Hindawi

Journal of Oncology
Volume 2018, Article ID 2830503, 7 pages
https://doi.org/10.1155/2018/2830503

Research Article
The Association of Simultaneous Increase in Interleukin-6, C
Reactive Protein, and Matrix Metalloproteinase-9 Serum Levels
with Increasing Stages of Colorectal Cancer

Ismar Rasic ,1 Velma Rebic,2 Azra Rasic,3 Goran Aksamija,1 and Svjetlana Radovic4
1
Clinic for General and Abdominal Surgery, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
2
Department of Microbiology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
3
Clinic for Oncology, Clinical Center of the University of Sarajevo, Sarajevo, Bosnia and Herzegovina
4
Department of Pathology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Correspondence should be addressed to Ismar Rasic; rasicismar@gmail.com

Received 4 February 2018; Revised 23 June 2018; Accepted 28 June 2018; Published 30 July 2018

Academic Editor: Akira Hara

Copyright © 2018 Ismar Rasic et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Tumor development and growth are driven in many cases by inflammatory cells, which can produce cytokines and
other factors that can stimulate the development of the malignant process. The aim of this study was to evaluate interleukin-6 (IL-6),
C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), serum levels in patients with colorectal cancer (CRC), and their
association with the stage of CRC. Methods. IL-6, MMP-9, and CRP serum levels were measured in 75 patients with CRC just before
surgical treatment, as well as in 20 healthy individuals as controls. Surgically obtained tissue material was subjected to pathological
analysis. Results. Significant increase in CRP and IL-6 serum concentration is associated with increasing stage of CRC (p <0.05),
where MMP-9 serum level was significantly higher in stages III and IV compared to the stage II CRC. Significant correlation was
found between IL-6 and MMP-9 serum levels (rho=0.478; p <0.001) as well as between IL-6 and CRP serum levels (rho=0.720; p
<0.001) and between MMP-9 and CRP serum levels (rho=0.379; p <0.001). Serum levels of MMP-9 and CRP have been shown to
be independent predictors of the CRC stage. Conclusion. Combined quantification of IL-6, MMP-9, and CRP serum levels seems
to be a reliable index of inflammation-related processes during colorectal carcinogenesis.

1. Introduction In epidemiological studies, chronic intestinal inflamma-

tion was closely associated with the risk of CRC, and several
Colorectal cancer (CRC) is one of the most frequent causes proinflammatory cytokines released from immune and other
of malignant morbidity worldwide and the second most cells infiltrated into the microenvironment are suggested to
frequent cause for cancer-related deaths in Europe [1, 2]. regulate tumor initiation and progression [5]. In recent years
The role of inflammation in the initiation and progression the pleiotropic cytokine interleukin-6 (IL-6) and its intracel-
of colorectal cancer has been the subject of intensive research lular signaling pathways, mostly JAK1/2-Stat3, attracted the
in recent years. Patients with inflammatory bowel disease attention of researchers as a possible link that connecting
(IBD) such as Crohn’s disease (CD) and ulcerative colitis chronic inflammation and CRC promotion, although the
(UC) have an increased risk for the development of CRC. mechanisms of its activation and the contribution to the
Colorectal cancer is observed in 5.5-13.5% of all patients with pathogenesis of chronic inflammatory diseases and cancer are
ulcerative colitis and 0.4-0.8% of patients with Crohn’s disease not fully understood [6–8]. Some studies have shown elevated
[3]. According to meta-analysis Eaden et al., cumulative risk serum and cancer tissue IL-6 levels in CRC patients, and its
for CRC is 1.6% at 10 years, 8.3% at 20 years, and 18.4% at 30 concentration is correlated with tumor size, metastasis, and
years of UC duration [4]. reduced survival [9–11].
2 Journal of Oncology

Inflammatory cytokines are potent activators of matrix laboratory. After spontaneous precipitation of the sample for
metalloproteinases (MMPs) which belong to a family of 20 minutes, the same were centrifuged at 3000 rpm for 10
endopeptidases with proteolytic activity. These enzymes are minutes, with separation of serum into three aliquots. Two
capable of degrading all kinds of extracellular matrix proteins serum samples were stored at -80∘ C until analysis of MMP-
including tumor matrix proteins, allowing tumor cells to 9 and IL-6 serum concentration, while CRP serum level
invade the surrounding connective tissue, enter and exit was determined on the day of the blood sample. MMP-9
the blood vessels, and metastasize to distant organs [9]. and IL-6 serum concentration was determined on duplicate
Matrix metalloproteinase-9 (MMP-9) is an important mem- aliquots of each sample using the technique of enzyme-
ber of the matrix metalloproteinase family. Many of the linked immunosorbent assay (ELISA) according to the man-
studies conducted up to date on the MMP-9 in CRC are ufacturer’s instructions (R&D Systems, Inc.; RD-DMP900).
focused on the correlation of its expression in tissue and Reading of the results was carried out spectrophotometri-
the clinicopathological features of the tumor [12, 13]. Recent cally at 450 nm on a plate reader BioTek ELX50, with the
publications about colorectal cancer indicate that matrix correction wavelength at 540 nm or 570 nm. Measured MMP-
metalloproteinase-9 (MMP-9) serum levels are elevated in 9 serum concentration was expressed in nanograms per
the patients with colorectal cancer [14, 15]. Increased MMP-9 milliliter (ng/mL), while IL-6 concentration was expressed
serum concentration is of special interest in the progression in picograms per milliliter (pg/mL). CRP serum level was
of this cancer and might also play a role in the carcinogen- estimated by turbidimetric immunoassay on the Dimension
esis from adenoma to colorectal carcinoma [16]. Although x Pand Plus system (Siemens) and expressed in milligram per
numerous studies have greatly improved the knowledge of liter (mg/L).
colorectal tumor genesis, the association between parameters
of chronic inflammation such as IL-6, C reactive protein 2.3. Methods. Colorectal cancer surgery was performed
(CRP) and MMP-9 is not fully understood as well as their according to the principle of en bloc resection of colon can-
relation to the progression of CRC. cer with associated lymph-vascular arcade. After resection
The aim of this study to evaluate mutual relation between and macroscopic examination of surgically obtained tissue
IL-6, CRP and MMP-9 serum levels in patients with CRC material, samples of tumor were fixed in 10% phosphate
and their association with staging and clinical-pathological buffered formalin. Paraffin blocks were cut to a thickness of 3-
features of colorectal cancer. 5 microns. The obtained sections were stained with standard
hematoxylin and eosin stain, followed by determination
2. Material and Methods of histological type and grade of colon cancer, the depth
invasion of the tumor in the intestine wall (pT), and the
2.1. Patients. Seventy-five patients of both genders who number of regional metastatic lymph nodes (pN) [17]. Stage
needed surgical treatment due to CRC confirmed by radio- of colorectal cancer was determined according to the TNM
logical, colonoscopic, and histological findings were included classification of the American Association of Cancer (AJCC)
in the cross-sectional study conducted from June 2014 to in 2010, in which “T” marks the depth of invasion of the bowel
January 2016 on Clinic for General and Abdominal Surgery, wall, “N” the number of lymph nodes involved in metastatic
Clinical Center of the University of Sarajevo. The patient process, and “M” means metastasis, while wider staging was
group consisted of 40 males and 35 females with mean defined by numbers from I to IV [18].
age of 65.7 years (47-78 years). Patients who had had some
other benign or malignant neoplasia, patients treated by 2.4. Statistical Analysis. The normality of data distribution
radiotherapy or chemotherapy before surgery treatment, and was determined by Shapiro-Wilk test. All data were expressed
those with inflammatory bowel disease or a known history as median and interquartile range. Mann–Whitney U test
of familial adenomatous polyposis were not included in was used to compare the differences in parameters between
the study. The control group of 20 healthy individuals was the patient and control groups. Mood’s Median test was used
recruited from the people of the appropriate age and gender for statistical evaluation of three or more groups. Spearman’s
subjected to preventive screening at the Counseling Centre Rank correlation was used to assess the association between
for Gastroenterology, who were without family history of parameters in the patient group. The predictive significance
cancer or clinical signs of malignant or inflammatory disease. of monitored biomarkers in assessing the stage of colorectal
All the subjects were included in the study with obtained cancer was determined by multinomial logistic regression.
informed consent. The study protocol was approved by the The level of significance was set at p <0.05. Statistical analysis
local Ethics committee. The study have been performed in was performed by the Minitab 17 Software for Windows
accordance with the ethical standards laid down in the 1964 (Minitab, Inc. 2014).
Declaration of Helsinki.

3. Results
2.2. Material. Five mL of peripheral venous blood was
sampled from the patients with colorectal cancer before their The most common localization of colon cancer was estimated
surgical treatment and from controls on the day of physical in the rectum (24 patients, 32%) and then in the sigmoid
examination. The blood was collected in BD Vacutainer test colon (11 patients, 14.7%), descending colon (10 patients,
tube with no additive and immediately transported to the 17.3%), while the rectosigmoid location of colon cancer was
Journal of Oncology 3

350
300 rho = 0.720; p<0.001
rho = 0.478; p<0.001 300

200 250

IL-6 (pg/mL)
IL-6 (pg/mL)

200
100 150
100
0
50
0
−100
0 50 100 150 200
100 200 300 400 500
CRP (mg/L)
MMP-9 (ng/mL)
Figure 2: Correlation between IL-6 and CRP serum levels in
Figure 1: Correlation between IL-6 and MMP-9 serum levels in patients with colorectal cancer. rho = correlation coefficient; dashed
patients with colorectal cancer. rho = correlation coefficient; dashed line indicates 95% confidence interval (95% CI); stages II, III, and
line indicates 95% confidence interval (95% CI); stages II, III, and IV CRC have been taken into account for statistical analyses, a total
IV CRC have been taken into account for statistical analyses, a total of 75 patients.
of 75 patients.

600
rho = 0.379; p=0.001
found in 9 (12%) patients. Right colon was affected in 17 500
(22.7%) patients, and transverse colon in 4 patients (5.3%).
MMP-9 (ng/mL)

Dominant histological tumor type was adenocarcinoma 400

(100%), predominantly grade 2 (65.5%).
Compared to controls, in the patient group there was 300
a significant different increase in IL-6, CRP and MMP-
9 serum levels according to the stage of CRC (Table 1). 200
A significant increase in CRP serum value was associated
with an increase in CRC stage (from 7.2 (2.3-13.0) mg/L 100
in stage II to 38.6 (21.4-74.5) mg/L in stage IV, p <0.001),
whereas MMP-9 serum level was significantly higher in stage 0 50 100 150 200
III (458.4 (447.0-464.1) ng/mL) and stage IV (459.7 (453.2- CRP (mg/L)
469.6) ng/mL) compared to MMP-9 serum value in stage II
CRC (434.8 (373.3-447.4) ng/mL) (p <0.001). IL-6 serum con- Figure 3: Correlation between MMP-9 and CRP serum levels in
centration was significantly higher in the stage IV (28.8 (10.4- patients with colorectal cancer. rho = correlation coefficient; dashed
75.6) pg/mL) compared to stage III (6.5 (0.2-21.3) pg/mL) and line indicates 95% confidence interval (95% CI); stages II, III, and
IV CRC have been taken into account for statistical analyses, a total
stage II CRC (2.5 (0.0-4.0) pg/mL) (p <0.001).
of 75 patients.
With regard to the depth invasion of the bowel wall (pT),
CRP serum level was increased with increasing the depth of
tumor invasion from pT2 to pT4 bowel wall infiltration (from
17.75 (7.3-20.25) mg/L to 29.7 (14.7-50) mg/L, p <0.05), while to IV stages of this cancer all tracked biomarkers, other than
there were no important difference in IL-6 and MMP-9 serum IL-6, have a significant predictive value (p <0.05) in assessing
levels between the patients with pT2-pT4. colorectal cancer stage, but from stages III to IV none of the
However, IL-6, CRP, and MMP-9 serum concentrations monitored biomarkers had not a significant predictive value
were significantly higher in CRC patients with N1 lymph in the assess of colorectal cancer stage (Table 2).
node status (1-3 regional metastatic lymph nodes) and N2
involvement of regional lymph nodes (4 or more metastatic 4. Discussion
lymph nodes) compared to patients with absence of invasion
in regional lymph nodes (N0) (p <0.001). Chronic inflammatory bowel diseases, particularly ulcerative
By analyzing the correlation of the investigated parame- colitis, increase the risk of developing colorectal cancer,
ters in all patients with CRC (stages II, III, and IV, a total of which emphasizes the importance of chronic inflammation
75 patients), significant positive correlation between IL-6 and in colon carcinogenesis. In addition, the cells of colorectal
MMP-9 serum levels was confirmed (rho=0.478; p <0.001) cancer, stimulated by preexisting inflammation or carried by
(Figure 1), as well as between IL-6 and CRP serum levels intrinsic pathways related to genetic defects, may secrete a
(rho=0.720; p <0.001) (Figure 2) and between MMP-9 and variety of cytokines and activated local stromal cells [19].
CRP serum levels (rho = 0.379; p = 0.001) (Figure 3). The role of immune cells and their products in pro-
In the multinomial logical regression analysis of indepen- gression and metastasis of colorectal cancer is not yet well
dent predictors of CRC staging, it has been shown that from II known. Recently published studies suggested that, among
4 Journal of Oncology

Table 1: IL-6, CRP, and MMP-9 serum concentrations in relation to clinicopathological features of the colorectal cancer.

CRC stage
Control II III IV
Variabe p Value
(n=20) (n=22) (n=27) (n=26)
IL-6 0.0 2.5 6.5 28.8
<0.001
(pg/mL) (0.0-0.0)a (0.0-4.0)b (0.2-21.3)b (10.4-75.6)c
CRP 2.3 7.2 19.0 38.6
<0.001
(mg/L) (0.7-3.8)a (2.3-13.0)b (8.5-45.0)c (21.4-74.5)d
MMP-9 310.6 434.8 458.4 459.7
<0.001
(ng/mL) (205.0-356.3)a (373.3-447.4)b (447.0-464.1)c (453.2-469.6)c
Bowel wall infiltration (pT)
pT2 pT3 pT4
p Value
(n=10) (n=38) (n=27)
IL-6 0.0 6.6 8.9 6.5
0.306
(pg/mL) (0.0-0.0)a (0.3-21.1)b (2.1-29.2)b (0.2-21.3)b
CRP 2.3 17.75 19.9 29.7
<0.05
(mg/L) (0.7-3.8)a (7.3-20.25)b (7.9-45.7)b (14.7-50)c
MMP-9 310.6 450.35 450.9 458.4
0.103
(ng/mL) (205.0-356.3)a (438-454.8)b (435.8-460.5)b (447-464.1)b
Lymph nodes invasion (pN)
pN0 (n=25) pN1 (n=26) pN2 (n=24) p Value
IL-6 0.0 3.0 10.3 20.1
<0.001
(pg/mL) (0.0-0.0)a (0.0-5.2)b (2.5-44.8)c (6.4-46.7)c
CRP 2.3 8.3 26.7 33.7
<0.001
(mg/L) (0.7-3.8)a (2.4-20.3)b (15.9-59.3)c (14.7-68.5)c
MMP-9 310.6 437.4 458.9 458.2
<0.001
(ng/mL) (205.0-356.3)a (383.3-448.8)b (452.8-465.4)c (449.8-464.6)c
Data are presented as median and interquartile range q1-q3 (25%-75%).
abcd
Values in the same row that do not contain a common lettering differ significantly on the level p <0.05.
CRC: colorectal cancer; IL-6: interleukin-6; CRP: C-reactive protein; MMP-9: matrix metalloproteinase-9; pT2: tumor invades muscularis propria; pT3: the
tumor invades through the muscularis propria in the pericolic tissue; pT4: the tumor penetrates the surface of visceral peritoneum or other organs; pN0: no
invasion to regional lymph nodes; pN1: 1-3 regional metastatic lymph nodes; pN2: 4 or more metastatic lymph nodes.

Table 2: Independent predictors of the colorectal cancer stage.

95% CI
Predictor coefficient SE p Value OR lower upper
II/IV stage of CRC
Constant 108.075 44.860 0.016
MMP-9 (ng/mL) -0.208 0.091 0.022 0.81 0.68 0.97
CRP (mg/L) -0.216 0.103 0.036 0.81 0.66 0.99
IL-6 (pg/mL) 0.016 0.017 0.360 1.02 0.98 1.05
III/IV stage of CRC
Constant 21.663 14.244 0.128
MMP-9 (ng/mL) -0.042 0.030 0.164 0.96 0.90 1.02
CRP (mg/L) -0.022 0.013 0.082 0.98 0.95 1.00
IL-6 (pg/mL) -0.011 0.008 0.182 0.99 0.97 1.01
CRC: colorectal cancer; SE: standard error of coefficient; OR: odds ratio; CI: confidence interval.

cytokines involved in intestinal tumor genesis associated with pathogenesis of IBD and cancer are not fully understood. The
inflammation, an important role belongs to IL-6 [20, 21]. action of IL-6 is conditioned by binding to IL-6 receptor-
This cytokine is considered a key link between inflammation alpha on target cells and then by binding this complex to
and tumor genesis due to the confirmed association of IL-6 the receptor subunit gp130 leading to the activation of the
expression and CRC prognosis, as well as association with JAK/STAT signaling pathway in classic signaling [22]. Belluco
IBD. The mechanisms by which IL-6 contributes to the with associates [23] described an association of a common
Journal of Oncology 5

functional single G>C base polymorphism in the human IL- macrophage expression of MMP-9, which has been directly
6 gene promoter (chromosome 7p21) with serum levels of this associated with the pathogenesis of chronic inflammatory
cytokine in patients with CRC, particularly in the presence of diseases and cancer. Inflammatory cytokines are believed to
hepatic metastasis. increase matrix metalloproteinase (MMP) dysfunction, while
In our research IL-6 serum levels were statistically signif- MMPs increase tissue inflammation.
icantly different between controls and patients with CRC and We have found that CRP serum level in patients with CRC
showed marked increase with increasing stages of colorectal was significantly higher with increasing stage of this disease,
cancer. Median IL-6 serum levels statistically significantly as well as with increasing of tumor bowel wall infiltration
differed between the individual stages of CRC, reaching the and regional lymph nodes invasion, reaching the highest
highest level in stage IV. We found that IL-6 serum levels values in the IV stage CRC. Significant positive correlation
were higher in patients suffering from CRC with N1 and N2 between IL-6 and CRP serum levels was confirmed in the
lymph nodes status compared to patients without metastasis patients with CRC strongly suggesting that CRP as a general
to regional lymph nodes (N0). Median IL-6 serum values marker of inflammation should be combined with the other
increased with an increase of invasion in the intestinal wall inflammatory molecules in patients with colorectal cancer.
(pT), but without statistical significance. Italian authors also demonstrated an increase in CRP serum
Several studies have found an increased expression of levels in the patients with colorectal cancer, particularly in the
IL-6 in patients with CRC, where IL-6 levels are elevated second and third stages of the disease [30], comparable to the
in the serum of patients and in tumor tissue itself [10, tendency we found.
24]. The results of the recently published Chinese study Several meta-analyses and systematic reviews have
suggest that IL-6 expression in the CRC tissue is associated assessed the association between IL-6 serum levels and
with tumor TNM stage, invasion depth, and lymph node risk of CRC, whereas these pooled results were insignificant
metastasis in CRC [25]. Finding a parallel increase in IL- [31, 32]. Kakourou with associates [31] reported a significantly
6 serum levels with increasing stage of colorectal cancer positive association between IL-6 serum level and risk of
and increasing metastatic regional lymph nodes in our study colon cancer, but the results were opposite for rectal cancer.
supports that opinion. Since intestinal epithelial cells usually The results of our study indicate that all tracked biomarkers,
do not express the membrane-bound IL-6R, some authors other than IL-6, have a significant predictive value in the
consider that effects of IL-6 on colorectal cancer cells are assessment of stage II to stage IV CRC but not from stage III
mainly modulated through IL-6 trans-signaling promoting to stage IV which suggests the prognostic importance of the
tumor cell proliferation and inhibiting apoptosis through stage II in colon carcinogenesis.
gp130 activation on tumor cells and then with signaling This is one of the few studies which have followed
through Janus kinases (JAKs) and signal transducer and simultaneously several biomarkers in patients with CRC in
activator of transcription 3 (STAT3) [24, 26]. order to identify an inflammatory network that contributes to
Inflammatory cytokines are potent matrix metallopro- the progression of CRC. This study has a few limitations. This
teinase (MMP) activators. The study of Kothari and associates is a study of a single center, which is the reason for involving
[27] demonstrated that IL-6 induces macrophage expression a relatively small number of surgically treated patients with
of MMP-9 via Cox-2-dependent and Cox-2-independent CRC. A comparison between rectal cancer and other parts of
mechanisms, which has been directly associated with the the colon as well as the analysis the following biomarkers after
pathogenesis of chronic inflammatory diseases and cancer. surgical removal of colon cancer had not been made.
MMP-9 serum levels were found to be elevated in many
studies about CRC [15, 28, 29]. Our results indicate that
MMP-9 serum concentration was significantly higher in 5. Conclusion
patients with colorectal cancer than in the control group and
IL-6, CRP, and MMP-9 serum levels showed very similar
significantly increased in stages III and IV CRC compared
trends, increasing concomitantly and reaching the highest
to stage II suggesting that MMP-9 is primarily involved in
values in stage IV CRC, indicating they are involved in
the occurrence of metastatic colorectal cancer. The similar
tumor promotion and proliferation. Our results showed
relationship was confirmed according to the tumor size (pT)
that there is strong association between MMP-9 and CRP
and the spread of tumor process to the regional lymph nodes
serum levels and progression of colorectal cancer. MMP-
(pN). A study by Biasi and associates [30] has indicated
9 and CRP serum levels have a significant predictive value
that MMP-9 serum levels significantly increased during
in the assessment stage II to IV colorectal cancer which
the carcinogenic process in human colorectal tract, with a
points to persisting inflammation-related process and its
significant difference in the mean value of this biomarker in
importance in the colorectal tumor genesis. These biomarkers
stage III CRC compared to control. That research confirmed
in combination might be considered as a potential tool for
a significant correlation between MMP-9 and IL-8 serum
monitoring colorectal cancer progression.
levels precisely in stage III CRC, while our study confirmed
a significant positive correlation between MMP-9 and IL-6
serum levels, as well as between MMP-9 and CRP serum lev- Data Availability
els in all patients with CRC indicating the mutual stimulated
interaction of these biomarkers in colorectal carcinogenesis. The data used to support the findings of this study are
A study of Kothari et al. [27] demonstrated that IL-6 induces available from the corresponding author upon request.
6 Journal of Oncology

Conflicts of Interest in colorectal cancer,” International Journal of Molecular Sciences,

vol. 13, no. 10, pp. 13240–13263, 2012.
The authors declare that they have no conflicts of interest. [17] S. R. Hamilton and L. A. Aaltonen, Eds., World Health Orga-
nization Classification of Tumours. Pathology and Genetics of
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