release
of
saturated
fatty
acids
from
adipocytes
via
lipolysis,
which
in
turn,
induces
inflammatory
changes
in
macrophages
via
TLR4.
Such
a
paracrine
loop
between
adipocytes
and
macrophages
constitutes
a
vicious
cycle,
thereby
accelerating
further
adipose
tissue
inflammation.
Recent
evidence
has
also
pointed
to
the
heterogeneity
of
adipose
tissue
macrophages;
i.e.,
M1
or
‘‘classically
activated’’
(proinflammatory)
macrophages
and
M2
or
‘‘alternatively
activated’’
(anti-inflammatory)
macrophages.
Infiltrated
macrophages
exhibit
a
phenotypic
change
from
M2
to
M1
polarization
in
obese
adipose
tissue,
thereby
accelerating
adipose
tissue
inflammation.
TNF-R,
TNF-a
receptor.
Source:
Adapted
from
Suganami
and
Ogawa
(2010).
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x
5
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
(FAs)
de
novo,
despite
having
adequate
nutritional
lipid
supply.
Evidence
from
published
studies
indicates
that
activation
of
endogenous
FA
biosynthesis
was
sufcient
to
signicantly
enhance
breast
epithelial
cell
proliferation
and
survival
(Vazquez-Martin
et
al.,
2008).
When
analysing
molecular
mechanisms
by
which
acute
activation
of
de
novo
FA
biosynthesis
triggered
a
transformed
phenotype,
it
was
shown
that
HBL100
cells,
transiently
transfected
with
pCMV6-
XL4/FASN,
to
enhance
their
endogenous
lipid
synthesis,
were
found
to
exhibit
a
dramatic
increase
in
the
number
of
phosphor-tyrosine
(Tyr)-containing
proteins,
especially
among
the
key
members
of
the
HER
family
(erbB)
network,
which
were
found
switched-off
in
mock-transfected
HBL100
cells
(Vazquez-Martin
et
al.,
2008).
Further
analysis
from
that
study
suggested
that
FASN
over
activation
signicantly
increased
(>200%)
expression
levels
of
epidermal
growth
factor
receptor
and
HER2
proteins
in
HBL100
cells,
and
conrmed
that
acute
activation
of
endogenous
FA
biosynthe-
sis
specically
promoted
hyper-Tyr-phosphorylation
of
HER1
and
HER2
in
MCF10A
cells;
which
triggered
HER1/HER2-breast
cancer-like
phenotype
(Vazquez-Martin
et
al.,
2008).
This
suggests
that
exacerbated
endogenous
FA
biosynthesis
in
non-cancerous
epithelial
cells
may
be
sufcient
to
induce
a
cancer-like
phenotype.
Exogenous
fatty
acid
resources
Recently,
it
has
been
shown
that
show
that
cancer
cells
and
tumors
robustly
incorporate
and
remodel
exogenous
palmi-
tate
into
structural
and
oncogenic
glycerophospholipids,
sphingolipids,
and
ether
lipids;
and
that
fatty
acid
incorpo-
ration
into
oxidative
pathways
was
reduced
in
aggressive
human
cancer
cells,
and
instead
shunted
into
pathways
for
generating
structural
and
signaling
lipids,
suggesting
that
cancer
cells
do
not
solely
rely
on
de
novo
lipogenesis,
but
also
utilize
exogenous
fatty
acids
for
generating
lipids
required
for
proliferation
and
protumorigenic
lipid
signaling
(Louie
et
al.,
2013).
In
fact,
by
comparing
the
rate
of
incorporation
of
exogenously
fatty
acid,
palmitate
and
endogenous
fatty
acid,
acetate,
in
MCF-10A,
non-transformed
human
breast
epithe-
lial
cells,
and
MCF-7
(ER+)
and
MDA-MB-231
(ER)
human
breast
cancer
cells,
Hopperton
et
al.
(2014)
showed
that
cancer
cell
lines
incorporated
23
fold
more
radioactive
acetate
into
their
total
lipids
than
the
non-cancer
cells,
reecting
a
higher
rate
of
endogenous
fatty
acid
synthesis.
This
suggests
that
cancer
cells
explore
both
the
endogenous
and
exogenous
lipid
resources
to
promote
phospholipid
requirements
to
sustain
cell
survival
advantage.
In
addition,
it
appears
that
the
increased
usage
of
exogenous
fatty
acid
by
cancer
cells
is
for
used
in
supporting
membrane
synthesis.
For
example
evidence
from
experimental
studies
have
shown
that
cancer
cell
lines
incorporated
a
signicantly
higher
proportion
of
exogenous
palmitate
into
ChoGpl
a
predominant
compo-
nent
of
cell
membranes,
compared
to
fatty
acids
derived
endogenously
from
acetate
(Hopperton
et
al.,
2014).
This
selectivity
for
exogenously-derived
fatty
acids
for
membrane
synthesis
does
not
support
the
notion
that
endogenously
synthesized
fatty
acids
are
either
required
for,
or
specically
directed
toward,
membrane
synthesis
in
cancer
cells.
It
appears
that
endogenously
synthesized
fatty
acids
may
be
utilized
in
the
same
ways
as
those
supplied
exogenously,
given
that
that
cancer
cells
do
not
seem
to
have
a
preference
for
endogenously
synthesized
fatty
acids
(Hopperton
et
al.,
2014).
Thus
phospholipid
composition
of
cancer
cell
mem-
branes,
may
depends
on
the
identity
and
quantity
of
exogenous
fatty
acids
as
well
as
those
synthesized
endoge-
nously
(Hopperton
et
al.,
2014).
This
suggest,
that
therapy
targeting
on
the
endogenous
sources
of
fatty
acid
may
fail
since
the
cancer
cells
depend
more
on
exogenous
source
of
fatty
acid
for
synthesis
of
cell
membrane
lipids.
Adipocytes
interacts
with
cancer
microenvironment
From
practice
point
of
view,
cancers
occur
in
close
proximity
to
adipose
tissue.
This
is
often
seen
in
cancer
of
the
breast,
colon,
pancreas,
ovary,
uterus,
and
liver
which
are
all
surrounded
by
and/or
inltrated
by
adipose
tissue.
Extension
of
these
cancer
types
outside
of
their
originating
organ
often
takes
them
into
direct
contact
with
adipose
tissue.
Furthermore,
adipocytes
are
found
in
the
bone
marrow,
a
common
site
for
solid
tumor
metastasis
(Aldhari
et
al.,
2014).
Bone
marrow
adiposity
is
not
only
affected
by
obesity
but
also
has
recently
been
shown
to
be
inuenced
by
ALL
treatment.
Vicente
López
et
al.
isolated
mesenchymal
stem
cells
(MSCs)
from
bone
marrow
aspirates
of
ALL
patients
at
various
time
points:
diagnosis,
during
therapy,
and
after
therapy,
and
showed
that
ALL-MSC
from
treated
patients
had
an
increased
adipogenic
differentiation
potential,
including
a
higher
expression
of
adipogenic
genes
(CEBP
and
PPAR-
gamma),
compared
to
healthy
MSC
(Vicente
López
et
al.,
2014)
another
study
also
demonstrated
that
whenever
syngeneic
ALL
cells
were
implanted
into
mice
by
a
retro-
orbital
injection,
clones
of
inltrated
adipose
tissue
were
found
within
10
days,
at
a
similar
degree
as
other
more
classic
sites
for
ALL,
such
as
spleen
and
liver,
indicating
that
the
cancer
cells
migrate
toward
adipocytes;
this
action
could
perhaps
be
mediated
by
adipocyte
secretion
of
stoma
cell-
derived
factor
1
alpha
(SDF-1a
or
CXCL12)
(Pramanik
et
al.,
2013).
Generally,
obesity
is
not
known
to
be
associated
with
increased
serum
levels
of
SDF-1a;
however,
there
are
indica-
tions
that
obese
mice
have
a
signicantly
higher
burden
of
leukemia
cells
in
visceral
fat
compared
to
control
mice
(Pramanik
et
al.,
2013).
Put
together,
it
appears
that
adipocytes
may
facilitate
cancer
microenvironment
including
bone
marrow
engraftment
via
secretion
of
adipocytes
derived
factors
like
SDF-1a
and
leptin
(Fig.
3).
Adipose
tissue
and
carcinogenesis;
leukemia,
clinical
evidence
From
the
forgoing,
efforts
have
been
spent
to
illustrate
the
role
of
adipose
tissue
and
adipocytes
in
supporting
progression
of
several
types
of
cancer.
Bone
marrow,
a
major
site
of
metastasis
for
solid
tumors
and
an
important
microenviron-
ment
for
hematological
malignancies,
is
also
rich
in
adipo-
cytes.
In
fact,
after
induction
chemotherapy
for
acute
lymphoblastic
leukemia
(ALL),
adipocytes
can
represent
the
primary
cellular
component
of
bone
marrow
which
is
easily
visualized
under
microscope.
Given
the
effects
of
obesity
on
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x6
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
cancer
prognosis,
one
can
ask
if
fat
cells
may
have
a
role
in
leukemias
as
in
other
cancers.
Several
studies
have
found
an
increased
risk
of
developing
leukemia
among
the
obese,
for
example,
a
meta-analysis
of
cohort
studies,
Larsson
and
Wolk
found
that
excess
body
weight
was
associated
with
an
increased
risk
of
developing
all
four
major
subtypes
of
hematologic
malignancies
[ALL,
acute
myelogenous
leuke-
mia
(AML),
chronic
lymphocytic
leukemia
(CLL),
and
chronic
myelogenous
leukemia
(CML)]
(Larsson
and
Wolk,
2008).
The
author
showed
that
compared
with
nonoverweight
individu-
als
(BMI
<
25
kg/m(
2
)),
that
relative
risks
(RRs)
of
leukemia
were
1.14
[95%
condence
interval
(CI),
1.031.25]
for
overweight
individuals
(BMI
2530
kg/m(
2
))
and
1.39
(95%
CI,
1.251.54)
for
obese
(BMI
30
kg/m(
2
))
individuals,
and
that
a
continuous
scale
of
5
kg/m(
2
)
increase
in
BMI
was
associated
with
a
13%
increased
risk
of
leukemia
(RR,
1.13;
95%
CI,
1.07
1.19)
(Larsson
and
Wolk,
2008).
In
addition
In
a
meta-analysis
of
4
studies
reporting
results
on
subtypes
of
leukemia,
also
found
RRs
associated
with
obesity
of
1.25
(95%
CI,
1.111.41)
for
chronic
lymphocytic
leukemia,
1.65
(95%
CI,
1.162.35)
for
acute
lymphocytic
leukemia,
1.52
(95%
CI,
1.191.95)
for
acute
myeloid
leukemia
and
1.26
(95%
CI,
1.091.46)
for
chronic
myeloid
leukemia
(Larsson
and
Wolk,
2008).
This
clearly
suggest
that
that
excess
body
weight
is
associated
with
an
increased
risk
of
developing
leukemia
and
that
a
5
kg/m
2
of
increased
BMI
is
associated
with
a
13%
increase
risk
of
developing
leukemia.
Others
have
shown
that
obesity
increases
the
risk
of
developing
Hodgkin's
lymphoma,
non-
Hodgkin's
lymphoma,
and
multiple
myeloma
(Larsson
and
Wolk,
2011).
For
example,
a
meta-analysis
of
prospective
studies
on
epidemiologic
evidence
for
association
of
body
mass
index
(BMI)
with
non-Hodgkin's
lymphoma
(NHL)
and
Hodgkin's
lymphoma
(HL)
incidence
and
NHL
mortality
found
that
BMI
was
signicantly
positively
associated
with
risk
of
diffuse
large
B-cell
lymphoma
(RR,
1.13;
95%
CI,
1.021.26),
but
not
other
NHL
subtypes;
and
a
RRs
of
HL
of
0.97
(95%
CI,
0.851.12)
for
overweight
and
1.41
(95%
CI,
1.141.75)
for
obesity,
indicating
that
BMI
is
positively
associated
with
risk
of
NHL
and
HL
as
well
as
with
NHL
mortality
(Larsson
and
Wolk,
2011).
Adipocytes
and
treatment
outcome
in
leukemia
The
association
between
obesity
and
leukemia
prognosis
has
also
been
examined
in
many
studies,
with
some
detecting
an
effect
of
obesity
to
worsen
prognosis
and
others
nding
a
conicting
result.
For
instance,
two
independent
studies
acknowledged
that
their
failure
to
detect
an
association
between
BMI
and
ALL
outcomes
may
have
been
due
to
small
sample
size
(Baillargeon
et
al.,
2006;
Hijiya
et
al.,
2006).
Furthermore,
the
risk
estimates
of
overall
survival
and
event-
free
survival
from
were
shown
to
be
worse
in
overweight/
obese
patients
(Butturini
et
al.,
2007).
The
largest
study
was
done
by
the
CCG,
and
included
over
5000
children
(Butturini
et
al.,
2007).
This
study
found
that
obesity
was
associated
with
a
signicantly
increased
risk
of
relapse,
particularly
in
children
over
10
years
of
age
(considered
high
risk).
This
nding
are
in
line
with
the
report
of
another
study
which
included
only
standard
risk
patients,
and
concluded
that
overweight
or
obesity
at
diagnosis
was
unlikely
to
impair
prognosis
(Aldhari
et
al.,
2014).
Thus,
it
appears
that
obesity
can
impair
ALL
outcomes
at
least
in
high
risk,
older
patients.
The
adipocyte-macrophage
cross-talk
theory
for
lipid
driven
carcinogenesis:
adipocyte-derived
free
fatty
acids
(FFAs)
and
macrophages
secreted
TNF
to
promote
cancer
progression
In
healthy
adults,
endogenous
fatty
acid
synthesis
takes
place
in
specialized
tissues,
such
as
the
liver,
adipose,
cycling
endometrium
and
the
lactating
breast;
these
tissues
have
a
lot
of
fatty
acid
synthase
(FASN)
expression.
In
contrast,
over-
expression
of
FASN
has
been
detected
in
many
types
of
established
tumors
and
pre-malignant
lesions.
This
over-
expression
appears
to
confer
a
survival
advantage
to
cancer
cells
since
it
is
often
associated
with
advanced
cancer
stage,
metastasis
and
poor
prognosis.
The
mechanism
leading
to
this
survival
advantage,
however,
is
not
understood.
How
does
adipose
tissue
promote
inammation
and
disease
development
(see
Fig.
3)?
The
changes
that
occur
in
adipose
tissue
during
obesity
have
been
characterized.
For
example,
using
microarray
analysis,
the
mass
of
adipose
tissue
was
shown
to
be
an
independent
regulator
of
its
gene
expression
prole
(Weisberg
et
al.,
2003).
The
quantity
of
transcripts
from
microarray
analysis
from
mouse
adipose
tissue
was
found
to
correlate
signicantly
with
its
mass
(Weisberg
et
al.,
2003),
further
analysis
in
the
study
revealed
three
groups
of
functionally
related
genes
that
were
collec-
tively
regulated
by
mass.
Thirty
percent
of
the
transcripts
signicantly
encoded
proteins
that
are
characteristically
expressed
by
macrophages;
these
include
the
CSF-1
receptor,
and
the
CD68
antigen.
In
same
study,
a
quantitative
RT-PCR
experiment
also
conrmed
the
expression
prole
of
the
ve
genes
identied
including
(colony-stimulating
factor
1
recep-
tor
[Csf1r],
CD68,
Pex11a,
Emr1,
and
Mcp1).
Clearly,
the
study
pointed
that
that
macrophage
content
of
adipose
tissue
may
positively
correlate
with
adiposity
or
its
mass.
This
means
that
weight
gain
might
be
associated
with
inltration
of
fat
by
macrophages.
To
understand
the
role
of
inltrated
macro-
phages
characterizing
the
microenvironment
of
a
fat
cell,
Suganami
et
al.
(2005)
developed
an
in
vitro
coculture
system
which
composed
of
adipocytes
and
macrophages,
and
exam-
ined
the
molecular
mechanism
whereby
these
cells
commu-
nicate.
The
author
showed
that
coculture
of
differentiated
3T3-L1
adipocytes
cell
lines
and
macrophage
cell
line
RAW264
resulted
in
marked
upregulation
of
proinammatory
cyto-
kines,
such
as
tumor
necrosis
factor
alpha
(TNF-alpha)
(Fig.
3),
and
in
downregulation
of
anti-inammatory
cytokine
adipo-
nectin
(Suganami
et
al.,
2005).
Importantly,
the
inammatory
changes
induced
by
the
coculture
occurred
without
direct
contact
between
the
two
cell
types;
pointing
to
the
role
of
soluble
factors
(Suganami
et
al.,
2005).
To
further
clarify
that
soluble
factors
were
secreted
by
the
cells
were
responsible,
the
author
used
a
conditioned
media
experiment
and
demon-
strated
that
media
from
RAW264
cells
signicantly
induced
MCP-1
(P
<
0.01),
interleukine-6
(IL-6)
(P
<
0.05),
and
TNF-a
(P
<
0.01)
mRNA
expression
in
3T3-L1;
and
the
media
from
3T3-L1
showed
no
induction
of
MCP-1
but
a
signicant
increase
in
IL-6
and
TNF-a
in
RAW264
(P
<
0.05),
suggesting
j
o
u
r
n
a
l
o
f
a
p
p
l
i
e
d
b
i
o
m
e
d
i
c
i
n
e
x
x
x
(
2
0
1
4
)
x
x
x
x
x
x
7
JAB-43;
No.
of
Pages
13
Please
cite
this
article
in
press
as:
Omabe,
M.,
et
al.,
Lipid
metabolism
and
cancer
progression:
The
missing
target
in
metastatic
cancer
treatment.
J.
Appl.
Biomed.
(2014),
http://dx.doi.org/10.1016/j.jab.2014.09.004
that,
TNF-a
was
mostly
derived
from
RAW264,
and
only
a
small
amount
of
TNF-a
was
secreted
from
3T3-L1
(Suganami
et
al.,
2005).
By
adding
a
neutralizing
antibody
to
TNF-alpha,
which
is
a
well
known
cytokine
secreted
by
macrophages;
the
author
observed
an
inhibition
of
the
inammatory
changes
in
3T3-L1,
suggesting
that
TNF-alpha
was
a
major
macrophage-derived
mediator
of
inammation
in
adipocytes.
The
author
also
noted
that
production
of
TNF-alpha
in
RAW264
was
markedly
increased
by
palmitate,
a
major
free
fatty
acid
(FFA)
released
from
3T3-L1,
indicating
that
free
fatty
acids
(FFAs)
may
be
important
adipocyte-derived
mediators
of
inammation
in
macrophages.
Thus,
while
adipocytes
release
FFA,
macro-
phages
secret
TNF-alpha;
the
two
products
may
form
synergy
to
promote
inammation
at
various
rates,
which
may
compromise
a
number
of
biological
functions
in
many
ways
(see
Fig.
3).
Put
together,
it
appears
there
might
be
a
paracrine
interaction
between
adipocytes
and
macrophages
which
controls
inammation
in
adipose
tissue
in
vivo;
in
this
state,
it
is
likely
mature
adipocytes
become
enlarged
in
size,
and
the
inltrated
macrophages
become
increased
in
number.
Adipokines
including
TNF
promotes
tumorigenesis
The
biological
role
of
adipokines,
such
as
tumor
necrosis
factor
a
(TNF-a),
on
cell
growth
and
differentiation
has
been
investigated.
Using
human
adipocytes
(SW872
and
human
uterine
leiomyoma
(HuLM)
cells,
Nair
and
Al-Hendy
(2011),
demonstrated
that
both
SW872-conditioned
media
and
coculture
with
SW872
cells
resulted
in
increased
HuLM
cell
proliferation
signicantly
(P
<
.05),
and
by
the
adding
neutral-
izing
antibodies,
anti-TNF-a,
to
SW872-conditioned
media
cell
proliferation
of
leiomyoma
cells
was
dramatically
reversed,
and
the
cells
had
reduced
expression
of
antiapoptotic
marker
BCL-2
indicating
marked
apoptosis.
This
suggests
that
TNF-a
may
be
involved
in
initiation
and/or
progression
of
uterine
leiomyoma
by
inducing
survival
advantage
and
inhibit
apoptosis
to
the
uterine
cells.
In
addition,
a
study
on
the
effect
of
human
adipocyte
cells
(SW872)
on
growth
of
endometrial
glandular
epithelial
cells
(EGE)
demonstrated
a
signicant
increase
in
EGE
cell
proliferation
including
upre-
gulation
of
proliferation
markers
PCNA,
cyclin
D1,
CDK-1,
and
BCL-2
and
decrease
in
BAK
(P
<
0.05)
(Nair
et
al.,
2013).
This
strongly
indicates
that
adipocytes
may
have
proliferative
paracrine
effect
on
EGE
cells
which
may,
in
part,
be
mediated
via
TNF-a;
perhaps,
by
interaction
with
macrophages
as
discussed
above.
From
the
preceding
paragraph,
it
was
claried
that
microphages
releases
2
folds
concentration
of
TNF-a
than
the
adipocytes,
in
this
regard,
the
physiologic
role
of
microphages
and
adipocytes
released
TNF-a
may
be
a
dysregulation
of
cycle
circle,
promotion
of
cell
proliferation
and
decrease
apoptosis.
Adipose
tissue
and
treatment
outcome
in
breast
cancer
Emerging
evidence
suggests
that,
adipose
tissue
and
its
associated
cytokine-like
proteins,
adipokines,
particularly
leptin
and
adiponectin,
may
mediate
breast
cancer
initiation
and
progression
(Grossmann
et
al.,
2010;
Cleary
et
al.,
2010).
For
instance,
whenever
the
carcinogen,
7,12,
dimethylbenz[a]
anthracene
(DMBA)
was
administered
to
normal
weight
and
diet-induced
obese
female
Sprague-Dawley
rats,
cell
prolifer-
ation
was
signicantly
increased
particularly
in
mammary
glands
and
inguinal
lymphatic
nodes
of
the
rats,
indicating
a
signicant
inuence
of
obesity
on
breast
cancer
(Lautenbach
et
al.,
2009).
Furthermore,
using
MTT
assay,
Lautenbach
et
al.
(2009),
assessed
effects
of
leptin,
estrogen,
and
IGF-I
(com-
monly
produced
by
adipose
tissue)
on
proliferation
of
MCF-7
cells
(human
breast
cells),
and
observed
a
mitogenic
role
for
these
three
mediators
on
cell
proliferation,
suggesting
the
ability
of
these
molecules
produced
by
adipose
tissue
to
promote
uncontrolled
cell
proliferation
and
initiate
breast
cancer.
This
means
that
obesity-related
adipokines
and
mediators,
leptin,
IGT-1,
and
estrogen
enhance
cell
prolifera-
tion
in
mammary
gland
and
increase
risk
for
breast.
Furthermore,
emerging
evidence
suggest
that
adipokines
may
aggravate
breast
cancer
toward
more
invasive
and
treatment
resistant
state.
For
example,
a
study
that
examined
the
expression
of
leptin
and
its
receptor
(ObR)
in
primary
and
metastatic
breast
cancer
and
noncancerous
mammary
epi-
thelium,
revealed
that
Leptin
and
ObR
were
signicantly
over
expressed
in
primary
and
metastatic
breast
cancer
relative
to
noncancerous
tissues
(Garofalo
et
al.,
2006).
That
study
included
148
primary