CXCL5 and CXCL14, but not CXCL16 as potential non-invasive biomarkers of colorectal cancer?

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Monika Zajkowska, Maciej Dulewicz, Agnieszka Kulczyńska-Przybik, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2615376/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Oct, 2023 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Purpose Experts emphasize that incidence and mortality of colorectal cancer (CRC) is increasing. That is why, its early detection is of utmost importance. Patients with cancer diagnosed in earlier stages have better prognosis and chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis. Methods Therefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 subjects (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA. Results Concentrations of CXCL5 were statistically higher in CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19 − 9. Conclusions Obtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM stages, as well as usefulness of CXCL14 and CRP combination in CRC detection. However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers. Biological sciences/Biochemistry/Cytokines/Chemokines Health sciences/Biomarkers CRC cytokines chemokines biomarker metastasis Figures Figure 1 1. Introduction Annually, approximately 2,000,000 new cases of intestinal malignant neoplasm (C18-C20) are diagnosed. Analyzing the incidence structure, it can be concluded that colorectal cancer is the third most common malignant neoplasm afflicted by women and the second most common among men. Experts emphasize that the incidence and mortality of colorectal cancer in both sexes has been increasing year-to-year. Early detection of colorectal neoplasms and rectal cancer is of utmost importance for the effectiveness of the therapy. Patients with cancers diagnosed in earlier stages have an enhanced prognosis and a chance for faster implementation of cancer treatment. In this context, it is worth remembering about the possibility of taking advantage of screening for colorectal cancer [ 1 ]. Most cases of colorectal cancer are diagnosed in patients over 50 years of age, and very rare in patients under the age of 40. The disease usually progresses slowly and the symptoms of colorectal cancer are partially dependent on the location of the malignant processes. In the early stages of the disease, the symptoms of colorectal cancer are usually non-specific and have the form of abdominal pain and flatulence, which may suggest less serious problems from the gallbladder or peptic ulcer disease. Most patients with colorectal cancer do not report significant symptoms, or they are slight or nonspecific - matching many different digestive system diseases. Those symptoms are often underestimated and not equated with threats such as colorectal cancer. Stool disorders are most often attributed to stress and poor diet. In addition to neoplastic changes, they can also be caused by inflammation in the large intestine, food poisoning or infections with intestinal parasites [ 2 – 4 ]. The most commonly used techniques used in CRC detection are colonoscopy and sigmoidoscopy. In some cases, imaging diagnostics, computed tomographic colonography or magnetic resonance method, are used. Even though significant improvement has been made in this area in latest years, in the case of small lesions, these procedures might be unsuccessful. Alternative diagnostic tool, useful in the discovery of colorectal cancer are tumor markers, which are synthesized mostly by tumor cells. Tumor markers have a particular utility not only in detecting of malignancies and determining tumor advancement, but also in monitoring of treatment and early detection of recurrence [ 3 , 4 ]. The example of tumor markers engaged in the identification of CRC are CEA (carcinoembryonic antigen) and CA 19 − 9 (cancer antigen 19 − 9). Regrettably, the diagnostic usefulness of these biomarkers is relatively low as they are not specific to the CRC itself [ 5 ]. Taking into account the above evidences, there is an critical need to find novel biomarkers, the use of which will allow for early recognition of emerging cancer earlier than it was probable previously. Increasing evidence suggests that small inflammatory cytokines (8–12 kDa) known as chemokines are key regulators of angiogenesis, including pathological angiogenesis. In chemical terms, chemokines are peptides composed of 70–130 amino acids [ 6 ], structurally and functionally similar to growth factors. They are characterized by 20–50% sequence homology between molecules, which is reflected in their structural similarities. According to the nomenclature, the names of individual types of these compounds are created by adding the letter L (ligand) together with a sequential number. Most of the compounds in their structure contain four characteristic cysteine residues which, by forming disulfide bridges, determine their three-dimensional structure. Chemokines, on a basis of this structure, have been classified into 4 groups: CC, CXC, CX3C and X chemokines [ 7 , 8 ]. The present state of knowledge allows us to suspect that all these proteins play a significant role in cancer advancement [ 9 ]. In cancer development and metastasis, these chemokines exert a complex outcome on angiogenesis, tumor cell proliferation and apoptosis regulation, facilitating tumor cell metastasis in an organ specific manner [ 10 ]. It is postulated that the CC and CXC chemokines could be the most active in the regulation of angiogenesis [ 11 , 12 ]. That is why the aim of our study was an effort to elucidate and evaluate the utility of selected CXC-chemokines determination (CXCL5, CXCL14 and CXCL16) in patients with colorectal cancer compared to the healthy control. We have also compared the obtained results to CA 19 − 9, CEA, and inflammatory parameter such as C-reactive protein (CRP). 2. Materials And Methods 2.1. Patients The study included 75 patients diagnosed by the oncology group for colorectal cancer (CRC) (Table 1 ). All patients were treated in the Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, Bialystok, Poland. Tumor classification and staging were conducted in accordance with the UICC-TNM (International Union Against Cancer Tumor-Node-Metastasis) classification. Table 1 Characteristics of colorectal cancer and healthy patients groups. Study Group No. of patients Colorectal Cancer 75 (100%) Gender: Female Male 26 (35%) 49 (65%) Type: Colon Cancer Rectal Cancer Sigmoid Cancer 25 (33%) 41 (55%) 9 (12%) TNM Stage: 0 I II III IV 1 (1%) 15 (20%) 13 (17%) 25 (34%) 21 (28%) Depth of tumor invasion: In situ T1 T2 T3 T4 1 (1%) 2 (3%) 19 (25%) 41 (55%) 12 (16%) Nodal involvement: N0 N1 N2 34 (45%) 25 (34%) 16 (21%) Distant metastasis: M0 M1 54 (72%) 21 (28%) Age: 33–89 Control Group 40 (100%) Gender: Female Male 12 (30%) 28 (70%) Age: 34–80 Colorectal cancer histopathology was based on the microscopic examination of tissue samples. Moreover, all patients were grouped according to tumor stage (TNM), depth of tumor invasion (T factor), presence of lymph node (N factor) and distant metastases (M factor) as well as the histological grade (G factor) of the tumor. The pretreatment staging procedures included physical and blood examinations, CT scans (computed tomography) and in case of patients with rectal cancer – MRI (magnetic resonance imaging) of the small pelvis. Additionally, all patients were assessed according to the ECOG score (Eastern Cooperative Oncology Group). The control group included 40 healthy volunteers. For each of patient qualified for the control group, the exclusion criteria such as: obesity, active infections and symptoms of an infection, respiratory diseases, digestive tract diseases or systemic diseases were applied. 2.2. Biochemical analyses The biochemical analysis of the tested parameters was performed as described previously [ 13 , 14 ]. 2.3. Statistical analysis Statistical analysis was performed by RStudio and Statistica 13.0 as described pre-viously [ 13 , 14 ]. The cut-off points for each of the tested parameters were designated as fol-lows: CXCL5–953.96 pg/mL, CXCL14–650.92 pg/mL, CXCL16–926.01 pg/mL, CA 19 − 9–5.30 U/mL, CEA – 1.70 ng/mL, CRP – 2.50 mg/L. 3. Results 3.1. CXC chemokines Concentration of CXCL5, CXCL14, CXCL16, CA 19 − 9, CEA and CRP in sera of CRC patients and healthy patients (control group) were presented in Table 2 . The non-parametric test (U Mann-Whitney) which compared the levels obtained in the above mentioned groups have revealed that concentration of CXCL5, CEA and CRP in total CRC group were statistically higher, and CXCL14 significantly lower when compared to healthy controls (in all cases p < 0.05). Table 2 Serum levels of tested parameters in cancer and control groups. Parameter Colorectal Cancer Control Group p* CXCL5 [pg/mL] Me Min - Max 1299.8 185.2–7500.0 894.2 204.2–2634.5 0.01 CXCL14 [pg/mL] Me Min – Max 595.6 312.3–8654.0 671.5 338.0–1968.8 0.03 CXCL16 [pg/mL] Me Min – Max 927.2 288.9–2876.0 910.2 540.4–1307.1 0.67 CA 19 − 9 [U/mL] Me Min – Max 5.3 2.1–8199.9 5.4 2.1–33.3 0.82 CEA [ng/mL] Me Min – Max 3.9 0.5–3688.0 1.0 0.5–15.6 < 0.001 CRP [mg/L] Me Min - Max 6.0 1.0–248.5 1.4 0.2–5.8 < 0.001 * U Mann-Whitney test Furthermore, we performed a more exhaustive investigation with use of two different tests used in statistics (Kruskal–Wallis and Dwass–Steel–Critchlow–Fligner). That is why, we have divided the group in which colorectal cancer patients were included into four subgroups with use of TNM grading into I-IV advancement groups. After Kruskal-Wallis analysis, we obtained significant results for CXCL5, CXCL14 and comparative parameters (Table 3 ). Taking the acquired results, it can be suggested that the CXCL5, CEA, and CA 19 − 9 concentration rises with the development of tumor. Interestingly, the CXCL14 analysis reveals that there is a significant difference between control group and I stage of CRC, which in our opinion is a very important observation as it may serve as a potential marker of early neoplastic changes. Table 3 Kruskal-Wallis and Dwass-Steel-Crithlow-Fligner tests analysis results. Parameter CXCL5 CXCL14 CXCL16 CA 19 − 9 CEA CRP Kruskal-Wallis p -value < 0.001 0.04 0.07 0.003 < 0.001 < 0.001 Dwass-Steel-Crithlow-Fligner p -value Control vs. I 0.98 0.02 0.42 0.19 0.34 < 0.001 Control vs. II 0.85 0.99 0.87 0.83 0.08 < 0.001 Control vs. III 0.21 0.78 0.88 0.50 0.002 < 0.001 Control vs. IV < 0.001 0.80 0.07 0.25 < 0.001 < 0.001 I vs.II 0.82 0.12 0.74 0.98 1.00 0.99 I vs.III 0.23 0.18 0.19 0.033 0.77 1.00 I vs.IV 0.004 0.61 0.07 0.013 < 0.001 0.99 II vs.III 0.93 0.98 0.63 0.17 0.68 0.95 II vs.IV 0.048 0.97 0.08 0.15 < 0.001 0.99 III vs.IV 0.39 1.00 0.35 0.99 0.005 0.97 As the number of cases in stage I and II of TNM classification was lower than 20, what may have an impact at the correctness of the acquired outcomes, we wanted to check their exactness using another test. We separated all colorectal cancer patients into two groups: less-advanced (TNM I + II) and advanced tumors (TNM III + IV). Furthermore, we separated the group of advanced tumors into single TNM’s (III and IV) due to the satisfactory number of patients in each stage to perform an accurate investigation in those groups and in comparison to healthy volunteers (control). Remarkably, we have observed significant differences between healthy patients and IV stage CRC in case of CXCL5 and CXCL16 which may suggest its involvement in distant metastasis processes and what is of utmost importance, significant differences between all CRC stages (same as CA 19 − 9). In case of CXCL14, we have observed differences between control and less-advanced stages (I and II) of CRC, which as previously mentioned, is an extremely important result considering the fact, that there are no widely available, non-invasive methods that would be useful in case of asymptomatic patients (Table 4 ). Table 4 U Mann-Whitney test analysis results between control group and TNM subgroups. Parameter CXCL5 CXCL14 CXCL16 CA 19 − 9 CEA CRP U Mann-Whitney test p -value Control vs. I + II 0.99 0.05 0.13 0.05 0.04 < 0.001 Control vs. III + IV < 0.001 0.30 0.11 0.10 < 0.001 < 0.001 Control vs. III 0.11 0.43 0.67 0.30 < 0.001 < 0.001 Control vs. IV < 0.001 0.45 0.03 0.14 < 0.001 < 0.001 I + II vs. III + IV < 0.001 0.31 < 0.001 < 0.001 < 0.001 1.00 I + II vs. III 0.05 0.27 0.02 < 0.001 0.10 0.70 I + II vs. IV < 0.001 0.56 0.001 < 0.001 < 0.001 0.67 Table 5 shows the parameters of diagnostic utility of all tested parameters, except for CXCL16, which was the only newly tested parameter that did not show statistical significance. We showed that the highest sensitivity (SE) from all parameters revealed CXCL5 and CXCL14 (68 and 67%, respectively). The detected value is slightly lower than SE of CEA (75%) and CRP (73%), but much higher than SE of CA 19 − 9 (51%). What is more, the specificity (SP) of CXCL5 and CXCL14 showed high value (both 58%), but was lower than SP of CRP (78%) and CEA (70%), nevertheless higher than CA 19 − 9 (48%). Positive predictive value (PPV) was high for CXCL5 and CXCL14 (both 75%). Negative predictive value (NPV) was calculated on 49% for CXCL5 and 48% for CXCL14. All these values were slightly lower than PPV and NPV of CEA and CRP. Additionally, all utility values of newly tested parameters (CXCL5, CXCL14) were greater than those obtained for CA 19 − 9, which suggests their higher utility than this routine marker for colorectal cancer patients. Table 5 Diagnostic criteria of tested parameters in patients with colorectal cancer. Tested parameters Diagnostic criteria Colorectal Cancer CXCL5 SE 68% SP PPV NPV AUC 58% 75% 49% 0.65 CXCL14 SE 67% SP PPV NPV AUC 58% 75% 48% 0.62 CA 19 − 9 SE 51% SP PPV NPV AUC 48% 64% 34% 0.51 CEA SE 75% SP PPV NPV AUC 70% 82% 60% 0.79 CRP SE 73% SP PPV NPV AUC 78% 86% 61% 0.84 We observed that the AUC of CXCL5 (0.65) in the total group of CRC was highest from all obtained results, but lower than area under the ROC curve obtained for CEA and C-reactive protein. Nevertheless, in case of both assessed CXC chemokines, AUC was higher than AUC of CA 19 − 9 (Fig. 1 ). We have also tested the Spearman’s rank correlation coefficient to indicate the strength and direction of monotonic association between variables. All results are presented in Table 6 . Table 6 Spearman’s rank correlation coefficient for tested variables. Tested variables CXCL5 CXCL14 CXCL16 CA 19 − 9 CEA CRP Age CXCL14 0.06 p = 0.60 - CXCL16 0.32 p = 0.005 0.17 p = 0.16 - CA 19 − 9 0.24 p = 0.04 0.09 p = 0.44 0.22 p = 0.06 - CEA 0.46 p < 0.001 0.05 p = 0.68 0.43 p < 0.001 0.51 p < 0.001 - CRP 0.25 p = 0.03 0.06 p = 0.61 0.47 p < 0.001 -0.01 p = 0.91 0.17 p = 0.16 - Age 0.04 p = 0.76 -0.13 p = 0.27 -0.01 p = 0.92 0.22 p = 0.06 0.36 p < 0.001 -0.07 p = 0.55 - TNM stage 0.47 p < 0.001 0.15 p = 0.20 0.42 p < 0.001 0.43 p < 0.001 0.57 p < 0.001 0.05 p = 0.67 0.34 p = 0.003 We observed a moderate positive correlation for CXCL5, CXCL16, as well as CEA and CA 19 − 9 with tumor TNM stage. This may indorse (as observed previously) that the growing level of those factors are associated with the amount of tumor cells. Moderate, positive correlation was also detected between CXCL5, CXCL16 with CEA concentration, CXCL16 with CRP levels, and both markers (CEA and CA 19 − 9). Rest of witnessed significant correlations revealed weak strength (coefficient < 0.40). 3.2. CXC and CC chemokines combination In order to continue the research on the usefulness of different chemokine groups in the diagnosis of colorectal cancer, we decided to use the previous assays [ 14 ] in a combined analysis with the currently obtained concentrations. The obtained results turned out to be very interesting, which in our opinion significantly influences the validity of the published work. Significant combinations of all tested chemokine analyses were presented in Table 7 (all p < 0.001). Table 7 Diagnostic criteria of chemokine combinations in patients with colorectal cancer. Tested parameters Diagnostic criteria Colorectal Cancer CCL2/CRP ratio SE 55% SP ACC AUC 85% 75% 0.80 CXCL14 + CRP SE 83% SP ACC AUC 75% 80% 0.88 CEA + CRP SE 79% SP ACC AUC 75% 77% 0.88 The obtained results suggest that the simultaneous analysis of the two parameters determination significantly influences the area under the ROC curve (AUC), which con-firms the usefulness of the parameters tested. The performed comparative analysis for the routine marker (CEA) and CRP (Table 7 ) additionally confirms the usefulness of CXCL14 and suggests the need to continue research on this parameter and its use in the diagnosis of CRC, as the values of the obtained diagnostic criteria indicate greater usefulness of simultaneous CXCL14 and CRP determinations. In order to complete the statistical analysis, we also checked whether there were any correlations between the previously and currently studied chemokines. As a result of this analysis, we found a moderate positive correlation between CCL4 and CXCL5 (r = 0.46; p < 0.001) as well as CCL4 and CXCL16 (r = 0.54; p < 0.001). 4. Discussion The search for new biomarkers that could prove their usefulness in cancer screening remains a serious global problem. Early diagnosis, especially concerning the non-invasive lesions, remains unattainable. In the case of colorectal cancer, but also other neoplasms, researchers are constantly searching for biomarkers, which would indicate the presence of neoplastic or even pre-neoplastic changes at the earliest possible stage and would replace or supplement the currently used imaging or histopathological tests [ 4 ]. There are few studies on the usefulness of selected CXC-chemokines in the course of colorectal cancer, which prompted us to carry out the above analyzes. We indicated that serum concentration of CXCL5 was statistically higher in group of colorectal cancer patients when compared to healthy controls (p = 0.01). Similar results were obtained in work of Kawamura et al. [ 15 ]. These authors also revealed that preoperative serum levels of CXCL5 were significantly elevated in patients with CRC compared with healthy volunteers. Interestingly, the researchers pointed out that high serum CXCL5 was also associated with female sex, liver metastasis and poor overall survival. In addition, they have also measured the CXCL5 level in CRC cell lines, which confirmed previously mentioned results. These authors concluded, that CXCL5 preoperative serum level could serve as a novel predictive marker for prognosis determination of CRC which fully corresponds with our results. Different researchers in work of Yildirim et al. [ 16 ] all these results in their work, where serum CXCL5 and CEA levels were significantly higher in CRC group. In addition, these authors also performed immunohistochemical studies which revealed high number cases who were stained positive in CRC group. Although the studies by Yilidirim et al. [ 16 ] were carried out on a small study group, a group of patients with benign lesions was specified, for which neither the CXCL5 concentration nor tissue expression differed when compared to the study group. This may indicate, on the one hand, the low usefulness of CXCL5 in the detection of benign lesions, but on the other hand it can be a useful parameter when detecting tumor initiation. These assumptions require further analysis and confirmation using a much larger study group. In contrast, we also found work by Dimberg et al. [ 17 ], in the course of which the researchers showed that the concentration of the CXCL5 protein in homogenates of neoplastic tissues were statistically higher compared to normal tissues, however, the concentrations of this parameter in the blood serum were significantly lower in the CRC group. These discrepancies were explained by the authors by the different origin of CXCL5 (leukocytes, epithelial and endothelial cells) and by immunologic imbalance in case of CRC patients. Perhaps an additional factor influencing these differences was the degree of neoplastic lesions advancement, as in the studies conducted by Dimberg et al. [ 17 ] most of the patients were classified as Duke's A and B grades, and in our results, CXCL5 showed the highest con-centration in case of patients with distant metastases (TNM stage IV). As there are only a few studies concerning the concentration of CXCL5 in the course of human colorectal cancer, we decided to focus also at the studies regarding tissue and gene expression, and studies on CXCL5 in other species. All the studies indicate the high usefulness of this parameter in the course of CRC. For example, in the work of Baier et al. [ 18 ] it was proved that the concentration in cancer tissue is significantly higher compared to normal tissue. Similar results were also obtained by other researchers such as Hu et al. [ 19 ], Yu et al. [ 20 ], Meng et al. [ 21 ], Rubie et al. [ 22 ] and Zhang et al. [ 23 ]. In the case of two last of mentioned studies, the authors additionally performed an analysis of gene expression (qRT-PCR), which, along with similar results obtained in the work of Novillo et al. [ 24 ], confirmed the increase of CXCL5 in the course of CRC. Also in TCM (tumor conditioned media), similar results were obtained [ 25 ]. All the above-mentioned studies conclude unequivocally that CXCL5 is a very important factor in the progression of colorectal cancer and may be a useful prognostic factor. We have found also studies pointing to elevated CXCL5 expression in murine models [ 26 ], also those, fed with a high-fat diet [ 27 ]. This may indicate a relationship of this parameter with obesity, which indicates the high safety of our research, as obesity was one of the excluding parameters. However, in the absence of statistical significance obtained in the studies by Dimberg et al. [ 17 ], it would be worth to analyze these reports. In case of CXCL14, we have observed statistically lower concentration of this parameter in serum of colorectal cancer patients when compared to healthy volunteers. Unfortunately, we did not found any similar works which could confirm or deny our studies. In case of CXCL14 gene or tissue expression, there were few studies, which partially con-firmed our investigations. For example, in paper of Lin et al. [ 28 ] using both PCR and IHC methods, the authors showed significantly lower expression of CXCL14 when compared to normal mucosa. Similarly, paper of Cao et al. [ 29 ] revealed methylation and silencing of CXCL14 in 5 different CRC cell lines. These authors concluded, that restoration of CXCL14 expression suppressed CRC proliferation, inhibited its migration, invasion, and epithelial-to-mesenchymal transition. These findings seems extremely important as this information could provide a new target for the treatment of colorectal cancer. Moreover, it can be assumed that, potentially, the high concentration of this parameter in the course of CRC may be a positive prognostic factor for CRC patients. However, some other researchers [ 30 ] revealed, that CXCL14 mRNA expression was higher in case of CRC tissues. Also research conducted by Zeng et al. [ 31 ] proved that CXCL14 is involved in the proliferation and migration of ROS-induced CRC cells, as the expression level of CXCL14 was elevated in CRC cell lines treated with H2O2. The observed discrepancies significantly drew our attention, however, they were also noticed by other researchers [ 32 ]. The mechanisms that control the CXCL14 functions are hypothetically defined by the cell and tissue types that synthesize CXCL14 and respond to CXCL14 concentration, as well as by other proteins that co-operates with CXCL14. Mostly, CXCL14 produced by epithelial cells has been shown to overwhelm the tumor cells growth. On the other hand, CXCL14 produced from cancer-associated fibroblasts stimulates tumor growth and metastasis. While CXCL14-mediated tumor suppression and altered expression correlates with better patient survival in cancer such as head and neck, colorectal, and liver, CXCL14-mediated tumor promotion mostly occurs in tumors of breast and pancreas. Accordingly, further studies concerning CXCL14 are absolutely vital. Taking into account the concentration of CXCL16, we showed no statistically significant differences, however, the concentrations of this parameter in the study group were higher than in the control group. However, the work of different research groups [ 30 , 33 – 38 ] has shown that the concentration and expression (both tissue and mRNA) of CXCL16 in the group of patients with colorectal cancer is higher compared to the control group, the same as in investigations with use of cell lines. In addition, Chen et al. [ 38 ] revealed, that CXCL16-positive tissue expression was significantly related to tumor size, its differentiation and distant metastasis. Comparing these results to the results of our analysis using the Mann-Whitney U test, it can be assumed that we showed a similar trend, as this parameter seems to be useful in differentiation between CRC stages and demonstrated statistical significance in stage IV (distant metastases) of CRC compared to healthy controls. Perhaps, after enlarging the study group, it would be possible to prove statistical significance also in our research. Interestingly, some authors indicate that CXCL16 levels may promote tumor angiogenesis after minimally invasive colorectal resection [ 39 ] and demonstrate the inhibitory effect on liver metastasis [ 40 ]. The only investigators who assessed the diagnostic usefulness of CXCL5 in the blood serum of CRC patients were Yilidirim et al. [ 16 ]. They showed that the AUC for CXCL5 was 0.671, while SE, SP, PPV and NPV were 57%, 67%, 41.94% and 75%, respectively. The SE and PPV obtained by these researchers were lower than ours, while the SP, NPV and AUC were higher. These differences may result from the calculated cut-off point in both studies, which is related to the differences between the test and control groups. Interestingly, the authors, as in the case of our results, obtained slightly lower AUC for the tested parameter than the AUC of the routinely used marker, which is CEA. Regrettably, we have not found any further studies that would emphasize on demonstrating the dependency and statistical significance based on the division of the tested group into advancement stages. Consequently, we believe that this work is inventive in this matter, which significantly rises its value. A more precise demonstration of the associations between the control and study group may meaningfully affect the understanding of alterations in the development of CRC. Remarkably, our results presented significant alterations between the CXCL5 con-centration in stage IV/III + IV of CRC and healthy controls, and significant differences be-tween all TNM stages, which may indicate its contribution in the development of tumor progression and distant metastasis. What is more, CXCL14 showed statistical difference only between control group and stage I/I + II of CRC, which, in connection with the previously acquired information about the decreasing concentration of this parameter in the course of CRC, may indicate an attempt of healthy cells to equalize CXCL14 concentration in order to prevent tumor progression, or on the contrary, about the collapse of the organ-ism's antitumoral action, depending on the adopted functions performed by CXCL14. Due to the fact that these are one of the first reports on these dependencies, it is desirable to confirm them in further analysis. We also determined the correlation coefficients between the studied parameters, which confirmed that the concentration of CXCL5, CXCL16 and both tumor markers are closely related to the severity of CRC. Moreover, both CXCL5 and CXCL16 positively cor-related with CEA, and CXCL16 additionally with CRP concentration. It may be related to the ongoing inflammation during the cancer progression. Unfortunately, in the available literature, we did not find any papers that could confirm or contradict the results obtained, which proves the innovation of our work. In addition, we have proved, that of simultaneous CXCL14 and CRP determinations might be more useful in CRC diagnosis than commonly used tumor marker - CEA and CRP combination. As in the case of the above-mentioned analyzes, there are no studies available that would assess the parameters tested in a similar way. 5. Conclusions The present study, according to our knowledge, is the first to compare the diagnostic utility of CXCL5, CXCL14 and CXCL16 with the well-established colorectal cancer tumor markers such as CEA and CA 19 − 9, and CRP (the marker of inflammation), not only in the whole group of colorectal cancer patients, but also after division to TNM stages I-IV. The obtained results highly suggest importance of CXCL5 and CXCL16 in detection of distant metastases and differentiation between TNM stages, as well as combination of CXCL14 and CRP as potential CRC biomarkers. However, further studies concerning the concentrations of selected CXC chemokines in the course of CRC are necessary to confirm and clarify their diagnostic usefulness and clinical application as potential non-invasive biomarkers of CRC development. Declarations Competing Interest: The authors declare no conflict of interest. Funding: This research was funded by the Medical University of Bialystok, Poland, grant number: SUB/1/DN/22/004/1198. Author Contributions: Conceptualization, Monika Zajkowska and Barbara Mroczko; methodology, Monika Zajkowska and Agnieszka Kulczyńska-Przybik; formal analysis, Monika Zajkowska, Agnieszka Kulczyńska-Przybik and Maciej Dulewicz; investigation, Monika Zajkowska, Maciej Dulewicz, Kamil Safiejko, Marcin Juchimiuk, Marzena Konopko, Leszek Kozłowski and Agnieszka Kulczyńska-Przybik; resources, Monika Zajkowska; data curation, Monika Zajkowska and Maciej Dulewicz; writing—original draft preparation, Monika Zajkowska; writing—review and editing, Monika Zajkowska and Barbara Mroczko; supervision, Barbara Mroczko; project administration, Monika Zajkowska and Barbara Mroczko; funding acquisition, Monika Zajkowska. All authors have read and agreed to the published version of the manuscript. Ethics Committee approval: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Medical University of Bialystok (R-I-002/564/2019; 28.11.2019). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Key data are stated in the text. Acknowledgments: This study was conducted with the use of equipment purchased by Medical University of Bialystok as part of the RPOWP 2007-2013 funding, Priority I, Axis 1.1, contract No. UDA- RPPD.01.01.00-20-001/15-00 dated 26.06.2015. References Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLO-BOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021, 71(3), 209-249. doi: 10.3322/caac.21660. 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Eur J Cancer. 2012, 48(14), 2244-2251. doi: 10.1016/j.ejca.2011.11.032. Yildirim, K.; Colak, E.; Aktimur, R.; Gun, S.; Taskin, M.H.; Nigdelioglu, A.; Aktimur, S.H.; Karagöz, F.; Ozlem, N. Clinical Value of CXCL5 for Determining of Colorectal Cancer. Asian Pac J Cancer Prev. 2018, 19(9), 2481-2484. doi: 10.22034/APJCP.2018.19.9.2481. Dimberg, J.; Dienus, O.; Löfgren, S.; Hugander, A.; Wågsäter, D. Expression and gene polymorphisms of the chemokine CXCL5 in colorectal cancer patients. Int J Oncol. 2007, 31(1), 97-102. PMID: 17549409. Baier, P.K.; Eggstein, S.; Wolff-Vorbeck, G.; Baumgartner, U.; Hopt, U.T. Chemokines in human colorectal carcinoma. Anti-cancer Res. 2005, 25(5), 3581-3584. PMID: 16101183. Hu, B.; Fan, H.; Lv, X.; Chen, S.; Shao, Z. Prognostic significance of CXCL5 expression in cancer patients: a meta-analysis. Cancer Cell Int. 2018, 18, 68. doi:10.1186/s12935-018-0562-7. Yu, L.; Yang, X.; Xu, C.; Sun, J.; Fang, Z.; Pan, H.; Han, W. Comprehensive analysis of the expression and prognostic value of CXC chemokines in colorectal cancer. Int Immunopharmacol. 2020, 89, 107077. doi: 10.1016/j.intimp.2020.107077. Meng, J.; Su, R.; Liao, Y.; Li, Y.; Li, L. Identification of 10 Hub genes related to the progression of colorectal cancer by co-expression analysis. PeerJ. 2020, 8, e9633. doi:10.7717/peerj.9633. Rubie, C.; Frick, V.O.; Wagner, M.; Schuld, J.; Gräber, S.; Brittner, B.; Bohle, R.M.; Schilling, M.K. ELR+ CXC chemokine ex-pression in benign and malignant colorectal conditions. BMC Cancer. 2008, 8, 178. doi:10.1186/1471-2407-8-178. Zhang, Y.; Zheng, S.; Liao, N.; Huang, H.; Chen, W.; Wu, Z.; Wu, D. CircCTNNA1 acts as a ceRNA for miR-363-3p to facili-tate the progression of colorectal cancer by promoting CXCL5 expression. J Biol Res (Thessalon). 2021, 28(1), 7. doi: 10.1186/s40709-021-00135-8. Novillo, A.; Gaibar,. M.; Romero-Lorca, A.; Gilsanz, M.F.; Beltrán, L.; Galán, M.; Antón, B.; Malón, D.; Moreno, A.; Fernán-dez-Santander, A. Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: Six case reports. World J Gastroenterol. 2020, 26(16), 1979-1986. doi: 10.3748/wjg.v26.i16.1979. Michielsen, A.J.; Hogan, A.E.; Marry, J.; Tosetto, M.; Cox, F.; Hyland, J.M.; Sheahan, K.D.; O'Donoghue, D.P.; Mulcahy, H.E.; Ryan, E.J.; O'Sullivan, J.N. Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer. PLoS One. 2011, 6(11), e27944. doi:10.1371/journal.pone.0027944. Fujiwara, K.; Inoue, T.; Henmi, Y.; Hirata, Y.; Naka, Y.; Hara, A.; Kakimoto, K.; Nouda, S.; Okada, T.; Kawakami, K.; Takeuchi, T.; Higuchi, K. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not acceler-ate intestinal neoplasia formation in ApcMin/+ mice fed a high-fat diet. Oncol Lett. 2017, 14(4), 4355-4360. doi: 10.3892/ol.2017.6698. Coburn, L.A.; Singh, K.; Asim, M.; Barry, D.P.; Allaman, M.M.; Al-Greene, N.T.; Hardbower, D.M.; Polosukhina, D.; Wil-liams, C.S.; Delgado, A.G.; Piazuelo, M.B.; Washington, M.K.; Gobert, A.P.; Wilson, K.T. Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene. 2019, 38(7), 1067-1079. doi:10.1038/s41388-018-0492-9. Lin, K.; Zou, R.; Lin, F.; Zheng, S.; Shen, X.; Xue, X. Expression and effect of CXCL14 in colorectal carcinoma. Molecular Medi-cine Reports 2014, 10, 1561-1568. doi:10.3892/mmr.2014.2343. Cao, B.; Yang, Y.; Pan, Y.; Jia, Y.; Brock, M.V.; Herman, J.G.; Guo, M. Epigenetic silencing of CXCL14 induced colorectal can-cer migration and invasion. Discov Med. 2013, 16(88), 137-147. AbdelMageed, M.; Ali, H.; Olsson, L.; Lindmark, G.; Hammarström, M.L.; Hammarström, S.; Sitohy, B. The Chemokine CXCL16 Is a New Biomarker for Lymph Node Analysis of Colon Cancer Outcome. Int J Mol Sci. 2019, 20(22), 5793. doi:10.3390/ijms20225793. Zeng, J.; Li, M.; Xu, J.Y.; Xiao, H.; Yang, X.; Fan, J.X.; Wu, K.; Chen, S. Aberrant ROS Mediate Cell Cycle and Motility in Col-orectal Cancer Cells Through an Oncogenic CXCL14 Signaling Pathway. Front Pharmacol. 2021, 12, 764015. doi:10.3389/fphar.2021.764015. Westrich, J.A.; Vermeer, D.W.; Colbert, P.L.; Spanos, W.C.; Pyeon, D. The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses. Mol Carcinog. 2020, 59(7), 794-806. doi:10.1002/mc.23188. Matsushita, K.; Toiyama, Y.; Tanaka, K.; Saigusa, S.; Hiro, J.; Uchida, K.; Inoue, Y.; Kusunoki, M. Soluble CXCL16 in pre-operative serum is a novel prognostic marker and predicts recurrence of liver metastases in colorectal cancer patients. Ann Surg Oncol. 2012, 19, 518-527. doi: 10.1245/s10434-011-1993-8. Hojo, S.; Koizumi, K.; Tsuneyama, K.; Arita, Y.; Cui, Z.; Shinohara, K.; Minami, T.; Hashimoto, I.; Nakayama, T.; Sakurai, H.; Takano, Y.; Yoshie, O.; Tsukada, K.; Saiki, I. High-level expression of chemokine CXCL16 by tumor cells correlates with a good prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. Cancer Res. 2007, 67(10), 4725-4731. doi: 10.1158/0008-5472.CAN-06-3424. Yang, X.; Wei, Y.; Sheng, F.; Xu, Y.; Liu, J.; Gao, L.; Yang, J.; Sun, X.; Huang, J.; Guo, Q. Comprehensive analysis of the prog-nosis and immune infiltration for CXC chemokines in colorectal cancer. Aging (Albany NY). 2021, 13(13), 17548-17567. doi: 10.18632/aging.203245. Verbeke, H.; Struyf, S.; Laureys, G.; Van Damme, J. The expression and role of CXC chemokines in colorectal cancer. Cyto-kine Growth Factor Rev. 2011, 22(5-6), 345-358. doi: 10.1016/j.cytogfr.2011.09.002. Elemam, N.M.; Al-Jaderi, Z.; Hachim, M.Y.; Maghazachi, A.A. HCT-116 colorectal cancer cells secrete chemokines which induce chemoattraction and intracellular calcium mobilization in NK92 cells. Cancer Immunol Immunother. 2019, 68(6), 883-895. doi: 10.1007/s00262-019-02319-7. Chen, Z.; Dai, W.; Yang, L.; Yang, H.; Ding, L.; He, Y.; Song, X.; Cui, J. Elevated expression of CXCL16 correlates with poor prognosis in patients with colorectal cancer. Cancer Manag Res. 2019, 11, 4691-4697. doi: 10.2147/CMAR.S197354. Shantha Kumara, H.M.C.; Pettke, E.; Shah, A.; Yan, X.; Cekic, V.; Downing, M.A.; Gandhi, N.D.; Whelan, R.L. Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection. World J Surg Oncol. 2018, 16(1), 132. doi: 10.1186/s12957-018-1418-2. Kee, J.Y.; Ito, A.; Hojo, S.; Hashimoto, I.; Igarashi, Y.; Tsukada, K.; Irimura, T.; Shibahara, N.; Nakayama, T.; Yoshie, O.; Sa-kurai, H.; Saiki, I.; Koizumi, K. Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model. Oncol Rep. 2013, 29(3), 975-982. doi: 10.3892/or.2012.2185. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2615376","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":179856214,"identity":"7b0cede9-0bc8-4319-8245-b12bbc27d4f6","order_by":0,"name":"Monika Zajkowska","email":"data:image/png;base64,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","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Monika","middleName":"","lastName":"Zajkowska","suffix":""},{"id":179856215,"identity":"9dec0f34-abf7-4510-a428-e181145768b2","order_by":1,"name":"Maciej Dulewicz","email":"","orcid":"","institution":"Medical University of 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Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marcin","middleName":"","lastName":"Juchimiuk","suffix":""},{"id":179856219,"identity":"1187f7d9-b1e6-474f-a7f5-3f5f0e3a8630","order_by":5,"name":"Marzena Konopko","email":"","orcid":"","institution":"Maria Sklodowska-Curie Oncology Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marzena","middleName":"","lastName":"Konopko","suffix":""},{"id":179856220,"identity":"5545f975-9df8-4270-92de-f217ac8914d0","order_by":6,"name":"Leszek Kozłowski","email":"","orcid":"","institution":"Maria Sklodowska-Curie Oncology Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Leszek","middleName":"","lastName":"Kozłowski","suffix":""},{"id":179856221,"identity":"c19a40e2-0661-4257-9f6b-1e5d65026d1d","order_by":7,"name":"Barbara Mroczko","email":"","orcid":"","institution":"Medical University of Bialystok","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Mroczko","suffix":""}],"badges":[],"createdAt":"2023-02-22 08:44:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2615376/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2615376/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-023-45093-4","type":"published","date":"2023-10-17T15:01:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":33847739,"identity":"79d1d4ff-b514-45be-9ff5-4a7da2e22ce1","added_by":"auto","created_at":"2023-03-06 15:45:57","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129422,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristics for all significant ROC analysis results (p\u0026lt;0.05 in all cases).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2615376/v1/a5b392c9d1e343e9200141ae.jpeg"},{"id":45091178,"identity":"bd835ae4-873e-4a02-9eaa-cba39d9a273e","added_by":"auto","created_at":"2023-10-23 15:09:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":552151,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2615376/v1/52cee8dd-3b36-4544-aee2-ad0b95b72ddc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"CXCL5 and CXCL14, but not CXCL16 as potential non-invasive biomarkers of colorectal cancer?","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAnnually, approximately 2,000,000 new cases of intestinal malignant neoplasm (C18-C20) are diagnosed. Analyzing the incidence structure, it can be concluded that colorectal cancer is the third most common malignant neoplasm afflicted by women and the second most common among men. Experts emphasize that the incidence and mortality of colorectal cancer in both sexes has been increasing year-to-year. Early detection of colorectal neoplasms and rectal cancer is of utmost importance for the effectiveness of the therapy. Patients with cancers diagnosed in earlier stages have an enhanced prognosis and a chance for faster implementation of cancer treatment. In this context, it is worth remembering about the possibility of taking advantage of screening for colorectal cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMost cases of colorectal cancer are diagnosed in patients over 50 years of age, and very rare in patients under the age of 40. The disease usually progresses slowly and the symptoms of colorectal cancer are partially dependent on the location of the malignant processes. In the early stages of the disease, the symptoms of colorectal cancer are usually non-specific and have the form of abdominal pain and flatulence, which may suggest less serious problems from the gallbladder or peptic ulcer disease. Most patients with colorectal cancer do not report significant symptoms, or they are slight or nonspecific - matching many different digestive system diseases. Those symptoms are often underestimated and not equated with threats such as colorectal cancer. Stool disorders are most often attributed to stress and poor diet. In addition to neoplastic changes, they can also be caused by inflammation in the large intestine, food poisoning or infections with intestinal parasites [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most commonly used techniques used in CRC detection are colonoscopy and sigmoidoscopy. In some cases, imaging diagnostics, computed tomographic colonography or magnetic resonance method, are used. Even though significant improvement has been made in this area in latest years, in the case of small lesions, these procedures might be unsuccessful. Alternative diagnostic tool, useful in the discovery of colorectal cancer are tumor markers, which are synthesized mostly by tumor cells. Tumor markers have a particular utility not only in detecting of malignancies and determining tumor advancement, but also in monitoring of treatment and early detection of recurrence [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The example of tumor markers engaged in the identification of CRC are CEA (carcinoembryonic antigen) and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (cancer antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9). Regrettably, the diagnostic usefulness of these biomarkers is relatively low as they are not specific to the CRC itself [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Taking into account the above evidences, there is an critical need to find novel biomarkers, the use of which will allow for early recognition of emerging cancer earlier than it was probable previously.\u003c/p\u003e \u003cp\u003eIncreasing evidence suggests that small inflammatory cytokines (8\u0026ndash;12 kDa) known as chemokines are key regulators of angiogenesis, including pathological angiogenesis. In chemical terms, chemokines are peptides composed of 70\u0026ndash;130 amino acids [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], structurally and functionally similar to growth factors. They are characterized by 20\u0026ndash;50% sequence homology between molecules, which is reflected in their structural similarities. According to the nomenclature, the names of individual types of these compounds are created by adding the letter L (ligand) together with a sequential number. Most of the compounds in their structure contain four characteristic cysteine residues which, by forming disulfide bridges, determine their three-dimensional structure. Chemokines, on a basis of this structure, have been classified into 4 groups: CC, CXC, CX3C and X chemokines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe present state of knowledge allows us to suspect that all these proteins play a significant role in cancer advancement [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In cancer development and metastasis, these chemokines exert a complex outcome on angiogenesis, tumor cell proliferation and apoptosis regulation, facilitating tumor cell metastasis in an organ specific manner [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It is postulated that the CC and CXC chemokines could be the most active in the regulation of angiogenesis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. That is why the aim of our study was an effort to elucidate and evaluate the utility of selected CXC-chemokines determination (CXCL5, CXCL14 and CXCL16) in patients with colorectal cancer compared to the healthy control. We have also compared the obtained results to CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, CEA, and inflammatory parameter such as C-reactive protein (CRP).\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1. Patients\u003c/h2\u003e\n\u003cp\u003eThe study included 75 patients diagnosed by the oncology group for colorectal cancer (CRC) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). All patients were treated in the Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, Bialystok, Poland. Tumor classification and staging were conducted in accordance with the UICC-TNM (International Union Against Cancer Tumor-Node-Metastasis) classification.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of colorectal cancer and healthy patients groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy Group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo. of patients\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"8\" align=\"left\"\u003e\n\u003cp\u003eColorectal Cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75 (100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender:\u003c/p\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e26 (35%)\u003c/p\u003e\n\u003cp\u003e49 (65%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType:\u003c/p\u003e\n\u003cp\u003eColon Cancer\u003c/p\u003e\n\u003cp\u003eRectal Cancer\u003c/p\u003e\n\u003cp\u003eSigmoid Cancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e25 (33%)\u003c/p\u003e\n\u003cp\u003e41 (55%)\u003c/p\u003e\n\u003cp\u003e9 (12%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTNM Stage:\u003c/p\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003cp\u003eII\u003c/p\u003e\n\u003cp\u003eIII\u003c/p\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1%)\u003c/p\u003e\n\u003cp\u003e15 (20%)\u003c/p\u003e\n\u003cp\u003e13 (17%)\u003c/p\u003e\n\u003cp\u003e25 (34%)\u003c/p\u003e\n\u003cp\u003e21 (28%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDepth of tumor invasion:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIn situ\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eT1\u003c/p\u003e\n\u003cp\u003eT2\u003c/p\u003e\n\u003cp\u003eT3\u003c/p\u003e\n\u003cp\u003eT4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1 (1%)\u003c/p\u003e\n\u003cp\u003e2 (3%)\u003c/p\u003e\n\u003cp\u003e19 (25%)\u003c/p\u003e\n\u003cp\u003e41 (55%)\u003c/p\u003e\n\u003cp\u003e12 (16%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNodal involvement:\u003c/p\u003e\n\u003cp\u003eN0\u003c/p\u003e\n\u003cp\u003eN1\u003c/p\u003e\n\u003cp\u003eN2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e34 (45%)\u003c/p\u003e\n\u003cp\u003e25 (34%)\u003c/p\u003e\n\u003cp\u003e16 (21%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDistant metastasis:\u003c/p\u003e\n\u003cp\u003eM0\u003c/p\u003e\n\u003cp\u003eM1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e54 (72%)\u003c/p\u003e\n\u003cp\u003e21 (28%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge:\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33\u0026ndash;89\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eControl Group\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (100%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender:\u003c/p\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e12 (30%)\u003c/p\u003e\n\u003cp\u003e28 (70%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge:\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34\u0026ndash;80\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eColorectal cancer histopathology was based on the microscopic examination of tissue samples. Moreover, all patients were grouped according to tumor stage (TNM), depth of tumor invasion (T factor), presence of lymph node (N factor) and distant metastases (M factor) as well as the histological grade (G factor) of the tumor. The pretreatment staging procedures included physical and blood examinations, CT scans (computed tomography) and in case of patients with rectal cancer \u0026ndash; MRI (magnetic resonance imaging) of the small pelvis. Additionally, all patients were assessed according to the ECOG score (Eastern Cooperative Oncology Group). The control group included 40 healthy volunteers. For each of patient qualified for the control group, the exclusion criteria such as: obesity, active infections and symptoms of an infection, respiratory diseases, digestive tract diseases or systemic diseases were applied.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003e2.2. Biochemical analyses\u003c/h2\u003e\n\u003cp\u003eThe biochemical analysis of the tested parameters was performed as described previously [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\n\u003cp\u003eStatistical analysis was performed by RStudio and Statistica 13.0 as described pre-viously [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. The cut-off points for each of the tested parameters were designated as fol-lows: CXCL5\u0026ndash;953.96 pg/mL, CXCL14\u0026ndash;650.92 pg/mL, CXCL16\u0026ndash;926.01 pg/mL, CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u0026ndash;5.30 U/mL, CEA \u0026ndash; 1.70 ng/mL, CRP \u0026ndash; 2.50 mg/L.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1. CXC chemokines\u003c/h2\u003e\n\u003cp\u003eConcentration of CXCL5, CXCL14, CXCL16, CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, CEA and CRP in sera of CRC patients and healthy patients (control group) were presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The non-parametric test (U Mann-Whitney) which compared the levels obtained in the above mentioned groups have revealed that concentration of CXCL5, CEA and CRP in total CRC group were statistically higher, and CXCL14 significantly lower when compared to healthy controls (in all cases p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSerum levels of tested parameters in cancer and control groups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eColorectal Cancer\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl Group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep*\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCXCL5\u003c/p\u003e\n\u003cp\u003e[pg/mL]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin - Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1299.8\u003c/p\u003e\n\u003cp\u003e185.2\u0026ndash;7500.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e894.2\u003c/p\u003e\n\u003cp\u003e204.2\u0026ndash;2634.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCXCL14\u003c/p\u003e\n\u003cp\u003e[pg/mL]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin \u0026ndash; Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e595.6\u003c/p\u003e\n\u003cp\u003e312.3\u0026ndash;8654.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e671.5\u003c/p\u003e\n\u003cp\u003e338.0\u0026ndash;1968.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCXCL16\u003c/p\u003e\n\u003cp\u003e[pg/mL]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin \u0026ndash; Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e927.2\u003c/p\u003e\n\u003cp\u003e288.9\u0026ndash;2876.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e910.2\u003c/p\u003e\n\u003cp\u003e540.4\u0026ndash;1307.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e\n\u003cp\u003e[U/mL]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin \u0026ndash; Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.3\u003c/p\u003e\n\u003cp\u003e2.1\u0026ndash;8199.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.4\u003c/p\u003e\n\u003cp\u003e2.1\u0026ndash;33.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCEA\u003c/p\u003e\n\u003cp\u003e[ng/mL]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin \u0026ndash; Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.9\u003c/p\u003e\n\u003cp\u003e0.5\u0026ndash;3688.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0\u003c/p\u003e\n\u003cp\u003e0.5\u0026ndash;15.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003cp\u003e[mg/L]\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMe\u003c/p\u003e\n\u003cp\u003eMin - Max\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.0\u003c/p\u003e\n\u003cp\u003e1.0\u0026ndash;248.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.4\u003c/p\u003e\n\u003cp\u003e0.2\u0026ndash;5.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003e* U Mann-Whitney test\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eFurthermore, we performed a more exhaustive investigation with use of two different tests used in statistics (Kruskal\u0026ndash;Wallis and Dwass\u0026ndash;Steel\u0026ndash;Critchlow\u0026ndash;Fligner). That is why, we have divided the group in which colorectal cancer patients were included into four subgroups with use of TNM grading into I-IV advancement groups. After Kruskal-Wallis analysis, we obtained significant results for CXCL5, CXCL14 and comparative parameters (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Taking the acquired results, it can be suggested that the CXCL5, CEA, and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 concentration rises with the development of tumor. Interestingly, the CXCL14 analysis reveals that there is a significant difference between control group and I stage of CRC, which in our opinion is a very important observation as it may serve as a potential marker of early neoplastic changes.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eKruskal-Wallis and Dwass-Steel-Crithlow-Fligner tests analysis results.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL5\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL14\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL16\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCEA\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eKruskal-Wallis\u003c/strong\u003e \u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"10\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDwass-Steel-Crithlow-Fligner\u003c/strong\u003e \u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. I\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.78\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI vs.II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI vs.III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.77\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI vs.IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eII vs.III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.93\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.63\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.95\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eII vs.IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.048\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIII vs.IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eAs the number of cases in stage I and II of TNM classification was lower than 20, what may have an impact at the correctness of the acquired outcomes, we wanted to check their exactness using another test. We separated all colorectal cancer patients into two groups: less-advanced (TNM I\u0026thinsp;+\u0026thinsp;II) and advanced tumors (TNM III\u0026thinsp;+\u0026thinsp;IV). Furthermore, we separated the group of advanced tumors into single TNM\u0026rsquo;s (III and IV) due to the satisfactory number of patients in each stage to perform an accurate investigation in those groups and in comparison to healthy volunteers (control). Remarkably, we have observed significant differences between healthy patients and IV stage CRC in case of CXCL5 and CXCL16 which may suggest its involvement in distant metastasis processes and what is of utmost importance, significant differences between all CRC stages (same as CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9). In case of CXCL14, we have observed differences between control and less-advanced stages (I and II) of CRC, which as previously mentioned, is an extremely important result considering the fact, that there are no widely available, non-invasive methods that would be useful in case of asymptomatic patients (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eU Mann-Whitney test analysis results between control group and TNM subgroups.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL5\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL14\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL16\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCEA\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eU Mann-Whitney test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. I\u0026thinsp;+\u0026thinsp;II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.05\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.05\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. III\u0026thinsp;+\u0026thinsp;IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eControl vs. IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u0026thinsp;+\u0026thinsp;II vs. III\u0026thinsp;+\u0026thinsp;IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u0026thinsp;+\u0026thinsp;II vs. III\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.05\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u0026thinsp;+\u0026thinsp;II vs. IV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e shows the parameters of diagnostic utility of all tested parameters, except for CXCL16, which was the only newly tested parameter that did not show statistical significance.\u003c/p\u003e\n\u003cp\u003eWe showed that the highest sensitivity (SE) from all parameters revealed CXCL5 and CXCL14 (68 and 67%, respectively). The detected value is slightly lower than SE of CEA (75%) and CRP (73%), but much higher than SE of CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (51%). What is more, the specificity (SP) of CXCL5 and CXCL14 showed high value (both 58%), but was lower than SP of CRP (78%) and CEA (70%), nevertheless higher than CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (48%). Positive predictive value (PPV) was high for CXCL5 and CXCL14 (both 75%). Negative predictive value (NPV) was calculated on 49% for CXCL5 and 48% for CXCL14. All these values were slightly lower than PPV and NPV of CEA and CRP. Additionally, all utility values of newly tested parameters (CXCL5, CXCL14) were greater than those obtained for CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, which suggests their higher utility than this routine marker for colorectal cancer patients.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDiagnostic criteria of tested parameters in patients with colorectal cancer.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTested parameters\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDiagnostic criteria\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eColorectal Cancer\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCXCL5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003ePPV\u003c/p\u003e\n\u003cp\u003eNPV\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58%\u003c/p\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003cp\u003e49%\u003c/p\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCXCL14\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003ePPV\u003c/p\u003e\n\u003cp\u003eNPV\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e58%\u003c/p\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003cp\u003e48%\u003c/p\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003ePPV\u003c/p\u003e\n\u003cp\u003eNPV\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48%\u003c/p\u003e\n\u003cp\u003e64%\u003c/p\u003e\n\u003cp\u003e34%\u003c/p\u003e\n\u003cp\u003e0.51\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCEA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003ePPV\u003c/p\u003e\n\u003cp\u003eNPV\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70%\u003c/p\u003e\n\u003cp\u003e82%\u003c/p\u003e\n\u003cp\u003e60%\u003c/p\u003e\n\u003cp\u003e0.79\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCRP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003ePPV\u003c/p\u003e\n\u003cp\u003eNPV\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e78%\u003c/p\u003e\n\u003cp\u003e86%\u003c/p\u003e\n\u003cp\u003e61%\u003c/p\u003e\n\u003cp\u003e0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eWe observed that the AUC of CXCL5 (0.65) in the total group of CRC was highest from all obtained results, but lower than area under the ROC curve obtained for CEA and C-reactive protein. Nevertheless, in case of both assessed CXC chemokines, AUC was higher than AUC of CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWe have also tested the Spearman\u0026rsquo;s rank correlation coefficient to indicate the strength and direction of monotonic association between variables. All results are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab6\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eSpearman\u0026rsquo;s rank correlation coefficient for tested variables.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTested variables\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL5\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL14\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCXCL16\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCEA\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCRP\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCXCL14\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCXCL16\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.32\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;0.005\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.17\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCA 19\u0026thinsp;\u0026minus;\u0026thinsp;9\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.24\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCEA\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.46\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.43\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.51\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCRP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.25\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.47\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.01\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.17\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.13\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.01\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.92\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.36\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.07\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTNM stage\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.47\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.15\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.42\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.43\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.57\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.05\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.34\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ep\u003c/span\u003e\u0026thinsp;\u003cstrong\u003e=\u0026thinsp;0.003\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eWe observed a moderate positive correlation for CXCL5, CXCL16, as well as CEA and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9 with tumor TNM stage. This may indorse (as observed previously) that the growing level of those factors are associated with the amount of tumor cells. Moderate, positive correlation was also detected between CXCL5, CXCL16 with CEA concentration, CXCL16 with CRP levels, and both markers (CEA and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9). Rest of witnessed significant correlations revealed weak strength (coefficient\u0026thinsp;\u0026lt;\u0026thinsp;0.40).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e3.2. CXC and CC chemokines combination\u003c/h2\u003e\n\u003cp\u003eIn order to continue the research on the usefulness of different chemokine groups in the diagnosis of colorectal cancer, we decided to use the previous assays [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e] in a combined analysis with the currently obtained concentrations. The obtained results turned out to be very interesting, which in our opinion significantly influences the validity of the published work. Significant combinations of all tested chemokine analyses were presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab7\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDiagnostic criteria of chemokine combinations in patients with colorectal cancer.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTested parameters\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDiagnostic criteria\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eColorectal Cancer\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCCL2/CRP ratio\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003eACC\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85%\u003c/p\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003cp\u003e0.80\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCXCL14\u0026thinsp;+\u0026thinsp;CRP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003eACC\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003cp\u003e80%\u003c/p\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCEA\u0026thinsp;+\u0026thinsp;CRP\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79%\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSP\u003c/p\u003e\n\u003cp\u003eACC\u003c/p\u003e\n\u003cp\u003eAUC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e75%\u003c/p\u003e\n\u003cp\u003e77%\u003c/p\u003e\n\u003cp\u003e0.88\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe obtained results suggest that the simultaneous analysis of the two parameters determination significantly influences the area under the ROC curve (AUC), which con-firms the usefulness of the parameters tested. The performed comparative analysis for the routine marker (CEA) and CRP (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e7\u003c/span\u003e) additionally confirms the usefulness of CXCL14 and suggests the need to continue research on this parameter and its use in the diagnosis of CRC, as the values of the obtained diagnostic criteria indicate greater usefulness of simultaneous CXCL14 and CRP determinations. In order to complete the statistical analysis, we also checked whether there were any correlations between the previously and currently studied chemokines. As a result of this analysis, we found a moderate positive correlation between CCL4 and CXCL5 (r\u0026thinsp;=\u0026thinsp;0.46; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) as well as CCL4 and CXCL16 (r\u0026thinsp;=\u0026thinsp;0.54; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe search for new biomarkers that could prove their usefulness in cancer screening remains a serious global problem. Early diagnosis, especially concerning the non-invasive lesions, remains unattainable. In the case of colorectal cancer, but also other neoplasms, researchers are constantly searching for biomarkers, which would indicate the presence of neoplastic or even pre-neoplastic changes at the earliest possible stage and would replace or supplement the currently used imaging or histopathological tests [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There are few studies on the usefulness of selected CXC-chemokines in the course of colorectal cancer, which prompted us to carry out the above analyzes.\u003c/p\u003e \u003cp\u003eWe indicated that serum concentration of CXCL5 was statistically higher in group of colorectal cancer patients when compared to healthy controls (p\u0026thinsp;=\u0026thinsp;0.01). Similar results were obtained in work of Kawamura et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These authors also revealed that preoperative serum levels of CXCL5 were significantly elevated in patients with CRC compared with healthy volunteers. Interestingly, the researchers pointed out that high serum CXCL5 was also associated with female sex, liver metastasis and poor overall survival. In addition, they have also measured the CXCL5 level in CRC cell lines, which confirmed previously mentioned results. These authors concluded, that CXCL5 preoperative serum level could serve as a novel predictive marker for prognosis determination of CRC which fully corresponds with our results. Different researchers in work of Yildirim et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] all these results in their work, where serum CXCL5 and CEA levels were significantly higher in CRC group. In addition, these authors also performed immunohistochemical studies which revealed high number cases who were stained positive in CRC group. Although the studies by Yilidirim et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] were carried out on a small study group, a group of patients with benign lesions was specified, for which neither the CXCL5 concentration nor tissue expression differed when compared to the study group. This may indicate, on the one hand, the low usefulness of CXCL5 in the detection of benign lesions, but on the other hand it can be a useful parameter when detecting tumor initiation. These assumptions require further analysis and confirmation using a much larger study group. In contrast, we also found work by Dimberg et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], in the course of which the researchers showed that the concentration of the CXCL5 protein in homogenates of neoplastic tissues were statistically higher compared to normal tissues, however, the concentrations of this parameter in the blood serum were significantly lower in the CRC group. These discrepancies were explained by the authors by the different origin of CXCL5 (leukocytes, epithelial and endothelial cells) and by immunologic imbalance in case of CRC patients. Perhaps an additional factor influencing these differences was the degree of neoplastic lesions advancement, as in the studies conducted by Dimberg et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] most of the patients were classified as Duke's A and B grades, and in our results, CXCL5 showed the highest con-centration in case of patients with distant metastases (TNM stage IV).\u003c/p\u003e \u003cp\u003eAs there are only a few studies concerning the concentration of CXCL5 in the course of human colorectal cancer, we decided to focus also at the studies regarding tissue and gene expression, and studies on CXCL5 in other species. All the studies indicate the high usefulness of this parameter in the course of CRC. For example, in the work of Baier et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] it was proved that the concentration in cancer tissue is significantly higher compared to normal tissue. Similar results were also obtained by other researchers such as Hu et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], Yu et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], Meng et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], Rubie et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and Zhang et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the case of two last of mentioned studies, the authors additionally performed an analysis of gene expression (qRT-PCR), which, along with similar results obtained in the work of Novillo et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], confirmed the increase of CXCL5 in the course of CRC. Also in TCM (tumor conditioned media), similar results were obtained [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. All the above-mentioned studies conclude unequivocally that CXCL5 is a very important factor in the progression of colorectal cancer and may be a useful prognostic factor. We have found also studies pointing to elevated CXCL5 expression in murine models [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], also those, fed with a high-fat diet [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This may indicate a relationship of this parameter with obesity, which indicates the high safety of our research, as obesity was one of the excluding parameters. However, in the absence of statistical significance obtained in the studies by Dimberg et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], it would be worth to analyze these reports.\u003c/p\u003e \u003cp\u003eIn case of CXCL14, we have observed statistically lower concentration of this parameter in serum of colorectal cancer patients when compared to healthy volunteers. Unfortunately, we did not found any similar works which could confirm or deny our studies. In case of CXCL14 gene or tissue expression, there were few studies, which partially con-firmed our investigations. For example, in paper of Lin et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] using both PCR and IHC methods, the authors showed significantly lower expression of CXCL14 when compared to normal mucosa. Similarly, paper of Cao et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] revealed methylation and silencing of CXCL14 in 5 different CRC cell lines. These authors concluded, that restoration of CXCL14 expression suppressed CRC proliferation, inhibited its migration, invasion, and epithelial-to-mesenchymal transition. These findings seems extremely important as this information could provide a new target for the treatment of colorectal cancer. Moreover, it can be assumed that, potentially, the high concentration of this parameter in the course of CRC may be a positive prognostic factor for CRC patients. However, some other researchers [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] revealed, that CXCL14 mRNA expression was higher in case of CRC tissues. Also research conducted by Zeng et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] proved that CXCL14 is involved in the proliferation and migration of ROS-induced CRC cells, as the expression level of CXCL14 was elevated in CRC cell lines treated with H2O2. The observed discrepancies significantly drew our attention, however, they were also noticed by other researchers [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The mechanisms that control the CXCL14 functions are hypothetically defined by the cell and tissue types that synthesize CXCL14 and respond to CXCL14 concentration, as well as by other proteins that co-operates with CXCL14. Mostly, CXCL14 produced by epithelial cells has been shown to overwhelm the tumor cells growth. On the other hand, CXCL14 produced from cancer-associated fibroblasts stimulates tumor growth and metastasis. While CXCL14-mediated tumor suppression and altered expression correlates with better patient survival in cancer such as head and neck, colorectal, and liver, CXCL14-mediated tumor promotion mostly occurs in tumors of breast and pancreas. Accordingly, further studies concerning CXCL14 are absolutely vital.\u003c/p\u003e \u003cp\u003eTaking into account the concentration of CXCL16, we showed no statistically significant differences, however, the concentrations of this parameter in the study group were higher than in the control group. However, the work of different research groups [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] has shown that the concentration and expression (both tissue and mRNA) of CXCL16 in the group of patients with colorectal cancer is higher compared to the control group, the same as in investigations with use of cell lines. In addition, Chen et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] revealed, that CXCL16-positive tissue expression was significantly related to tumor size, its differentiation and distant metastasis. Comparing these results to the results of our analysis using the Mann-Whitney U test, it can be assumed that we showed a similar trend, as this parameter seems to be useful in differentiation between CRC stages and demonstrated statistical significance in stage IV (distant metastases) of CRC compared to healthy controls. Perhaps, after enlarging the study group, it would be possible to prove statistical significance also in our research. Interestingly, some authors indicate that CXCL16 levels may promote tumor angiogenesis after minimally invasive colorectal resection [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] and demonstrate the inhibitory effect on liver metastasis [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe only investigators who assessed the diagnostic usefulness of CXCL5 in the blood serum of CRC patients were Yilidirim et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. They showed that the AUC for CXCL5 was 0.671, while SE, SP, PPV and NPV were 57%, 67%, 41.94% and 75%, respectively. The SE and PPV obtained by these researchers were lower than ours, while the SP, NPV and AUC were higher. These differences may result from the calculated cut-off point in both studies, which is related to the differences between the test and control groups. Interestingly, the authors, as in the case of our results, obtained slightly lower AUC for the tested parameter than the AUC of the routinely used marker, which is CEA. Regrettably, we have not found any further studies that would emphasize on demonstrating the dependency and statistical significance based on the division of the tested group into advancement stages. Consequently, we believe that this work is inventive in this matter, which significantly rises its value. A more precise demonstration of the associations between the control and study group may meaningfully affect the understanding of alterations in the development of CRC.\u003c/p\u003e \u003cp\u003eRemarkably, our results presented significant alterations between the CXCL5 con-centration in stage IV/III\u0026thinsp;+\u0026thinsp;IV of CRC and healthy controls, and significant differences be-tween all TNM stages, which may indicate its contribution in the development of tumor progression and distant metastasis. What is more, CXCL14 showed statistical difference only between control group and stage I/I\u0026thinsp;+\u0026thinsp;II of CRC, which, in connection with the previously acquired information about the decreasing concentration of this parameter in the course of CRC, may indicate an attempt of healthy cells to equalize CXCL14 concentration in order to prevent tumor progression, or on the contrary, about the collapse of the organ-ism's antitumoral action, depending on the adopted functions performed by CXCL14. Due to the fact that these are one of the first reports on these dependencies, it is desirable to confirm them in further analysis.\u003c/p\u003e \u003cp\u003eWe also determined the correlation coefficients between the studied parameters, which confirmed that the concentration of CXCL5, CXCL16 and both tumor markers are closely related to the severity of CRC. Moreover, both CXCL5 and CXCL16 positively cor-related with CEA, and CXCL16 additionally with CRP concentration. It may be related to the ongoing inflammation during the cancer progression. Unfortunately, in the available literature, we did not find any papers that could confirm or contradict the results obtained, which proves the innovation of our work.\u003c/p\u003e \u003cp\u003eIn addition, we have proved, that of simultaneous CXCL14 and CRP determinations might be more useful in CRC diagnosis than commonly used tumor marker - CEA and CRP combination. As in the case of the above-mentioned analyzes, there are no studies available that would assess the parameters tested in a similar way.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eThe present study, according to our knowledge, is the first to compare the diagnostic utility of CXCL5, CXCL14 and CXCL16 with the well-established colorectal cancer tumor markers such as CEA and CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9, and CRP (the marker of inflammation), not only in the whole group of colorectal cancer patients, but also after division to TNM stages I-IV. The obtained results highly suggest importance of CXCL5 and CXCL16 in detection of distant metastases and differentiation between TNM stages, as well as combination of CXCL14 and CRP as potential CRC biomarkers. However, further studies concerning the concentrations of selected CXC chemokines in the course of CRC are necessary to confirm and clarify their diagnostic usefulness and clinical application as potential non-invasive biomarkers of CRC development.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interest: \u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding: \u003c/strong\u003eThis research was funded by the Medical University of Bialystok, Poland, grant number: SUB/1/DN/22/004/1198.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions: \u003c/strong\u003eConceptualization, Monika Zajkowska and Barbara Mroczko; methodology, Monika Zajkowska and Agnieszka Kulczyńska-Przybik; formal analysis, Monika Zajkowska, Agnieszka Kulczyńska-Przybik and Maciej Dulewicz; investigation, Monika Zajkowska, Maciej Dulewicz, Kamil Safiejko, Marcin Juchimiuk, Marzena Konopko, Leszek Kozłowski and Agnieszka Kulczyńska-Przybik; resources, Monika Zajkowska; data curation, Monika Zajkowska and Maciej Dulewicz; writing\u0026mdash;original draft preparation, Monika Zajkowska; writing\u0026mdash;review and editing, Monika Zajkowska and Barbara Mroczko; supervision, Barbara Mroczko; project administration, Monika Zajkowska and Barbara Mroczko; funding acquisition, Monika Zajkowska. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Committee approval: \u003c/strong\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Medical University of Bialystok (R-I-002/564/2019; 28.11.2019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement: \u003c/strong\u003eInformed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement: \u003c/strong\u003eThe data presented in this study are available on request from the corresponding author. Key data are stated in the text.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThis study was conducted with the use of equipment purchased by Medical University of Bialystok as part of the RPOWP 2007-2013 funding, Priority I, Axis 1.1, contract No. UDA- RPPD.01.01.00-20-001/15-00 dated 26.06.2015.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLO-BOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021, 71(3), 209-249. doi: 10.3322/caac.21660.\u003c/li\u003e\n\u003cli\u003eToma, M.; Beluşică, L.; Stavarachi, M.; Apostol, P.; Spandole, S.; Radu, I.; Cimponeriu, D. Rating the environmental and ge-netic risk factors for colorectal cancer. 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Cancer Manag Res. 2019, 11, 4691-4697. doi: 10.2147/CMAR.S197354.\u003c/li\u003e\n\u003cli\u003eShantha Kumara, H.M.C.; Pettke, E.; Shah, A.; Yan, X.; Cekic, V.; Downing, M.A.; Gandhi, N.D.; Whelan, R.L. Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection. World J Surg Oncol. 2018, 16(1), 132. doi: 10.1186/s12957-018-1418-2.\u003c/li\u003e\n\u003cli\u003eKee, J.Y.; Ito, A.; Hojo, S.; Hashimoto, I.; Igarashi, Y.; Tsukada, K.; Irimura, T.; Shibahara, N.; Nakayama, T.; Yoshie, O.; Sa-kurai, H.; Saiki, I.; Koizumi, K. Chemokine CXCL16 suppresses liver metastasis of colorectal cancer via augmentation of tumor-infiltrating natural killer T cells in a murine model. Oncol Rep. 2013, 29(3), 975-982. doi: 10.3892/or.2012.2185.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"CRC, cytokines, chemokines, biomarker, metastasis","lastPublishedDoi":"10.21203/rs.3.rs-2615376/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2615376/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eExperts emphasize that incidence and mortality of colorectal cancer (CRC) is increasing. That is why, its early detection is of utmost importance. Patients with cancer diagnosed in earlier stages have better prognosis and chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTherefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 subjects (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eConcentrations of CXCL5 were statistically higher in CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19\u0026thinsp;\u0026minus;\u0026thinsp;9.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eObtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM stages, as well as usefulness of CXCL14 and CRP combination in CRC detection. However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers.\u003c/p\u003e","manuscriptTitle":"CXCL5 and CXCL14, but not CXCL16 as potential non-invasive biomarkers of colorectal cancer?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-06 15:45:52","doi":"10.21203/rs.3.rs-2615376/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-09-08T04:29:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-31T15:32:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-10T09:22:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-07-22T20:45:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"cc1a4521-9ae4-46e2-83b6-98580ce9c2a8","date":"2023-07-10T14:39:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2edb344b-4959-49c6-b9b9-0a66cd6c70be","date":"2023-07-10T12:37:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-10T11:04:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-04T07:44:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-03-01T08:03:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-03-01T07:05:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-02-22T08:38:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83cf9090-98b9-4e1f-aa6d-de3e4f0ae2ca","owner":[],"postedDate":"March 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":19572068,"name":"Biological sciences/Biochemistry/Cytokines/Chemokines"},{"id":19572069,"name":"Health sciences/Biomarkers"}],"tags":[],"updatedAt":"2023-10-23T15:05:50+00:00","versionOfRecord":{"articleIdentity":"rs-2615376","link":"https://doi.org/10.1038/s41598-023-45093-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2023-10-17 15:01:20","publishedOnDateReadable":"October 17th, 2023"},"versionCreatedAt":"2023-03-06 15:45:52","video":"","vorDoi":"10.1038/s41598-023-45093-4","vorDoiUrl":"https://doi.org/10.1038/s41598-023-45093-4","workflowStages":[]},"version":"v1","identity":"rs-2615376","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2615376","identity":"rs-2615376","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}