Gunter MJ, Stolzenberg-Solomon R, Cross AJ, et al. A prospective study of serum C-reactive protein and colorectal cancer risk in men

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Rockville, Maryland 20852, USA.
Cancer Research (Impact Factor: 9.33). 03/2006; 66(4):2483-7. DOI: 10.1158/0008-5472.CAN-05-3631
Source: PubMed
ABSTRACT
Chronic inflammation has been implicated in the etiology of colorectal cancer. C-reactive protein (CRP), a sensitive marker of inflammation, has been investigated with regard to colorectal cancer in only three previous studies, and the results from these investigations were inconsistent. We examined serum CRP levels in relation to colorectal cancer incidence in a nested case-control study within the Alpha Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a cohort of 29,133 Finnish males enrolled from 1985 to 1988 with follow-up through April 2002. Colorectal cancer cases were ascertained by the Finnish Cancer Registry; this analysis included 130 cases of colorectal cancer (with available blood), which occurred between 1990 and April 30, 2002, and 260 matched controls. Baseline median CRP levels were approximately 25% higher among colorectal cancer cases (3.4 mg/L) than controls (2.6 mg/L; P = 0.04). Relative to men in the lowest quartile of CRP concentration, men in the highest quartile had an odds ratio of 2.9 (95% confidence interval, 1.4-6.0) for developing colorectal cancer with a dose-response relationship supported (P(trend) = 0.006). The relation between CRP and incident colorectal cancer was modified by body mass index such that the association was stronger among lean individuals than in heavier individuals (P(interaction) = 0.018). These results support the notion that chronic low-grade inflammation is a marker for increased risk of colorectal cancer.

Full-text

Available from: Richard J Wood, Apr 23, 2014
A Prospective Study of Serum C-Reactive Protein
and Colorectal Cancer Risk in Men
Marc J. Gunter,
1
Rachael Stolzenberg-Solomon,
1
Amanda J. Cross,
1
Michael F. Leitzmann,
1
Stephanie Weinstein,
1
Richard J. Wood,
2
Jarmo Virtamo,
3
Philip R. Taylor,
1
Demetrius Albanes,
1
and Rashmi Sinha
1
1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Ser vices, Rockville,
Maryland;
2
Mineral Bioavailability Laboratory, USDA, Human Nutrition Research Center on Aging at Tufts University, Boston,
Massachusetts; and
3
Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
Abstract
Chronic inflammation has been implicated in the etiology of
colorectal cancer. C-reactive protein (CRP), a sensitive marker
of inflammation, has been investigated with regard to
colorectal cancer in only three previous studies, and the
results from these investigations were inconsistent. We
examined serum CRP levels in relation to colorectal cancer
incidence in a nested case-control study within the Alpha
Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a
cohort of 29,133 Finnish males enrolled from 1985 to 1988
with follow-up through April 2002. Colorectal cancer cases
were ascertained by the Finnish Cancer Registry; this analysis
included 130 cases of colorectal cancer (with available blood),
which occurred between 1990 and April 30, 2002, and 260
matched controls. Baseline median CRP levels were f25%
higher among colorectal cancer cases (3.4 mg/L) than controls
(2.6 mg/L; P = 0.04). Relative to men in the lowest quartile of
CRP concentration, men in the highest quartile had an odds
ratio of 2.9 (95% confidence interval, 1.4-6.0) for developing
colorectal cancer with a dose-response relationship supported
(P
trend
= 0.006). The relation between CRP and incident
colorectal cancer was modified by body mass index such that
the association was stronger among lean individuals than
in heavier individuals (P
interaction
= 0.018). These results
support the notion that chronic low-grade inflammation is a
marker for increased risk of colorectal cancer. (Cancer Res
2006; 66(4): 2483-7)
Introduction
Mounting evidence suggests that chronic inflammation is
functionally involved in colorectal carcinogenesis. Among patients
with idiopathic inflammatory bowel disease (IBD), colorectal
cancer incidence rates increase progressively over time, reaching
19% after 30 years of disease (1). Conversely, habitual use of
nonsteroidal anti-inflammatory drugs such as aspirin confers a 40%
to 50% reduction in colorectal cancer risk (2). Laboratory data
further supports a mechanistic link between inflammation and
colorectal carcinogenesis; for example, precursor lesions of
colorectal cancer often display inflammatory histologic features
(3). The inflammator y response promotes carcinogenesis by
damaging DNA (4), stimulating angiogenesis and cell proliferation,
and inhibiting apoptosis (5). The association between serum levels
of C-reactive protein (CRP), a sensitive marker of inflammation,
and colorectal cancer risk has been examined in three previous
studies, yet existing data are inconsistent; with one study demon-
strating a strong positive relation (6) and the other two reporting
essentially null findings (7, 8).
To clarify and extend the current knowledge, we conducted a
nested case-control study within the Alpha Tocopherol, Beta
Carotene (ATBC) Cancer Prevention Study cohort to investigate the
relationship between serum CRP concentration and colorectal
cancer incidence. In addition, we addressed whether the associa-
tion between CRP level and colorectal cancer differed by body size
or colorectal cancer subsite.
Materials and Methods
Study sample. Colorectal cancer cases and controls were identified
among ATBC study participants, details of which have been published
previously (9). Briefly, between 1985 and 1988, 29,133 eligible male smokers
from southwest Finland were randomized to test whether supplements of
a-tocopherol or h-carotene reduced lung cancer incidence. Prior to
randomization, all participants completed a self-administered 276-item
food frequency questionnaire. Height and weight were measured by a
trained nurse. Additional information on aspirin use was obtained from a
questionnaire administered during the follow-up period to which 93% of
participants responded.
Colorectal cancer cases were identified using the Finnish Cancer Registry,
which has virtually 100% case ascertainment in Finland (10). To limit the
potential influence of preclinical cancer on serum CRP levels, only cases
diagnosed at least 5 years after baseline were included in the present
analysis. In total, 130 incident cases of colorectal cancer were available for
analysis. Controls were selected from participants of the ATBC study who
were alive at the time the case subject was diagnosed and free from cancer
(except non–melanoma skin cancer). Controls were matched to cases at a
ratio of 2:1 by age at randomization (F5 years), date of baseline serum
blood draw (F30 days), and intervention group (a-tocopherol, h-carotene,
both assignments, placebo).
Laboratory and statistical methods. CRP was measured in baseline
serum samples blinded to case-control status, using a high-sensitivity latex
particle enhanced immunoturbidometric assay (K-ASSAY CRP Ultra, EQual
Diagnostics, Exton, PA). Quality control samples (n = 47) were embedded
within batches to test for assay reproducibility. The overall coefficient of
variation for this assay was 6.3%.
The distributions of baseline characteristics between cases and controls
were compared using Wilcoxon rank sum tests for continuous variables and
m
2
tests for categorical variables. CRP levels were categorized into quartiles
based on the distribution among the controls. Generalized linear models
were used to assess the association between potential risk factors for
colorectal cancer and CRP level among controls. Odds ratios (OR) and 95%
confidence intervals (95% CI) relating CRP levels to colorectal cancer
incidence were estimated using conditional logistic regression. All models
Requests for reprints: Marc Gunter, Nutritional Epidemiology Branch, Division of
Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive
Boulevard, Rockville, MD 20852. Phone: 301-451-9581; E-mail: gunterm@mail.nih.gov.
I2006 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-05-3631
www.aacrjournals.org
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Research Article
Page 1
were adjusted for an a priori determined set of potential confounding
variables including age, body mass index [BMI; defined as weight /
(height)
2
], aspirin use, smoking duration (years), and usual number of
cigarettes smoked per day. Tests for trend were calculated using a single
ordinal variable corresponding to the median values for each CRP quartile.
We evaluated effect modification of the CRP and colorectal cancer relation
with BMI by entering a cross product term of continuous CRP and BMI into
a multivariable model, the coefficient of which was evaluated with the Wald
test, and with stratified analyses of CRP by low and high BMI categories,
based on the median value of BMI among the controls.
Subsite-specific colorectal cancer risks were determined for colon cancer
(ICD9 codes 153.1-4, 153.6 and 154.0) and rectal cancer (ICD9 code 154.1)
separately. All hypothesis tests were two-sided with P < 0.05 deemed
statistically significant, and were done using SAS release 8.2 (SAS Institute,
Inc., Cary, NC).
Results
Case and control subjects did not differ significantly by age,
BMI, smoking history, physical activity, or intake of major dietary
items. Daily use of aspirin was more common among controls
than cases (P = 0.002). Median serum CRP levels were statistically
significantly higher among cases (3.4 mg/L) compared with
controls (2.6 mg/L; P = 0.04). In addition, baseline a-tocopherol
levels were significantly lower in cases (11.3 mg/L) compared with
controls (12.0 mg/L; P = 0.04; Table 1). CRP concentrations were
positively related to BMI (P
trend
= <0.0001), total cigarettes
smoked per day (P
trend
= 0.05), and a personal history of coronary
heart disease (P
trend
= 0.03). An inverse relation was found
between CRP and baseline serum h-carotene (P
trend
= 0.03) and
dietary intake of n-3 fatty acids, specifically those of vegetable
origin (P
trend
= 0.01; Table 2).
Relative to men in the lowest quartile of CRP concentration, men
in the highest quartile had an almost 3-fold (OR, 2.9; 95% CI, 1.4-
6.0) increased odds of developing colorectal cancer in a significant
dose-response manner (P
trend
= 0.006; Table 3). We observed no
change in the risk estimates following adjustment for other
potential confounding variables such as family history of colorectal
cancer, history of diabetes mellitus, coronary heart disease or
rheumatoid arthritis, serum a-tocopherol and h-carotene levels,
and intakes of alcohol, n-3 fatty acids, and fiber.
The association between CRP and incident colorectal cancer
was modified by BMI such that the association was strongest
among subjects in the lower BMI category (OR, 4.6; 95% CI, 1.9-
10.7, comparing the upper quartile to the lower quartile )
compared with those in the upper BMI category (OR, 2.0; 95%
CI, 0.9-4.6, comparing the upper quartile to the lower quartile;
P
interaction
= 0.018; Table 3). By anatomic subsite, the association
between CRP level and colorectal cancer was stronger for rectal
cancer (OR, 7.8; 95% CI, 2.2-28.1) than in colon cancer (OR, 1.8;
95% CI, 0.7-4.4), when comparing the upper quartile with the
lower quartile, however, only 57 cases of rectal cancer were
included in the study (data not shown). We observed no
difference in the association between CRP and colorectal cancer
risk following stratification by aspirin use, years of being a
regular smoker or total cigarettes smoked per day, and intake of
n-3 fatty acids or serum a-tocopherol or h-carotene (data not
shown).
Discussion
In this prospective study, we showed that increased serum
CRP is predictive of subsequent enhanced colorectal cancer risk.
These data are consistent with the study by Erlinger et al. who
found a positive association between CRP and inc ident
colorectal cancer of similar magnitude and a stronger associ-
ation among leaner individuals compared with heavier individ-
uals (6). Our findings differ from those of Zhang et al. and Ito
et al. who observed no association between CRP levels and
colorectal cancer risk among subjects enrolled in the Women’s
Health Study and Japan Collaborative Cohort Study, respectively
(7, 8).
Obesity has recently been described as an ‘‘in flammatory
condition:’’ overweight and obese individuals have higher circulat-
ing levels of CRP and increased body mass engenders a
proinflammatory environment (11). This observation generated
the hypothesis that chronic inflammation may represent one
potential mechanism that mediates the association between
obesity and colorectal cancer. We showed that BMI modified the
CRP-colorectal cancer relation whereby the positive association
between CRP and colorectal cancer was stronger in lean versus
heavier men. One possible explanation for this observation is the
existence in leaner m en of fewer adiposity-related etiologic
exposures related to colorectal cancer risk (e.g., hyperinsulinemia),
with more sensitive and specific detection of the CRP association
resulting among them. This may also explain the differing relative
risks we observed for rectal and colon cancers, given that obesity
is not strongly associated with the former (12). Our primary
hypothesis, that chronic inflammation in the colorectum is a risk
factor for colorectal cancer is supported by our data. The lack of
association among heavier men may reflect increased CRP levels
that are elevated in response to adipokines such as interleukin-6
and tumor necrosis factor-a which are up-regulated in heavier
individuals. Controls that fall into the heavier category will have
higher CRP levels than the leaner controls, and in support of this,
BMI is positively related with CRP levels among controls in this
study. Thus, the differences in inflammation levels between cases
and controls among heavier men may be masked by this
phenomenon.
Our study is limited by the relatively modest number of cases
overall and only one baseline measurement of CRP. However, CRP
levels have been found to remain reasonably stable over time (13),
suggesting that a single baseline measurement can be used to
represent long-term levels (14–17). Because our study participants
were apparently healthy at the time of enrollment, it is unlikely
that the presence of undetected colorectal neoplasia at baseline
contributed to the observed positive association between CRP
levels and colorectal cancer incidence. We further minimized this
potential bias by including only cases diagnosed after the first
5 years of follow-up. Although we lacked CRP data on cases
diagnosed within the first 5 years of follow-up, exclusion of cases
diagnosed up to 10 years of study entr y did not materially change
the risk estimates [i.e., OR for the top quartile versus the lowest
quartile, 3.0 (95% CI, 1.1-5.3)]. An important extension of this work
would be to investigate CRP levels in relation to premalignant
colorectal adenoma, with a demonstrable association further
supporting the causative role of chronic inflammation in colorectal
carcinogenesis.
Because our study was conducted in a cohort of male smokers,
the generalizability of our findings to a population that includes
nonsmokers may be limited. Smoking is known to be associated
with chronic inflammation and is consistent with other studies
(18). Our results show that smoking is positively associated with
CRP levels. Median CRP levels among the control subjects were
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higher in our population compared with previous studies on CRP
and colorectal cancer (6–8). However, the consistency of our data
with those from the study by Erlinger et al. (6), which was
conducted in a separate population of mixed gender and smoking
status, indicates that raised CRP levels may be a predictor of
colorectal cancer incidence among both smoking and nonsmoking
individuals. In addition, the relation between CRP and colorectal
cancer incidence did not vary across subgroups of men, defined by
smoking duration and smoking intensity in our study. Interestingly,
our results differed with those of Erlinger et al. (6) with regard to
anatomic subsite. We detected a stronger association for rectal
cancer compared with colon cancer, whereas the former report
reported the converse. Such differences based on subsite should be
interpreted with caution due to the small number of cases overall
(only 57 rectal cancers) in the current study.
It should be noted that although CRP is a highly sensitive marker
of inflammation, it is nonspecific, and may reflect on-going
inflammator y processes at any anatomic site. It is unlikely that
other diseases which are associated with raised CRP levels
substantially contributed to the association reported here, because
adjustment for a history of coronary heart disease, rheumatoid
arthritis, and lung emphysema resulted in virtually unaltered risk
estimates. Our study lacked information on IBD which is
associated with both inflammation and colorectal cancer. However,
Table 1. Baseline characteristics of the study population
Characteristic Cases (n = 130) Controls (n = 260) P*
Age (y) 56 (53-61) 57 (53-59) 0.37
BMI (kg/m
2
) 26.0 (24.0-28.8) 26.1 (23.7-28.3) 0.65
Smoking history
Total cigarettes per day 20 (13-25) 20 (15-25) 0.53
Smoking duration (y) 36 (30-41) 36 (31-40) 0.94
Medical history
Family history of colorectal cancer (%) 2.6 3.1 0.82
c
Diabetes mellitus (%) 3.8 2.7 0.53
c
Coronary heart disease (%) 6.9 5.4 0.54
c
Lung emphysema (%) 5.4 4.6 0.74
c
Rheumatoid arthritis (%) 1.5 2.3 0.61
c
Prior daily aspirin use (%)
b
6.2 19.6 0.002
c
Physical activity
Occupational 0.36
c
Sedentary (%) 13.0 15.0
Light (%) 20.8 28.9
Moderate (%) 20.8 17.3
Heavy (%) 5.4 5.4
Nonworking (%) 40.7 33.5
Recreational 0.75
c
Light (%) 36.9 33.1
Moderate (%) 56.2 59.6
Heavy (%) 6.9 7.3
Dietary intake
Total energy (kcal/d) 2,756 (2,230-3,377) 2,767 (2,242-3,250) 0.81
Fiber (g/d) 24 (18-33) 37 (22-56) 0.58
Alcohol (g/d) 16 (4-29) 13 (4-25) 0.45
Folate (Ag/d) 325 (200-450) 334 (217-451) 0.73
Calcium (mg/d) 1,324 (674-1974) 1,330 (713-1947) 0.62
n-3 fatty acids (FA; g/d) 2.1 (0.9-3.3) 2.1 (1.0-3.2) 0.59
Marine, n-3 FA (g/d) 0.4 (0.2-0.6) 0.4 (0.1-0.7) 0.64
Vegetable, n -3 FA (g/d) 1.6 (0.7-2.5) 1.7 (0.7-2.7) 0.56
n-6 fatty acids (g/d) 7.5 (0.5-14.5) 7.7 (1.8-13.6) 0.92
Baseline serum measurements
Serum CRP level (mg/L) 3.4 (1.7-6.5) 2.6 (1.4-4.8) 0.04
Serum a-tocopherol (mg/L) 11.3 (7.9-14.7) 12.0 (8.3-15.7) 0.04
Serum h-carotene (Ag/L) 159.0 (12.0-306.0) 182.0 (13.5-350.5) 0.07
Anatomic subsite
Colon, n (%) 73 (56%)
Rectum, n (%) 57 (44%)
NOTE: All values are medians (interquartile range) unless otherwise indicated.
*P values derived from the Wilcoxon signed rank sum test unless otherwise indicated.
c
P value derived from the m
2
test.
b
Aspirin data available on 93% of the study participants.
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given the low incidence rates of IBD in Finland at the time of the
baseline blood draw (fthree cases per 100,000 person-years; ref.
19), it is improbable that failure to account for this condition would
have influenced the results.
In conclusion, CRP is a well-established, highly sensitive clinical
gauge of inflammation, and this is the second study to report a
strong, positive association between CRP and incident colorectal
cancer. Our findings support the hypothesis that chronic
Table 2. Association between CRP and covariates among controls at baseline
Variable Quartile of CRP (mg/L)
0.2-1.4 1.5-2.6 2.7-4.8 4.9-49.5 P-trend
Age (y) 56.3 (0.48) 56.0 (0.50) 57.1 (0.49) 56.5 (0.50) 0.42
BMI (kg/m
2
) 24.5 (0.40) 26.4 (0.42) 26.2 (0.41) 27.9 (0.42) <0.0001
Cigarettes per day 17.5 (0.9) 20.4 (1.0) 20.8 (0.9) 20.3 (0.9) 0.05
Smoking duration (y) 34.7 (0.8) 36.2 (0.9) 36.1 (0.9) 36.5 (0.9) 0.44
Prior daily aspirin use (%)* 12.4 20.2 10.5 20.6 0.35
Alcohol (g/d) 15.1 (2.6) 18.8 (2.7) 20.0 (2.6) 19.5 (2.7) 0.54
n-3 fatty acids (g/d) 2.5 (0.1) 2.2 (0.1) 2.4 (0.1) 2.0 (0.1) 0.03
Marine, n-3 FA (g/d) 0.4 (0.04) 0.5 (0.04) 0.6 (0.04) 0.5 (0.04) 0.21
Vegetable, n -3 FA (g/d) 2.0 (0.1) 1.7 (0.1) 1.8 (0.1) 1.6 (0.1) 0.01
n-6 fatty acids (g/d) 10.2 (0.7) 9.7 (0.7) 9.5 (0.7) 7.7 (0.7) 0.08
Fiber (g/d) 27.8 (1.2) 26.6 (1.2) 25.9 (1.2) 24.1 (1.2) 0.19
Energy (kcal/d) 2,996 (95) 2,720 (99) 2,879 (98) 2,727 (98) 0.14
Folate (Ag/d) 362.2 (11.8) 334.3 (12.3) 350.5 (12.1) 329.1 (12.2) 0.19
Calcium (mg/d) 1,429 (63) 1,309 (65) 1,395 (64) 1,390 (65) 0.60
Serum a-tocopherol (mg/L) 11.4 (0.4) 12.6 (0.5) 13.0 (0.5) 12.8 (0.5) 0.05
Serum h-carotene (Ag/L) 232.0 (17.5) 238.9 (18.2) 215.6 (17.9) 169.5 (18.1) 0.03
Moderate/heavy physical work (%) 29.4 21.7 21.4 23.2 0.36
Moderate/heavy physical recreation (%) 67.4 60.8 67.4 67.0 0.78
Family history of colorectal cancer (%) 1.4 1.3 1.2 4.4 0.18
History of coronary heart disease (%) 3.3 4.1 4.5 10.7 0.03
History of diabetes mellitus (%) 0 5.2 2.3 4.5 0.18
History of lung emphysema (%) 5.4 2.1 4.5 7.1 0.38
NOTE: Values are means (SE) unless otherwise specified. All nutrients were adjusted for energy intake using the residuals method.
*Aspirin data only available for 93% of study participants.
Table 3. Association between serum CRP level and subsequent colorectal cancer risk with stratification by BMI level
Quartile of CRP (mg/L)
All colorectal cancers
Quartile range 0.2-1.4 1.5-2.6 2.7-4.8 4.9-49.5 P-trend*
Quartile median 0.9 1.8 3.5 6.8
n (case/control) 24/68 34/63 24/65 48/64
OR (95% CI)
c
1.0 (ref) 1.5 (0.8-2.7) 1.0 (0.5-1.9) 2.0 (1.1-3.7) 0.02
OR (95% CI)
b
1.0 (ref) 1.9 (1.0-3.8) 1.2 (0.6-2.6) 2.9 (1.4-6.0) 0.006
BMI level
V26.1 kg/m
c
n (case/control) 17/49 16/33 8/30 26/20
OR (95% CI)
x
1.0 1.6 (0.7-3.9) 0.8 (0.3-2.1) 4.6 (1.9-10.7) 0.01
>26.1 kg/m
b
n (case/control) 7/19 18/30 16/35 22/44
OR (95% CI)
x
0.9 (0.3-2.7) 2.2 (0.9-5.3) 1.6 (0.7-3.7) 2.0 (0.9-4.6) 0.43
P (interaction) for CRP
BMI = 0.018
*P-trend based on continuous data.
c
ORs adjusted for age only.
b
ORs adjusted for age, BMI, smoking duration (years), number of cigarettes smoked per day, and prior daily use of aspirin.
x
ORs adjusted for age, smoking duration (years), number of cigarettes smoked per day, and prior daily use of aspirin.
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inflammation is causally related to this disease. The utility of CRP
assessment for the clinical prediction of colorectal cancer requires
further attention, whereas studies that incorporate measurements
of other inflammatory variables and cytokines may potentially be
very useful in elucidating the inflammation–colorectal carcinogen-
esis relation.
Acknowledgments
Received 10/7/2005; revised 11/16/2005; accepted 12/12/2005.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. Paul Limburg of the Mayo Clinic, Rochester, MN, for helpful
comments during the preparation of this manuscript.
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    • "Chronic inflammation is considered a risk factor for many common malignancies including cancers of the breast [1], lung [2], and colon [3]. Colorectal cancer is the third most common type of cancer and the third leading cause of cancer-associated mortality in both males and females in the United States [4]. "
    [Show abstract] [Hide abstract] ABSTRACT: Necroptosis, a novel form of programmed cell death, was recently shown to be strongly associated with intestinal inflammation in mice and in pediatric patients with inflammatory bowel disease (IBD). Persistent inflammation of the colon is an important risk factor for colorectal cancer. Necrostatin-1 (Nec-1), known as a specific inhibitor of necroptosis, through preventing the receptor-interacting protein (RIP) 1 and RIP3 interaction. In the present study, the anti-inflammatory and antitumorigenic efficacy of necrostatin-1 was studied in mouse models of colitis and colitis-associated cancer (CAC). We found that in acute dextran sulfate sodium (DSS)-induced colitis, treatment with necrostatin-1 significantly suppressed colitis symptoms in mice, including weight loss, colon shortening, colonic mucosa damage and severity, and excessive production of interleukin-6. Necrostatin-1 administration inhibited the upregulation of RIP1 and RIP3 and enhanced the expression of caspase-8 in DSS-induced colitis. In addition, the anti-inflammatory effect of necrostatin-1 was confirmed by in vitro analyses. Necrostatin-1 treatment reduced the production of proinflammatory cytokine and extracellular HMGB1 release in HT-29 cells in active necroptosis. Furthermore, In a mouse model of colitis-associated tumorigenesis, necrostatin-1 administration significantly suppressed tumor growth and development through inhibiting JNK/c-Jun signaling. Taken together, these findings suggest that necrostatin-1 might be a promising therapeutic option for the treatment of colitis-associated colorectal cancer in patients with IBD.
    Full-text · Article · Dec 2015 · American Journal of Cancer Research
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    • "Cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) were found to decrease the incidence of colorectal adenoma, and NSAIDs were also found to reduce the incidence of CRC [4]. Elevated C-reactive protein (CRP), which is a marker of systemic inflammation was reported as the risk factor for CRC [5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose This study was conducted to evaluate the systemic inflammatory response in colorectal cancer patients, and to estimate the usefulness of the Glasgow prognostic score (GPS) as a prognostic factor. Methods Patients with biopsy-proven colorectal adenocarcinoma who were operated between April 2005 and December 2008 were enrolled in this study. The GPS was estimated based on the measurement of CRP and serum albumin level. The GPS was compared with other clinicopathological factors. Univariate and multivariate analyses were performed to evaluate the factors affecting cancer-specific survival. Results GPS was significantly higher in patients with anemia, thrombocytosis, a high neutrophil to lymphocyte ratio, tumor of the colon, and large tumor. Patient age, gender, serum CEA level, tumor gross appearance, TNM stage, and tumor differentiation were not related with the GPS. In univariate analysis, hemoglobin, CEA, gross appearance of tumor, TNM stage, tumor differentiation, and GPS were associated with cancer-specific survival. In multivariate analysis, TNM stage (III or IV : I or II; hazard ratio [HR], 12.322; P = 0.015), tumor differentiation (poorly differentiated : well or moderately differentiated; HR, 3.112; P = 0.021), and GPS (GPS 2 : GPS 0 or 1; HR, 5.168; P = 0.003) were identified as independent prognostic factors in colorectal cancer. Conclusion Our study showed that the GPS was an independent variable from tumor stage and a good and convenient prognostic factor in colorectal cancer patients.
    Full-text · Article · Jun 2014 · Annals of Surgical Treatment and Research
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    • "These results suggest the predictable potency of CRP in the mortality of CRC patients. Therefore, the results of the present study to a certain extent confirmed the conclusions of a number of previous studies which considered the positive pathological role of CRP in CRC (32–34,43). Possible reasons for the difference between the previous studies which indicated a negative association between CRP levels and clinical and pathological features in CRC patients, and other previous positive studies including the present one are probably partly attributable to the variable potential biological features, different stages, distribution of the patient population and the disparate territory. "
    [Show abstract] [Hide abstract] ABSTRACT: Elevated levels of C-reactive protein (CRP) have been described as a prognostic factor in various types of human malignancy. In the present study, the prognostic potency of CRP was validated for patients with colorectal cancer (CRC) in order to guide patient management and define high-risk populations for follow-up or for therapeutic purposes. The association between the high sensitivity-CRP (hs-CRP) levels of a total of 123 patients with CRC and their clinicopathological characteristics was explored. Subsequently, univariate and multivariate analyses were performed to investigate the survival impact of pre-treatment hs-CRP levels in this cohort study. Statistically significant correlations between the serum levels of hs-CRP and lymph node and distant metastasis (P<0.001 and P=0.012, respectively), vascular and perineural invasion (P<0.001 and P<0.001), grades (P=0.022) and clinical stages (P=0.001), but not age and gender (P=0.616 and 0.676, respectively), were found. The five-year survival rate of patients with elevated (>5.0 mg/l) hs-CRP levels was demonstrated to be significantly less than that of those in the normal group (≥5.0 mg/l) by applying the Kaplan-Meier method (13.3 versus 57.0%, log-rank test P<0.001). Furthermore, following identification as a prognostic factor through using univariate analysis, high levels of hs-CRP (P<0.001) were validated as an independent prognosticator in CRC in the present study through using multivariate analysis. Pre-treatment serum CRP levels were associated with advanced and progressed CRC patients, therefore these levels may serve as a potential prognostic marker for CRC patients.
    Full-text · Article · Dec 2013 · Experimental and therapeutic medicine
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