Metabolic biomarkers of colorectal cancer
Author(s)
Alfa-Wali, Maryam
Type
Thesis
Abstract
Colorectal
cancer
(CRC)
remains
a
major
public
health
problem
with
advanced
and
recurrent
disease
being
a
management
challenge
due
to
the
lack
of
efficacy
of
currently
available
monitoring
tools.
Carcinoembryonic
antigen
is
used
as
a
marker
for
recurrent
disease
but
has
limited
sensitivity.
Early
sensitive
markers
of
disease
severity
and
recurrence
are
required.
The
aim
of
this
thesis
was
to
identify
potential
metabolic
biomarkers
of
CRC
patients
using
‘Metabonomics’
based
on
proton
nuclear
magnetic
resonance
(1H
NMR)
spectroscopy.
The
breadth
of
1H
NMR
metabonomics
exploring
different
aspects
of
CRC
pathogenesis
was
investigated.
A
global
approach
profiling
a
large
number
of
metabolites
was
undertaken
in
cell
line
and
chemoprevention
studies
with
subsequent
targeted
profiling
experiments
using
human
polypoid
tissue
samples.
The
studies
primarily
exhibited
changes
in
choline
and
lipids
to
be
associated
with
CRC.
Although
these
metabolites
are
well
reported,
this
thesis
presents
contemporary
metabolic
profiling
using
systems
not
previously
reported.
Tumour
extracts
of
CRC
xenografts
showed
higher
levels
in
the
ratio
of
phosphocholine
and
glycerophosphocholine
between
poorly
and
well-differentiated
cell
lines.
Human
tissue
and
biofluids
were
used
to
define
metabolic
phenotypes.
Normal
and
polypoid
colorectal
tissues
were
also
metabolically
characterised
by
changes
in
choline
using
magic
angle
spinning
(MAS)
1
H
NMR.
Investigating
chemoprevention
strategies
with
bile
acids
in
adenoma
patients
indicated
alterations
in
short
chain
fatty
acids,
related
to
gut
microflora
metabolism.
In
clinical
studies,
higher
levels
of
lactate
and
glycoproteins
were
identified
in
rectal
cancer
patients,
as
potential
metabolic
predictors
of
response
to
chemoradiotherapy.
A metabolically
translational
feature
of
the
thesis
in
a
heterogeneous
population
confers
a
significant
increase
in
the
risk
of
CRC
incidence
with
metabolic
syndrome
(MetS).
Thus,
inferring
identification
of
MetS
components
as
part
of
screening
measures.
In
vivo
studies
provide
a
functional
way
of
networking
metabolic
pathways
to
pathological
states,
thereby
unifying
perspectives
post
hoc.
cancer
(CRC)
remains
a
major
public
health
problem
with
advanced
and
recurrent
disease
being
a
management
challenge
due
to
the
lack
of
efficacy
of
currently
available
monitoring
tools.
Carcinoembryonic
antigen
is
used
as
a
marker
for
recurrent
disease
but
has
limited
sensitivity.
Early
sensitive
markers
of
disease
severity
and
recurrence
are
required.
The
aim
of
this
thesis
was
to
identify
potential
metabolic
biomarkers
of
CRC
patients
using
‘Metabonomics’
based
on
proton
nuclear
magnetic
resonance
(1H
NMR)
spectroscopy.
The
breadth
of
1H
NMR
metabonomics
exploring
different
aspects
of
CRC
pathogenesis
was
investigated.
A
global
approach
profiling
a
large
number
of
metabolites
was
undertaken
in
cell
line
and
chemoprevention
studies
with
subsequent
targeted
profiling
experiments
using
human
polypoid
tissue
samples.
The
studies
primarily
exhibited
changes
in
choline
and
lipids
to
be
associated
with
CRC.
Although
these
metabolites
are
well
reported,
this
thesis
presents
contemporary
metabolic
profiling
using
systems
not
previously
reported.
Tumour
extracts
of
CRC
xenografts
showed
higher
levels
in
the
ratio
of
phosphocholine
and
glycerophosphocholine
between
poorly
and
well-differentiated
cell
lines.
Human
tissue
and
biofluids
were
used
to
define
metabolic
phenotypes.
Normal
and
polypoid
colorectal
tissues
were
also
metabolically
characterised
by
changes
in
choline
using
magic
angle
spinning
(MAS)
1
H
NMR.
Investigating
chemoprevention
strategies
with
bile
acids
in
adenoma
patients
indicated
alterations
in
short
chain
fatty
acids,
related
to
gut
microflora
metabolism.
In
clinical
studies,
higher
levels
of
lactate
and
glycoproteins
were
identified
in
rectal
cancer
patients,
as
potential
metabolic
predictors
of
response
to
chemoradiotherapy.
A metabolically
translational
feature
of
the
thesis
in
a
heterogeneous
population
confers
a
significant
increase
in
the
risk
of
CRC
incidence
with
metabolic
syndrome
(MetS).
Thus,
inferring
identification
of
MetS
components
as
part
of
screening
measures.
In
vivo
studies
provide
a
functional
way
of
networking
metabolic
pathways
to
pathological
states,
thereby
unifying
perspectives
post
hoc.
Date Issued
2012
Date Awarded
2013-03
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Antoniou, Anthony
Keun, Hector
Darzi, Ara
Sponsor
Bowel Disease Research Foundation (Great Britain) ; Royal Marsden Hospital (London, England)
Publisher Department
Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)