ORIGINAL ARTICLE

The Value of Fecal Tumor M2 Pyruvate Kinase

as a Diagnostic Tool for Colorectal Cancer Screening

Murdani Abdullah, Abdul A. Rani, Marcellus Simadibrata, Ahmad Fauzi,

Ari F. Syam
Department of Internal Medicine, Faculty of Medicine, University of Indonesia - Cipto Mangunkusumo Hospital.
Jl. Diponegoro No. 71, Jakarta 10430, Indonesia. Correspondence mail: murdani.abdullah@ui.ac.id.

ABSTRAK
Tujuan: untuk mengevaluasi kemampuan M2 piruvat kinase tinja sebagai penanda diagnostik untuk
penapisan kanker kolorektal (colorectal cancer – CRC) pada populasi risiko tinggi atau simtomatik.
Metode: sebanyak 328 pasien yang menjalani pemeriksaan kolonoskopi elektif direkrut secara konsekutif.
Sampel tinja berukuran kacang walnut diambil dari tiap pasien untuk kemudian diuji kandungan M2PK-tumor
dengan menggunakan ELISA. Tidak ada pembatasan asupan makan pada pasien. Ahli patologi klinik yang
menganalisa kandungan M2PK disamarkan terhadap diagnosis pasien. Kadar tumor M2PK tinja kemudian
dibandingkan dengan hasil histopatologis dari biopsi kolorektal. Hasil: dari 328 pasien yang menjalani
pemeriksaan kolonoskopi, didapatkan 197 orang (60.1%) lelaki dan 131 orang (39.9%) perempuan. Berdasarkan
pemeriksaan histopatologis, 83 (25.3%) pasien memiliki gambaran histologi usus normal, 42 pasien (12.8%)
memiliki CRC, 67 pasien (20.4%) pasien memiliki adenoma, 19 pasien (5.8%) memiliki inflammatory bowel
disease, 3 pasien (0.9%) memiliki kolitis amuba, dan 114 pasien (34.8%) memiliki kolitis infektif. Batas kadar
M2PK-tumor tinja adalah 4.0 U/ml. Sensitivitas, spesifitas, positive predictive value dan negative predictive
value secara berurutan adalah 71.4%, 71%, 73.5% dan 94.4%. Didapatkan hubungan yang signifikan antara
CRC dengan kadar M2PK-tumor tinja (p<0.001). Uji M2PK mendeteksi adanya 16 tumor di antara 67 kasus
(23.9%) adenoma, 8 tumor di antara 19 kasus (42.1%) inflammatory bowel disease, 35 tumor di antara 114
kasus (30.7%) kolitis infektif, dan 2 tumor di antara 3 kasus (66.7%) kolitis amuba. Kesimpulan: uji M2PK-
tumor tinja memiliki sensitivitas dan spesifisitas yang baik untuk mendeteksi kasus CRC, terutama pada populasi
risiko tinggi atau simtomatik.

Kata kunci: kanker kolorektal, M2PK-tumor tinja, penanda diagnostik, penyaring

ABSTRACT
Aim: to evaluate the performance of fecal tumor M2 pyruvate kinase (M2PK) as a diagnostic biomarker for
colorectal cancer (CRC) screening in high-risk or symptomatic populations. Methods: consecutive patients (N
= 328) who were referred for elective colonoscopy were prospectively enrolled. One walnut-sized stool sample
was collected from each patient for analysis of tumor M2PK content using an ELISA kit. No dietary restrictions
were applied. The clinical pathologists who conducted the M2PK analyses were blinded to the patients’ confirmed
diagnoses. Levels of fecal tumor M2PK were compared with histopathological results from colorectal biopsies.
Results: of the 328 patients who underwent colonoscopy examinations, 197 (60.1%) were men and 131 (39.9%)
were women. Based on histopathological examination, 83 (25.3%) patients had normal bowel histology, 42
(12.8%) patients had CRC, 67 (20.4%) patients had adenoma, 19 (5.8%) patients had inflammatory bowel
disease, three (0.9%) patients had amoebic colitis, and 114 (34.8%) patients had infective colitis. The cutoff
level for tumor M2PK concentration was defined as 4.00 U/mL. The sensitivity, specificity, positive predictive
value, and negative predictive value of the M2PK test were 71.4%, 71.0%, 73.5%, and 94.4%, respectively. There

94 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

Vol 44 • Number 2 • April 2012 The Value of Fecal Tumor M2 Pyruvate Kinase as a Diagnostic Tool

was a significant association between CRC and fecal tumor M2PK level (P < 0.001). The M2PK test detected
16 tumors among 67 (23.9%) cases of adenoma, eight tumors among 19 (42.1%) cases of inflammatory bowel
disease, 35 tumors among 114 (30.7%) cases of infective colitis, and two tumors among three (66.7%) cases of
amoebic colitis. Conclusion: the fecal tumor M2PK test has good sensitivity and specificity for CRC detection,
especially in high-risk or symptomatic populations.

Key words: colorectal cancer, fecal tumor M2PK, diagnostic biomarker, screening.

INTRODUCTION the FOBT is associated with a high probability

Colorectal cancer (CRC) is a malignant
disease that constitutes a serious health care
problem. According to GLOBOCAN 2002, the
worldwide prevalence of CRC is second to that
of breast cancer. One million new cases of CRC
and 529,000 deaths from CRC were recorded
in 2002.1 The GLOBOCAN 2002 database also
shows that the incidence of CRC is increasing
rapidly in countries where the overall risk of
CRC was previously low, especially in Japan
and elsewhere in Asia. In high-risk countries,
the incidence of CRC has gradually increased,
stabilized (North and West Europe), or declined
(North America).2 Attenuation of the incidence
of CRC over time is particularly evident in the
younger age groups (less than 50 years old).
Analysis of data collected between 1985
and 2005 by the Asia-Pacific Working Group
on CRC has shown that the incidence of CRC
increased by two- to fourfold over this period in
many Asian countries, including China, Japan,
South Korea, and Singapore. Based on this fact,
the Asia-Pacific Working Group on Colorectal
Cancer stated that prompt action should be
taken to prevent and diagnose CRC as early
as possible. One of the actions that should be
undertaken is to increase public awareness of
CRC screening.3 Routine screening is effective
for detecting CRC because it may be present for
an extended period before clinical symptoms
become evident. This provides clinicians with a
window of opportunity for screening, effective
intervention, and prevention.4–8 If the cancer is
found at an early, preinvasive stage, the 5-year
survival rate is about 95%.9–11
The most commonly used screening method
for CRC is the fecal occult blood test (FOBT).
A meta-analysis in which data from three studies
and a Swedish trial were pooled estimated that
FOBT screening could reduce CRC mortality by
as much as 16%–23%.12 CRC screening using
of false-positive results, which may be caused
by occult blood from nonneoplastic lesions
(hemorrhoid, diverticulosis, colitis) or NSAID-
associated gastrointestinal bleeding. False-
negative results can occur because of bleeding
from some carcinomas and most adenomas are
occult or intermittent. False-negative results
are usually observed with small lesions (less
than 1 cm in diameter) or proximal lesions in
which globin is degraded before it can appear
in the stool. The immunochemical FOBT
(iFOBT) is a development of the FOBT that can
differentiate between peroxidase and heme in
dietary components from human hemoglobin.
However, the iFOBT has limitations. Lieberman
et al.13 reported that among 3,121 asymptomatic
people who underwent colonoscopy, the FOBT
was positive for only 23.9% of cases of advanced
neoplasia; thus, FOBT failed to detect 76.1%
cases of advanced neoplasia.14 In addition, there is
increasing demand for a more reliable screening
tool for CRC because nonpolypoidal (flat or
depressed) lesions and colorectal neoplasm,
which develop without a preceding adenoma
(i.e., de novo cancer), seem to be more common
in Asians than in other populations. There is also
a trend towards an increase in the proportion of
proximal CRC in several Asian countries.3 These
findings stimulated work on the development
of a more reliable CRC screening tool that is
not affected by the presence of hemoglobin and
detects metabolic changes in CRCs cells directly.
The aim of this study was to evaluate
the performance of fecal tumor M2 pyruvate
kinase (M2PK) as a diagnostic biomarker for
CRC screening in high-risk or symptomatic
populations. Pyruvate kinase, which converts
phosphoenolpyruvate to pyruvate, is a key
enzyme in glucose metabolism and is present in
organ-specific isoforms (the L, R, M1, and M2
isoforms). In normal proliferating cells, M2PK

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Murdani Abdullah
is mainly tetrameric and has a high affinity for
phosphoenolpyruvate. In contrast, the M2PK
isoenzyme found in tumor cells is usually dimeric
and has a low affinity for phosphoenolpyruvate.
Dissociation of the tetrameric form to the
dimeric form in tumor cells is induced by direct
interaction of M2PK with various oncoproteins.
For this reason, the dimeric form of M2PK
has been named tumor M2PK. Because of its
low affinity for phosphoenolpyruvate, tumor
M2PK is easily released from tumor cells and is
quantitatively detectable in body fluids.15 Tumor
M2PK can also be detected and quantified in stool
samples using an ELISA.16–18
METHODS
Study Protocol
Three hundred twenty-eight consecutive
patients who were admitted to six centers in
Jakarta between August 2009 and April 2010
participated in this study. The samples were
collected from six hospitals in Jakarta (Cipto
Mangunkusumo Hospital, Abdi Waluyo Hospital,
Pluit Hospital, Gading Pluit Hospital, Islam
Cempaka Putih Hospital and Mitra Keluarga
Kelapa Gading Hospital). These high-risk or
symptomatic patients underwent colonoscopy
for various indications such as CRC screening,
investigation of colonic symptoms, CRC high-
risk subject examination, a family history of
colorectal neoplasia (CRN), and clinically
suspected CRC. Patients who underwent removal
surgery or chemotherapy for CRC or polyps were
excluded.
One walnut-sized stool sample was collected
before preparation of the bowel for the endoscopy
procedure or after the colonoscopy when the
patient’s stool had become sufficiently firm. A
clean plastic container (100 mL) and a plastic
spoon were provided for stool sample collection.
No dietary restrictions were imposed. The stool
sample collection procedure was explained to
the patient by the study coordinator or a nurse.
Patients who returned very watery stool
samples were asked to collect a firm stool sample.
Patients were instructed not to contaminate stool
samples with toilet bowl water. Fecal M2PK is
stable for 48 hours at room temperature, 72 hours
at 4–8 0C, and 1 year at –20 0C. Undiluted stool
extracts may be stored without adverse effects for
1 day at 4–8 0C or for 4 weeks at –20 0C.
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Acta Med Indones-Indones J Intern Med
Clinical history data were recorded on
standardized forms. Demographic data (age,
sex, ethnicity, and the location size and histology
of the CRC) were recorded. The results of
histopathological analyses were obtained
from patients with neoplastic abnormalities.
The location of the most advanced lesion was
noted. Irritable bowel disease (IBD) patients
were included to investigate the influence of
inflammation on fecal tumor M2PK level. Dukes’
stage and tumor node metastasis stage were not
determined. The adenomas were classified as
nonadvanced or advanced (i.e., an adenoma with
significant villous features [>25%], a diameter
of 1 cm or more, high-grade dysplasia, or an
adenoma containing early invasive cancer).19
The study protocol was approved by the ethics
committee of Cipto Mangunkusumo Hospital
Faculty of Medicine, University of Indonesia.
Written informed consent was obtained from all
patients before they were enrolled in the study.
M e a s u r e m e n t o f F e c a l Tu m o r M 2 P K
Concentrations
Stool extraction was done using the
Fecal Tumor M2PK Quick Prep kit (ScheBo
Biotech AG, Giessen, Germany). Fecal tumor
M2PK level was measured using an ELISA kit
(ScheBo Biotech AG) in accordance with the
manufacturer’s protocol. The kit was validated
for quantification of fecal tumor M2PK levels
between 1 U/mL and 30 U/mL; values outside
this range are specified as <1 U/mL or >30 U/
mL. An M2PK cutoff level of 4 U/mL was used
according to the manufacturer’s instructions and
other similar studies.16,20 Patients whose fecal
tumor M2PK levels were greater than the cutoff
level were classified as positive for tumor M2PK.
Statistical Analysis
Descriptive statistics were used to analyze
and report the data. Specificity and sensitivity
were calculated using the colonoscopy and
histopathology results as references.
RESULTS
The general characteristics of the 328 patients
who underwent colonoscopic examinations
between August 2009 and April 2010 are shown
in Table 1. The sample consisted of 197 (60.1%)
males and 131 (39.9%) females. The ethnicities
of the patients were Javanese (42.6%), Chinese
(23.5%), Malay (17.4%) and others (16.5%).
Vol 44 • Number 2 • April 2012 The Value of Fecal Tumor M2 Pyruvate Kinase as a Diagnostic Tool

Table 1. Patient demographics Table 2. Tumor M2PK test results according to colonoscopy
findings
Positive Negative
tumor M2PK tumor M2PK Colonoscopy Positive tumor Negative tumor
finding M2PK M2PK
Frequency 113 (34.5%) 215 (65.5%)
Adenoma 16 (23.9%) 51 (76.1%)
Age
55.9+10.7 50.9+14.5 Inflammatory
(Mean+SD; years) 8 (42.1%) 11 (57.9%)
bowel disease
Sex
Infective colitis 35 (30.7%) 79 (69.3%)
-- Male 71 (36.0%) 126 (64.0%)
Amoebic colitis 2 (66.7%) 1 (33.3%)
-- Female 42 (32.1%) 89 (67.9%)
Normal 22 (26.5%) 61 (73.5%)
Ethnicity
-- Javanese 54 (38.6%) 86 (61.4%)
-- Malay 17 (29.8%) 40 (70.2%)
-- Tionghoa 24 (31.2%) 53 (68.8%) Table 3. The association between tumor M2PK test
results and cancer
-- Other 18 (33.3%) 36 (66.7%)
Cancer
Body mass index Total
21.4+4.3 22.7+3.5 Positive Negative
(Mean+SD; kg/m2)
Positive tumor
30 83 113
M2PK
Negative tumor
12 203 215
Twenty patients (6.1%) had a personal history of M2PK
malignancy and 42 (12.8%) patients had a family Total 42 286 328
history of malignancy.
The indications for colonoscopic examination
were gastrointestinal bleeding (36.0%),
abdominal pain (30.5%), change in bowel habits
(33.8%), screening (6.4%), and an abdominal
mass (4.6%). Hemorrhoids were observed in 241
(73.5%) patients and the colonoscopy findings
were colitis, 123 patients (37.5%); polyps, 83
patients (25.3%); tumor, 59 patients (18.0%);
sensitivity

IBD, 31 patients (9.5%); and amoebic colitis,

seven patients (2.1%). Based on histopathological
examination, 83 (25.3%) patients had normal
bowel histology, 42 (12.8%) patients had CRC,
67 (20.4%) patients had adenoma, 19 (5.8%)
patients had IBD, three (0.9%) patients had
amoebic colitis, and 114 (34.8%) patients had
infective colitis.
The median tumor M2PK levels was 2.50 U/ 1-specificity
mL (SD, 7.5; minimum, 0.50 U/mL; maximum,
37.7 U/mL). According to the receiver operating Figure 1. Receiver operating characteristic (ROC) curve for
tumor M2PK
characteristics curve (ROC) curve, the tumor
M2PK cutoff level was 4.00 U/mL (the sensitivity,
specificity, positive predictive value, and negative DISCUSSION
predictive value were 71.4%, 71.0%, 73.5%, and A highly sensitive and specific yet noninvasive
94.4%, respectively) (Figure 1). The M2PK test screening tool for CRC is of major importance
detected 16 tumors among 67 (23.9%) cases of for lowering the incidence of CRC. In this study,
adenoma, eight tumors among 19 (42.1%) cases the performance of a fecal tumor M2PK test
of IBD, 35 tumors among 114 (30.7%) cases of was evaluated using high-risk or symptomatic
infective colitis, and two tumors among three Indonesian patients. Several studies have
(66.7%) cases of amoebic colitis (Table 2). evaluated the accuracy of Tumor M2PK as a

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CRC screening tool. It was shown that fecal
tumor M2PK is more accurate for CRC screening
than serum or plasma tumor M2PK.16,21–23 The
sensitivity and specificity of fecal tumor M2PK
in previous studies ranged from 69% to 85%
and from 65% to 93%, respectively.24,25 The
sensitivity and specificity of the fecal tumor
M2PK test evaluated in this study (71.4% and
71.0%, respectively) were within the range of
reported values. In addition, there was significant
association between CRC and fecal tumor M2PK
level (P < 0.000).
The cutoff value for fecal tumor M2PK levels
was defined as 4 U/mL, as recommended by
the manufacturer and other similar studies.16,20
However, further study with larger number of
patients and a more adequate stool sample size is
needed to determine the most appropriate cutoff
value for CRC in the Indonesian population. This
can be accomplished by comparing the predictive
value of fecal tumor M2PK level over a wide
range of cutoff values using ROC curve analysis.
We observed that fecal tumor M2PK had
low sensitivity for detecting adenomas. Shastri
et al.24,25 and Mulder et al.26 showed that the
sensitivity of fecal tumor M2PK for detection of
adenomas is between 25.8% and 37.7% (cutoff
value >4 U/mL). The iFOBT also has a low
sensitivity for detecting adenomas (30–40%).24–26
The sensitivity of fecal tumor M2PK level for
detecting adenomas should be evaluated using
a larger sample size. Recent studies suggest that
inflammatory reactions in the bowel can cause
an elevation in fecal tumor M2PK level.24–26 In
our study, eight of 19 patients with IBD (42.1%)
had positive M2PK test results. Most IBD
patients with positive results had colitis IBD.
Colitis IBD is a risk factor for the development
of CRC. It is possible that IBD patients with
positive fecal tumor M2PK test results also had
ulcerative colitis associated with a neoplastic
premalignant process.27 The iFOBT also showed
a high positivity rate in IBD patients, which is
consistent with Mulder et al.26 They reported that
of IBD patients, 79% were positive according to
the fecal tumor M2PK and iFOBT immoCARE
tests and 89% were positive according to the
iFOBT OC-Light test.26 Further study with a
follow-up is needed to determine the positivity
rate of the fecal tumor M2PK test for ulcerative
colitis-associated neoplasia.
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Acta Med Indones-Indones J Intern Med
False-negative results may have been
produced in our study because of dilution of stool
samples with toilet bowl water. Positive results
in patients with normal colonoscopy results
(22/83 patients; 26.5%) may have been caused
by inflammation, which could have been detected
by microscopic examination. Therefore, further
studies using several CRC diagnostic tools are
required. Shastri et al.25 showed that 26.2% of
normal subjects, including patients with irritable
bowel syndrome, (135/156; cutoff value >4 U/
mL) had positive fecal tumor M2PK test results.
Cancer cells have higher rates of glucose
uptake than normal cells. However, only a
small fraction of the glucose taken up is used
for oxidative phosphorylation. The decrease in
aerobic glycolysis in these cells may be due to
reprogramming of metabolic genes, enabling
cancer cells to partition glucose metabolites
away from oxidation towards the synthesis of
macromolecules. In cancer cells, M2PK regulates
the balance between the synthesis of ATP and
macromolecules (fatty acids and nucleic acids).
M2PK is crucial for rapid tumor growth and
aerobic glycolysis during tumorigenesis. 28,29
Therefore, M2PK can be used as a noninvasive
biomarker and a diagnostic tool for the detection
of cancer. M2PK level may also be of use for
prognostic purposes because a proteomic study
revealed that M2PK expression is predictive of
patient response during treatment oxaliplatin.30
CONCLUSION
Fecal tumor M2PK has potential as a
screening diagnostic biomarker for CRC and has
high overall sensitivity and acceptable specificity.
It is expected that the tumor M2PK test will
be more specific for cancer than the iFOBT.
The specificity of the fecal tumor M2PK test
is acceptable for screening diagnostic purposes
because the positivity rate in IBD patients was
less than that reported for other tests.24–26
ACKNOWLEDGEMENTS
We acknowledge the Directorate for Research
and Public Service of the University of Indonesia
for supporting the study. We thank all the
gastroenterologists who recruited patients and
performed the endoscopy procedures and the
clinical pathologists who examined the samples.
Vol 44 • Number 2 • April 2012 The Value of Fecal Tumor M2 Pyruvate Kinase as a Diagnostic Tool
We thank Vita Kurniati Lubis, MD, PhD., Vinci
Lorensia, MD., Aan Santi, BSc., and Cecilia
Anggraini, MSc., for their support and assistance
in managing, analyzing, and compiling the data
and Irwin Tedja, MD for editing the manuscript.
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