Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer

Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer Rongfa Chen, Linna Liu, Hui Chen, Chao Xing, Tingting Zhang, Yilin Pang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3992209/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Jun, 2024 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted 7 You are reading this latest preprint version Abstract Background The significance of tumor-secreted cytokines in tumor development has gained substantial attention. Nevertheless, the precise role of tumor-related inflammatory cytokines in prostate cancer (PCa) remains ambiguous. Objectives To gain deeper insights into the inflammatory response in the process of PCa. Methods A total of 141 cases were collected, including 70 cases of prostate hyperplasia and 9 cases of prostatitis as disease control, 41 cases of postoperative prostate cancer and 21 cases of prostate cancer as PCa group. Additionally, 31 patients undergoing physical examinations during the same period were collected as the healthy control. The levels of 12 inflammatory cytokines in peripheral blood samples were analyzed using flow cytometric bead array technology. The levels of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) in peripheral blood samples were analyzed using electrochemiluminescence technology. Results Our results showed that serum IL-5, IL-6, IL-8 levels were significantly increased in PCa group compared to those in the control group (all p < 0.05). While, the level of IL-2, IL-10, TNF-α, IL-1β, IL-12p70, and IFN-α were lower in PCa than in healthy control. The concentration of IL-6 decreased but the concentrations of IL-4, IL-10, TNF-α, and IL-17A increased after surgery, showing significant differences (p < 0.05). The differential upregulation of IL-6 and IL-8 in peripheral blood have diagnostic efficacy in PCa patients. Conclusion The peripheral blood cytokines are closely associated with the occurrence and development of prostate cancer, especially the serum levels of IL-6 and IL-8 may be useful as potential predictors of PCa diagnosis. Prostate cancer Cytokines Peripheral blood Luminex Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Prostate diseases are prevalent worldwide and are among the most common diseases of the male genitourinary system. PCa is the second most common cancer in men globally, with a mortality rate second only to lung cancer[ 1 , 2 ]. Currently, there are multiple theories and hypotheses regarding the pathogenesis of PCa, but the exact causes are still unclear. However, the occurrence and development of the disease are often accompanied by inflammation[ 3 ]. The activation and recruitment of immune cells during the cellular inflammatory response can lead to the enrichment of cytokines and chemokines in the tumor microenvironment, thereby affecting cancer development [ 4 – 6 ]. After infection, sentinel immune cells in the body recognize invading pathogens and release inflammatory mediators, including cytokines [ 7 – 9 ]. Therefore, inflammation can promote the occurrence and progression of tumors by affecting the body's immune system [ 5 ]. Multiple studies have shown that Th17 cells are considered an important group of cells that mediate inflammatory responses, and the release of interleukin-17A (IL-17A) by Th17 cells contributes to the maintenance of chronic inflammatory states and the development of a cancer-promoting microenvironment, which is closely related to the occurrence and development of PCa[ 10 – 13 ]. In addition, recent studies have indicated that interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have different expressions in PCa tissues[ 14 – 16 ]. Another study found that interleukin-8 (IL-8) is also expressed in various cancers such as gastric cancer, esophageal cancer, and lung cancer to varying degrees [ 17 – 20 ]. These cytokines are complex responses stimulated during the tumor evolution process, and there have been few comprehensive reports on the comprehensive detection and analysis of cytokines in relation to the evolution of prostate cancer. Therefore, in this study, in order to better elucidate the relationship between prostate cancer and cytokines during the evolutionary process, we conducted a case-control study and systematically analyzed the concentration levels of cytokines in prostate-related diseases. 2. Materials and Methods 2.1 Patients and Specimens This study was approved by the Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University, with ethics approval reference [NO: 2021-K-301-01] and conducted in accordance with the World Medical Association Declaration of Helsinki. Patients diagnosed and treated for prostate diseases at our hospital from January 2021 to April 2023 were included, with the following exclusion criteria: underlying metabolic or infectious diseases, recent use of antibacterial drugs, history of other tumors, previous radiotherapy or chemotherapy, in addition, patients with clear laboratory evidence, like CRP, SAA, and PCT levels are elevated, indicates signs of inflammation. 2.2 Diagnostic Criteria for Prostate Diseases According to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, prostate cancer is diagnosed based on prostate biopsy, with a positive diagnosis indicating prostate cancer[ 21 ]; benign prostatic hyperplasia is diagnosed based on rectal examination indicating enlarged and firm prostate, ultrasound showing an enlarged prostate, increased residual urine, and decreased urine flow rate; urinary frequency, urgency, dysuria, turbid urine, or the presence of white secretions and pain in the lower abdomen indicate prostatitis. 2.3 Sample Collection After standard aseptic procedures, 3 ml of residual serum from each participant was collected and immediately separated by centrifugation at 3000 rpm for 15 minutes, and the serum was stored in a -80°C freezer until further analysis. 2.4 Quantitative Detection of Cytokines, TPSA, and FPSA Flow cytometric bead array technology was used with a cytokine multiplex detection kit (immunofluorescence method, twelve-plex) on a BD FACS CANTO II flow cytometer to detect the levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, IFN-α, TNF-α, and twelve other cytokines in peripheral blood samples. Electrochemiluminescence technology was used with a TPSA and FPSA Roche original detection kit on a Roche e601 electrochemiluminescence immunoassay analyzer (Roche (Shanghai) Co., Ltd., Switzerland) for detection. 2.5 Statistical Analysis Quantitative data were compared using two-tailed unpaired Student's t-test or one-way analysis of variance. Pearson's chi-square test or Fisher's exact test was used to assess the associations between clinical characteristics. Data are presented as mean ± standard deviation, and statistical significance was set at p < 0.05. All data were analyzed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9.0 (GraphPad, San Diego, CA, USA). 3. Results 3.1 Participant characteristics A total of 172 participants were included in this study, and all patients informed consent, including 70 cases of prostate hyperplasia, 9 cases of prostatitis as disease controls, while 41 cases of postoperative prostate cancer and 21 cases of prostate cancer as PCa group. Additionally, 31 participants were collected as the healthy controls (Flow chart as seen in Fig. 1 ). The clinical information of all subjects as shown in Table 1 . The participants were age-matched, and there were no differences in white blood cell and neutrophil levels, indicating the absence of inflammatory response in both groups. While, as specific tumor markers for prostate cancer, TPSA and FPSA showed significantly increased expression in the tumor group, which is consistent with the expected results. Table 1 The Clinical Characteristics of the Enrolled Participant Variables Healthy control (n = 31) Disease control (n = 79) PCa group (n = 62) p value Age, years 65(50–74) 65(57–72) 64.5(59-69.3) 0.753 WBC (x10 9 /L) 6.14(5.16–7.21) 6.46(5.21–7.55) 6.28(5.20–7.49) 0.842 Neutrophils (x10 9 /L) 3.56(3.07–4.15) 3.41(2.80–5.11) 3.75(3.02–4.77) 0.522 Lymphocyte (x10 9 /L) 2.0(1.72–2.42) 1.94(1.47–2.23) 1.52(1.13–2.04) 0.005 Monocytes (x10 9 /L) 0.35(0.32–0.44) 0.48(0.36–0.57) 0.47(0.39–0.63) 0.004 Platelets (x10 9 /L) 205(170–241) 214(170–243) 203(151–252) 0.819 TPSA (ng/ml) 1.04(0.69–1.65) 3.68(1.25–6.50) 37.40(14.67–237.50 < 0.0001 FPSA (ng/ml) 0.28(0.19–0.38) 0.65(0.30–1.35) 8.64(2.95–44.4) < 0.0001 Note: Values are given as median (interquartile range), WBC means white blood cell 3.2 Cytokines characteristics in the Participant According to the hospital-recommended program, 12 candidate serum cytokines were selected for analysis. The heatmap displays the concentrations of these cytokines in the participants (Fig. 2 A). The correlation heatmap showed their correlation between the 12 cytokines (Fig. 2 B). 3.3 The distribution of cytokines in the peripheral blood of PCa patients To compared the distribution of cytokines between PCa and the control group. The result as shown in Fig. 3 , The levels of pro-inflammatory cytokines IL-5 and IL-8 were significantly increased in the peripheral blood of patients with PCa than in the healthy control group, while IL-6 was higher in patients with PCa than in the disease control group (all p 0.05). The surprising discovery is in the prostate cancer group, the concentrations of the inflammatory cytokines IL-2, IL-10, TNF-α, IL-1β, IL-12p70, and IFN-α were significantly lower than those in the healthy control group (all p < 0.05). 3.4 Relationship between distribution of peripheral blood cytokines and Prostate Cancer Surgery in PCa patients To analyze whether cytokines are associated with the surgical prognosis of prostate cancer patients, we compared the distribution of cytokines between prostate cancer patients and postoperative patients. In addition, we performed a more detailed analysis of the clinical data of PCa patients between these groups, and there were no significant differences in age, sex, BMI category, tumor location, tumor histology, and tumor size. Figure 4 shows the concentration of IL-6 decreased after surgery, showing a significant difference ( p < 0.05). The concentrations of IL-4, IL-10, TNF-α, and IL-17A increased after surgery, showing significant differences ( p 0.05). In this part of the analysis indicating that these cytokines are influenced by the excision of the primary tumor. 3.5 Serum Cytokines as Possible Diagnostic Biomarkers for Prostate Cancer To confirm the preceding findings, we performed ROC analysis. Figure 5 shows the ROC of the presence of PCa when IL-5, IL-6 and IL-8 were used. The area under the curve (AUC) of IL-5, IL-6 and IL-8 in the diagnosis of prostate cancer patients were 0.588, 0.763 and 0.679 respectively (all p < 0.05), among them IL-6 and IL-8 demonstrates “good” capability for discriminating between patients with PCa and controls. 4. Discussion PCa is the most common malignant tumor in males and the fifth leading cause of cancer-related death in men worldwide[ 22 ]. Inflammation plays a key role in the occurrence and development of tumors, and prostate cancer is characterized by excessive expression of inflammation. Inflammatory cytokines are essential in the development of diseases into tumors and can directly act on tumor cells or indirectly exert multifaceted effects through the tumor microenvironment, promoting cancer cell proliferation [ 4 – 6 ]. Cytokines are small protein molecules secreted by various cells in the body and have a wide range of biological activities. They can be divided into pro-inflammatory and anti-inflammatory cytokines. Pro-inflammatory cytokines primarily secreted by lymphocytes and monocytes include IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12p70, IL-17A, IFN-γ, IFN-α, and TNF-α. Anti-inflammatory cytokines include IL-4 and IL-10[ 23 – 25 ]. In this study, after comprehensive analysis of 12 cytokines involved in prostate cancer and related diseases, our observed results showed that the concentrations of the inflammatory cytokines IL-2, IL-10, TNF-α, IL-1β, IL-12p70, and IFN-α were significantly lower in the prostate cancer group compared to the normal control group, while the concentrations of IL-5, IL-6 and IL-8 were significantly higher than those in the control group. Paul Katongole and others also found increased IL-6 levels in the serum of prostate cancer patients[ 26 ]. These cytokines are mainly secreted by T and B lymphocytes and are important components of the immune response, playing important roles in various biological functions, including immune response against bacterial infections[ 27 ]. These results indicate that inflammation often occurs during the evolution of prostate cancer and these indicators may be essential in diagnosing the disease. In the comparison analysis between the disease control group and the prostate cancer group, our study found that the concentration of IL-6 was significantly higher in the prostate cancer group than in the disease control group, which suggests a potential role of IL-6 in prostate cancer progression. This finding is consistent with previous studies that reported increased IL-6 levels in the peripheral blood of prostate cancer patients[ 28 – 30 ]. IL-6 is known to play a critical role in prostate-mediated immune responses and can stimulate humoral and cellular immune responses by acting on B and T lymphocytes, promoting their growth and differentiation, and participating in inflammation induced by follicular Th cells [ 27 , 28 , 31 ]. Furthermore, we analyzed the changes in cytokine concentrations before and after prostate cancer surgery. We found that the concentration of IL-6 decreased after surgery, while the concentrations of IL-4, IL-10, TNF-α, and IL-17A increased significantly. These findings suggest that surgery may have an impact on the inflammatory response and cytokine levels in prostate cancer patients. In other words, it is possible that the presence of the tumor leads to the continuous production of certain cytokines. Additionally, our present data provide preliminary support for utilizing differential levels of IL-6 and IL-8 as indicators of existing PCa. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance. Our study also has certain limitations. Firstly, although there is a biological relationship between inflammatory cytokines and prostate cancer and they have some statistical significance, our observations may have certain limitations. Before these results can be widely applied in clinical settings, it is necessary for us to repeatedly validate these conclusions by increasing the size of our research cohort. Secondly, our samples were collected at the same time point, and the cytokine concentrations were measured at a single time point, potentially overlooking potential changes over time. Thirdly, the relative imbalance in the collected samples across different groups may introduce certain biases to the conclusions. 5. Conclusions In conclusion, our study provides insights into the distribution of peripheral blood cytokines in prostate cancer and related diseases, offering laboratory evidence for the relationship between disease occurrence, development, and prognosis. The changes in cytokine levels after prostate cancer surgery may also serve as targets for treatment. Nonetheless, our results contribute to the understanding of the role of cytokines in prostate cancer and provide potential avenues for further research and clinical applications. Declarations Ethics Declarations This study was reviewed and approved by the Second Affiliated Hospital of Wenzhou Medical University, with the approval number: NO: 2021-K-301-01. All participants provided informed consent to participate in the study. Authorship contribution statement Xunjun Yang Writing-original draft, Methodology, Investigation, Formal analysis, Funding acquisition, Resources. Rongfa Chen Validation, Methodology, Visualization. Linna Liu Investigation, Formal analysis. Hui Chen Software. Chao Xing and Yilin Pang Writing-review & editing. Tingting Zhang Project administration, Supervision, Conceptualization, Resources, Data curation. All authors agree to submit the article for publication. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments This research was supported by Zhejiang Medical and Health Science and Technology Plan Project (Fund No. 2022KY903); Science and Technology Plan Project of Wenzhou (Fund No. Y20210725). References K. Chen, K. Jiang, L. Tang, X. Chen, J. Hu, F. Sun, Analysis of Clinical Trials on Therapies for Prostate Cancer in Mainland China and Globally from 2010 to 2020, Front Oncol 11 (2021) 647110. H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA Cancer J Clin 71(3) (2021) 209-249. W. Li, F. Chen, H. Gao, Z. Xu, Y. Zhou, S. Wang, Z. Lv, Y. Zhang, Z. Xu, J. Huo, J. Zhao, Y. Zong, W. Feng, X. Shen, Z. Wu, A. 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Ryu, Inflammatory response to Trichomonas vaginalis in the pathogenesis of prostatitis and benign prostatic hyperplasia, Parasites Hosts Dis 61(1) (2023) 2-14. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 03 Jun, 2024 Read the published version in Cancer Immunology, Immunotherapy → Version 1 posted Editorial decision: Revision requested 12 Mar, 2024 Reviews received at journal 01 Mar, 2024 Reviewers agreed at journal 29 Feb, 2024 Reviewers invited by journal 28 Feb, 2024 Editor assigned by journal 27 Feb, 2024 Submission checks completed at journal 27 Feb, 2024 First submitted to journal 26 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yilin","middleName":"","lastName":"Pang","suffix":""},{"id":275349318,"identity":"54d63a3d-51d1-4d94-a902-bb828444547b","order_by":6,"name":"Xunjun Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYHCChAMfKiTkGBh4gOwChgRitCQenHHGxhiixcCAKC3Mh3nb0hIbiNZicCPhAVDL4fQN588efPDD4E8eA/vhoxvwajlzIOHgnHOHczccOJds2GNgUMzAk5Z2A6+W4w0JB96UHc7ddrDHTILHwCCxQYLHDL+Ww8AQ42E7nG52mMf85x+itABtOcjTlpZgdozHjJkoWyRBfgEGsuH+MzzG0jIGxolthPzCdyMn+QMwKuUl+88YfnxTIZfYz374GF4tCgd4ElBF2PApBwH5BvYDhNSMglEwCkbBSAcAZPVWQHc4MUIAAAAASUVORK5CYII=","orcid":"","institution":"Second Affiliated Hospital \u0026 Yuying Children's Hospital of Wenzhou Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xunjun","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-02-26 23:44:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3992209/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3992209/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00262-024-03723-4","type":"published","date":"2024-06-04T03:40:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51821073,"identity":"bdd6820a-9e8d-415b-a9c6-fef2c84e88c1","added_by":"auto","created_at":"2024-02-29 16:08:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39704,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eConsort diagram for the samples used in the study\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/37a08c7da5b9c0f994e32263.jpg"},{"id":51822864,"identity":"35e3bf79-9a14-4054-92c6-58bdcffcca01","added_by":"auto","created_at":"2024-02-29 16:24:23","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":102616,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe concentrations of cytokines in patients with PCa and control groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Heatmap of differentially expressed 12 serum multi-cytokines between participants with PCa patients and non-tumor patients (disease and healthy controls) using Luminex assay. (B) Correlation heatmap of 12 serum cytokines in all participant\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/0380232ba397517f47e42334.jpg"},{"id":51821076,"identity":"4919bb1b-6a39-47bf-9a93-7ceb53fef230","added_by":"auto","created_at":"2024-02-29 16:08:23","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":76534,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe distribution of cytokines in the peripheral blood of Participant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe levels of IL-6 (A), IL-5(B), IL-8(C), IL-4(D), IFN-γ(E), IL-17A (F), IL-2(G), IL-10 (H), TNF-α(I), IL-1β (J), IL-12p70(K), INF-α (L) in serum from healthy and disease controls and PCa group. The red horizontal lines show the medians and interquartile range. The difference between control and PCa was assessed using the Mann–Whitney U-test.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/4b38df70935735d10bc49de5.jpg"},{"id":51822623,"identity":"d6aef265-20c2-49ee-a302-527acaa68444","added_by":"auto","created_at":"2024-02-29 16:16:23","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44531,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between distribution of peripheral blood cytokines and prostate cancer surgery in PCa patients\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/99cc93078ab099f6de65d2ed.jpg"},{"id":51821077,"identity":"b639d603-2ce2-44f9-8fc8-efe01c61ba44","added_by":"auto","created_at":"2024-02-29 16:08:23","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":38875,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic illustration of ROC curve to evaluate the diagnostic potential of serum IL-6, IL-8 and IL-5 to differentiate PCa group from controls\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/2978ae1a974c5eaeeff24e45.jpg"},{"id":60867054,"identity":"93abf2ea-3884-4fcc-8077-c5e819de9254","added_by":"auto","created_at":"2024-07-23 03:40:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":909925,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3992209/v1/31834f24-e4b2-42f8-9fec-b2e6cb4405ce.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eProstate diseases are prevalent worldwide and are among the most common diseases of the male genitourinary system. PCa is the second most common cancer in men globally, with a mortality rate second only to lung cancer[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Currently, there are multiple theories and hypotheses regarding the pathogenesis of PCa, but the exact causes are still unclear. However, the occurrence and development of the disease are often accompanied by inflammation[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The activation and recruitment of immune cells during the cellular inflammatory response can lead to the enrichment of cytokines and chemokines in the tumor microenvironment, thereby affecting cancer development [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAfter infection, sentinel immune cells in the body recognize invading pathogens and release inflammatory mediators, including cytokines [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, inflammation can promote the occurrence and progression of tumors by affecting the body's immune system [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Multiple studies have shown that Th17 cells are considered an important group of cells that mediate inflammatory responses, and the release of interleukin-17A (IL-17A) by Th17 cells contributes to the maintenance of chronic inflammatory states and the development of a cancer-promoting microenvironment, which is closely related to the occurrence and development of PCa[\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, recent studies have indicated that interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have different expressions in PCa tissues[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Another study found that interleukin-8 (IL-8) is also expressed in various cancers such as gastric cancer, esophageal cancer, and lung cancer to varying degrees [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These cytokines are complex responses stimulated during the tumor evolution process, and there have been few comprehensive reports on the comprehensive detection and analysis of cytokines in relation to the evolution of prostate cancer. Therefore, in this study, in order to better elucidate the relationship between prostate cancer and cytokines during the evolutionary process, we conducted a case-control study and systematically analyzed the concentration levels of cytokines in prostate-related diseases.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients and Specimens\u003c/h2\u003e \u003cp\u003e This study was approved by the Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University, with ethics approval reference [NO: 2021-K-301-01] and conducted in accordance with the World Medical Association Declaration of Helsinki. Patients diagnosed and treated for prostate diseases at our hospital from January 2021 to April 2023 were included, with the following exclusion criteria: underlying metabolic or infectious diseases, recent use of antibacterial drugs, history of other tumors, previous radiotherapy or chemotherapy, in addition, patients with clear laboratory evidence, like CRP, SAA, and PCT levels are elevated, indicates signs of inflammation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Diagnostic Criteria for Prostate Diseases\u003c/h2\u003e \u003cp\u003eAccording to the 2022 National Comprehensive Cancer Network (NCCN) guidelines, prostate cancer is diagnosed based on prostate biopsy, with a positive diagnosis indicating prostate cancer[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; benign prostatic hyperplasia is diagnosed based on rectal examination indicating enlarged and firm prostate, ultrasound showing an enlarged prostate, increased residual urine, and decreased urine flow rate; urinary frequency, urgency, dysuria, turbid urine, or the presence of white secretions and pain in the lower abdomen indicate prostatitis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Sample Collection\u003c/h2\u003e \u003cp\u003eAfter standard aseptic procedures, 3 ml of residual serum from each participant was collected and immediately separated by centrifugation at 3000 rpm for 15 minutes, and the serum was stored in a -80\u0026deg;C freezer until further analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Quantitative Detection of Cytokines, TPSA, and FPSA\u003c/h2\u003e \u003cp\u003eFlow cytometric bead array technology was used with a cytokine multiplex detection kit (immunofluorescence method, twelve-plex) on a BD FACS CANTO II flow cytometer to detect the levels of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IFN-γ, IFN-α, TNF-α, and twelve other cytokines in peripheral blood samples. Electrochemiluminescence technology was used with a TPSA and FPSA Roche original detection kit on a Roche e601 electrochemiluminescence immunoassay analyzer (Roche (Shanghai) Co., Ltd., Switzerland) for detection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e \u003cp\u003eQuantitative data were compared using two-tailed unpaired Student's t-test or one-way analysis of variance. Pearson's chi-square test or Fisher's exact test was used to assess the associations between clinical characteristics. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All data were analyzed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9.0 (GraphPad, San Diego, CA, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Participant characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 172 participants were included in this study, and all patients informed consent, including 70 cases of prostate hyperplasia, 9 cases of prostatitis as disease controls, while 41 cases of postoperative prostate cancer and 21 cases of prostate cancer as PCa group. Additionally, 31 participants were collected as the healthy controls (Flow chart as seen in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The clinical information of all subjects as shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The participants were age-matched, and there were no differences in white blood cell and neutrophil levels, indicating the absence of inflammatory response in both groups. While, as specific tumor markers for prostate cancer, TPSA and FPSA showed significantly increased expression in the tumor group, which is consistent with the expected results.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe Clinical Characteristics of the Enrolled Participant\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHealthy control\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDisease control\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;79)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePCa group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\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\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65(50\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65(57\u0026ndash;72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64.5(59-69.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.753\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWBC (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.14(5.16\u0026ndash;7.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.46(5.21\u0026ndash;7.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.28(5.20\u0026ndash;7.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.842\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutrophils (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.56(3.07\u0026ndash;4.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.41(2.80\u0026ndash;5.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.75(3.02\u0026ndash;4.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphocyte (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0(1.72\u0026ndash;2.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.94(1.47\u0026ndash;2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.52(1.13\u0026ndash;2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonocytes (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.35(0.32\u0026ndash;0.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.48(0.36\u0026ndash;0.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.47(0.39\u0026ndash;0.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelets (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e205(170\u0026ndash;241)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e214(170\u0026ndash;243)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e203(151\u0026ndash;252)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.819\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTPSA (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.04(0.69\u0026ndash;1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.68(1.25\u0026ndash;6.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.40(14.67\u0026ndash;237.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFPSA (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.28(0.19\u0026ndash;0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.65(0.30\u0026ndash;1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.64(2.95\u0026ndash;44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eNote: Values are given as median (interquartile range), WBC means white blood cell\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Cytokines characteristics in the Participant\u003c/h2\u003e\n \u003cp\u003eAccording to the hospital-recommended program, 12 candidate serum cytokines were selected for analysis. The heatmap displays the concentrations of these cytokines in the participants (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). The correlation heatmap showed their correlation between the 12 cytokines (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 The distribution of cytokines in the peripheral blood of PCa patients\u003c/h2\u003e\n \u003cp\u003eTo compared the distribution of cytokines between PCa and the control group. The result as shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, The levels of pro-inflammatory cytokines IL-5 and IL-8 were significantly increased in the peripheral blood of patients with PCa than in the healthy control group, while IL-6 was higher in patients with PCa than in the disease control group (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no difference in the levels of IL-4, IFN-\u0026gamma; and IL-17A between the three groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The surprising discovery is in the prostate cancer group, the concentrations of the inflammatory cytokines IL-2, IL-10, TNF-\u0026alpha;, IL-1\u0026beta;, IL-12p70, and IFN-\u0026alpha; were significantly lower than those in the healthy control group (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Relationship between distribution of peripheral blood cytokines and Prostate Cancer Surgery in PCa patients\u003c/h2\u003e\n \u003cp\u003eTo analyze whether cytokines are associated with the surgical prognosis of prostate cancer patients, we compared the distribution of cytokines between prostate cancer patients and postoperative patients. In addition, we performed a more detailed analysis of the clinical data of PCa patients between these groups, and there were no significant differences in age, sex, BMI category, tumor location, tumor histology, and tumor size. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e shows the concentration of IL-6 decreased after surgery, showing a significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The concentrations of IL-4, IL-10, TNF-\u0026alpha;, and IL-17A increased after surgery, showing significant differences (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while the concentrations of the other cytokines showed no significant difference (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). In this part of the analysis indicating that these cytokines are influenced by the excision of the primary tumor.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Serum Cytokines as Possible Diagnostic Biomarkers for Prostate Cancer\u003c/h2\u003e\n \u003cp\u003eTo confirm the preceding findings, we performed ROC analysis. Figure \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e shows the ROC of the presence of PCa when IL-5, IL-6 and IL-8 were used. The area under the curve (AUC) of IL-5, IL-6 and IL-8 in the diagnosis of prostate cancer patients were 0.588, 0.763 and 0.679 respectively (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), among them IL-6 and IL-8 demonstrates \u0026ldquo;good\u0026rdquo; capability for discriminating between patients with PCa and controls.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003ePCa is the most common malignant tumor in males and the fifth leading cause of cancer-related death in men worldwide[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Inflammation plays a key role in the occurrence and development of tumors, and prostate cancer is characterized by excessive expression of inflammation. Inflammatory cytokines are essential in the development of diseases into tumors and can directly act on tumor cells or indirectly exert multifaceted effects through the tumor microenvironment, promoting cancer cell proliferation [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCytokines are small protein molecules secreted by various cells in the body and have a wide range of biological activities. They can be divided into pro-inflammatory and anti-inflammatory cytokines. Pro-inflammatory cytokines primarily secreted by lymphocytes and monocytes include IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12p70, IL-17A, IFN-γ, IFN-α, and TNF-α. Anti-inflammatory cytokines include IL-4 and IL-10[\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, after comprehensive analysis of 12 cytokines involved in prostate cancer and related diseases, our observed results showed that the concentrations of the inflammatory cytokines IL-2, IL-10, TNF-α, IL-1β, IL-12p70, and IFN-α were significantly lower in the prostate cancer group compared to the normal control group, while the concentrations of IL-5, IL-6 and IL-8 were significantly higher than those in the control group. Paul Katongole and others also found increased IL-6 levels in the serum of prostate cancer patients[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These cytokines are mainly secreted by T and B lymphocytes and are important components of the immune response, playing important roles in various biological functions, including immune response against bacterial infections[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. These results indicate that inflammation often occurs during the evolution of prostate cancer and these indicators may be essential in diagnosing the disease.\u003c/p\u003e \u003cp\u003eIn the comparison analysis between the disease control group and the prostate cancer group, our study found that the concentration of IL-6 was significantly higher in the prostate cancer group than in the disease control group, which suggests a potential role of IL-6 in prostate cancer progression. This finding is consistent with previous studies that reported increased IL-6 levels in the peripheral blood of prostate cancer patients[\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. IL-6 is known to play a critical role in prostate-mediated immune responses and can stimulate humoral and cellular immune responses by acting on B and T lymphocytes, promoting their growth and differentiation, and participating in inflammation induced by follicular Th cells [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, we analyzed the changes in cytokine concentrations before and after prostate cancer surgery. We found that the concentration of IL-6 decreased after surgery, while the concentrations of IL-4, IL-10, TNF-α, and IL-17A increased significantly. These findings suggest that surgery may have an impact on the inflammatory response and cytokine levels in prostate cancer patients. In other words, it is possible that the presence of the tumor leads to the continuous production of certain cytokines.\u003c/p\u003e \u003cp\u003eAdditionally, our present data provide preliminary support for utilizing differential levels of IL-6 and IL-8 as indicators of existing PCa. Emerging evidence suggests that chemokines and cytokines are responsible for the pleiotropic actions in cancer, including the growth, angiogenesis, endothelial mesenchymal transition, leukocyte infiltration, and hormone escape for advanced PCa and therapy resistance.\u003c/p\u003e \u003cp\u003eOur study also has certain limitations. Firstly, although there is a biological relationship between inflammatory cytokines and prostate cancer and they have some statistical significance, our observations may have certain limitations. Before these results can be widely applied in clinical settings, it is necessary for us to repeatedly validate these conclusions by increasing the size of our research cohort. Secondly, our samples were collected at the same time point, and the cytokine concentrations were measured at a single time point, potentially overlooking potential changes over time. Thirdly, the relative imbalance in the collected samples across different groups may introduce certain biases to the conclusions.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn conclusion, our study provides insights into the distribution of peripheral blood cytokines in prostate cancer and related diseases, offering laboratory evidence for the relationship between disease occurrence, development, and prognosis. The changes in cytokine levels after prostate cancer surgery may also serve as targets for treatment. Nonetheless, our results contribute to the understanding of the role of cytokines in prostate cancer and provide potential avenues for further research and clinical applications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the Second Affiliated Hospital of Wenzhou Medical University, with the approval number: NO: 2021-K-301-01.\u003c/p\u003e\n\u003cp\u003eAll participants provided informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXunjun Yang Writing-original draft, Methodology, Investigation, Formal analysis, Funding acquisition, Resources. Rongfa Chen Validation, Methodology, Visualization. Linna Liu Investigation, Formal analysis. Hui Chen Software. Chao Xing and Yilin Pang Writing-review \u0026amp; editing. Tingting Zhang Project administration, Supervision, Conceptualization, Resources, Data curation. All authors agree to submit the article for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by Zhejiang Medical and Health Science and Technology Plan Project (Fund No. 2022KY903); Science and Technology Plan Project of Wenzhou (Fund No. Y20210725).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eK. Chen, K. Jiang, L. Tang, X. Chen, J. Hu, F. 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Ma, S. Li, P. Wei, H. Zhang, J. Wang, Association between response to anti-PD-1 treatment and blood soluble PD-L1 and IL-8 changes in patients with NSCLC, Discov Oncol 14(1) (2023) 35.\u003c/li\u003e\n\u003cli\u003eE.M. Schaeffer, S. Srinivas, N. Adra, Y. An, D. Barocas, R. Bitting, A. Bryce, B. Chapin, H.H. Cheng, A.V. D\u0026apos;Amico, N. Desai, T. Dorff, J.A. Eastham, T.A. Farrington, X. Gao, S. Gupta, T. Guzzo, J.E. Ippolito, M.R. Kuettel, J.M. Lang, T. Lotan, R.R. McKay, T. Morgan, G. Netto, J.M. Pow-Sang, R. Reiter, M. Roach, T. Robin, S. Rosenfeld, A. Shabsigh, D. Spratt, B.A. Teply, J. Tward, R. Valicenti, J.K. Wong, R.A. Berardi, D.A. Shead, D.A. Freedman-Cass, NCCN Guidelines\u0026reg; Insights: Prostate Cancer, Version 1.2023, Journal of the National Comprehensive Cancer Network : JNCCN 20(12) (2022) 1288-1298.\u003c/li\u003e\n\u003cli\u003eP. Rawla, Epidemiology of Prostate Cancer, World J Oncol 10(2) (2019) 63-89.\u003c/li\u003e\n\u003cli\u003eA. Crucitti, M. Corbi, P.M. Tomaiuolo, C. Fanali, A. Mazzari, D. Lucchetti, M. Migaldi, A. Sgambato, Laparoscopic surgery for colorectal cancer is not associated with an increase in the circulating levels of several inflammation-related factors, Cancer Biol Ther 16(5) (2015) 671-7.\u003c/li\u003e\n\u003cli\u003eD.J. Propper, F.R. Balkwill, Harnessing cytokines and chemokines for cancer therapy, Nat Rev Clin Oncol 19(4) (2022) 237-253.\u003c/li\u003e\n\u003cli\u003eT.A. Waldmann, Cytokines in Cancer Immunotherapy, Cold Spring Harb Perspect Biol 10(12) (2018).\u003c/li\u003e\n\u003cli\u003eP. Katongole, O.J. Sande, S. Nabweyambo, M. Joloba, H. Kajumbula, S. Kalungi, S.J. Reynolds, K. Ssebambulidde, M. Atuheirwe, J. Orem, N. Niyonzima, IL-6 and IL-8 cytokines are associated with elevated prostate-specific antigen levels among patients with adenocarcinoma of the prostate at the Uganda Cancer Institute, Future Oncol 18(6) (2022) 661-667.\u003c/li\u003e\n\u003cli\u003eM. Kim, S. Reidenbach, T. Schlechter, A.C. Rothmann, R. Will, I. Hofmann, Plakophilin 1 deficiency in prostatic tumours is correlated with immune cell recruitment and controls the up-regulation of cytokine expression post-transcriptionally, Febs j 290(7) (2023) 1907-1919.\u003c/li\u003e\n\u003cli\u003eS. Chen, K. Lu, Y. Hou, Z. You, C. Shu, X. Wei, T. Wu, N. Shi, G. Zhang, J. Wu, S. Chen, L. Zhang, W. Li, D. Zhang, S. Ju, M. Chen, B. Xu, YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6, J Immunother Cancer 11(4) (2023).\u003c/li\u003e\n\u003cli\u003eC.V. Ene, I. Nicolae, B. Geavlete, P. Geavlete, C.D. Ene, IL-6 Signaling Link between Inflammatory Tumor Microenvironment and Prostatic Tumorigenesis, Anal Cell Pathol (Amst) 2022 (2022) 5980387.\u003c/li\u003e\n\u003cli\u003eJ. Zhang, Y. Ye, Z. Xu, M. Luo, C. Wu, Y. Zhang, S. Lv, Q. Wei, Histone methyltransferase KMT2D promotes prostate cancer progression through paracrine IL-6 signaling, Biochem Biophys Res Commun 655 (2023) 35-43.\u003c/li\u003e\n\u003cli\u003eI.H. Han, J.H. Kim, J.S. Ryu, Inflammatory response to Trichomonas vaginalis in the pathogenesis of prostatitis and benign prostatic hyperplasia, Parasites Hosts Dis 61(1) (2023) 2-14.\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":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Prostate cancer, Cytokines, Peripheral blood, Luminex","lastPublishedDoi":"10.21203/rs.3.rs-3992209/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3992209/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe significance of tumor-secreted cytokines in tumor development has gained substantial attention. Nevertheless, the precise role of tumor-related inflammatory cytokines in prostate cancer (PCa) remains ambiguous.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo gain deeper insights into the inflammatory response in the process of PCa.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA total of 141 cases were collected, including 70 cases of prostate hyperplasia and 9 cases of prostatitis as disease control, 41 cases of postoperative prostate cancer and 21 cases of prostate cancer as PCa group. Additionally, 31 patients undergoing physical examinations during the same period were collected as the healthy control. The levels of 12 inflammatory cytokines in peripheral blood samples were analyzed using flow cytometric bead array technology. The levels of total prostate-specific antigen (TPSA) and free prostate-specific antigen (FPSA) in peripheral blood samples were analyzed using electrochemiluminescence technology.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOur results showed that serum IL-5, IL-6, IL-8 levels were significantly increased in PCa group compared to those in the control group (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). While, the level of IL-2, IL-10, TNF-α, IL-1β, IL-12p70, and IFN-α were lower in PCa than in healthy control. The concentration of IL-6 decreased but the concentrations of IL-4, IL-10, TNF-α, and IL-17A increased after surgery, showing significant differences \u003cem\u003e(p\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The differential upregulation of IL-6 and IL-8 in peripheral blood have diagnostic efficacy in PCa patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe peripheral blood cytokines are closely associated with the occurrence and development of prostate cancer, especially the serum levels of IL-6 and IL-8 may be useful as potential predictors of PCa diagnosis.\u003c/p\u003e","manuscriptTitle":"Evaluation of the Clinical Application Value of Cytokine Expression Profiles in the Differential Diagnosis of Prostate Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-29 16:08:18","doi":"10.21203/rs.3.rs-3992209/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-12T11:25:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-01T06:47:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97d0044d-b3ea-45a3-9b45-5dffacf692f7","date":"2024-02-29T08:01:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-28T09:12:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-27T10:47:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-02-27T10:47:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2024-02-26T23:24:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"96680bb1-7020-410d-ad94-98e6893047a5","owner":[],"postedDate":"February 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-23T03:40:33+00:00","versionOfRecord":{"articleIdentity":"rs-3992209","link":"https://doi.org/10.1007/s00262-024-03723-4","journal":{"identity":"cancer-immunology-immunotherapy","isVorOnly":false,"title":"Cancer Immunology, Immunotherapy"},"publishedOn":"2024-06-04 03:40:33","publishedOnDateReadable":"June 4th, 2024"},"versionCreatedAt":"2024-02-29 16:08:18","video":"","vorDoi":"10.1007/s00262-024-03723-4","vorDoiUrl":"https://doi.org/10.1007/s00262-024-03723-4","workflowStages":[]},"version":"v1","identity":"rs-3992209","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3992209","identity":"rs-3992209","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}