Cited by 261Prostate Cancer Treatment and ResearchCytokine Signaling Pathways and InteractionsProstate Cancer Diagnosis and Treatment

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Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis.

Shariat, Shahrokh F., Andrews, Ben, Kattan, Michael W., Kim, JaHong, Wheeler, Thomas M., Slawin, Kevin M.·2001·Urology

DOI 10.1016/s0090-4295(01)01405-4

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Abstract

Objectives Elevated circulating levels of interleukin 6 (IL-6) have been associated with cancer metastasis. IL-6 binds either to membrane or to soluble IL-6 receptor (IL-6sR), which then induces homodimerization of gp130 that activates downstream signaling. We tested the hypothesis that preoperative plasma IL-6 and IL-6sR levels are associated with prostate cancer stage, progression, and metastasis after radical prostatectomy.Methods Plasma levels of IL-6 and IL-6sR were measured in 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer, 44 healthy men without any cancer, 19 men with prostate cancer metastatic to the regional lymph nodes, and 10 men with prostate cancer metastatic to bone.Results Plasma IL-6 and IL-6sR levels were highest in patients with bone metastases (P <0.001). The preoperative IL-6 and IL-6sR levels were associated with the preoperative prostate-specific antigen (PSA) level (P </=0.041), prostatectomy tumor volume (P </=0.048), and final Gleason sum (P </=0.042). The preoperative IL-6 and IL-6sR levels and biopsy Gleason sum were independent predictors of PSA progression (P </=0.029). However, in a model that included both IL-6 and IL-6sR, only IL-6sR and the biopsy Gleason sum predicted progression (P </=0.040). In patients whose disease progressed, the preoperative IL-6 and IL-6sR levels were highest in those with presumed aggressive failure (P </=0.042).Conclusions Plasma IL-6 and IL-6sR levels were dramatically elevated in the men with prostate cancer metastatic to bone. In patients with clinically localized prostate cancer, the preoperative plasma IL-6 and IL-6sR levels independently predicted biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy.

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Ugge, H., Carlsson, J., Söderquist, B., Fall, K., Andén, O., & Davidsson, S. (2018) · Infectious Agents and Cancer · doi:10.1186/s13027-018-0204-7 · Cited by 18
[Retracted] Silver Nanoparticles Stabilized by Poly (Vinyl Pyrrolidone) with Potential Anticancer Activity towards Prostate Cancer
Abdellatif, A. A. H., Abdelfattah, A. M., Bouazzaoui, A., Osman, S. K., Al-Moraya, I. S., Showail, A. M. S., Alsharidah, M. S., Aboelela, A., Rugaie, O. A., Faris, T. M., et al. (2022) · Bioinorganic Chemistry and Applications · doi:10.1155/2022/6181448 · Cited by 18
“IL-6 and TNF-α are two cytokines with multiple and overlapping biological properties, that are involved in the development of prostate cancer [36, 37].”
Background
Retracted
A Magnetic Bead-Based Sensor for the Quantification of Multiple Prostate Cancer Biomarkers
Jokerst, J. V., Chen, Z., Xu, L., Nolley, R., Chang, E., Mitchell, B. L., Brooks, J. D., & Gambhir, S. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139484 · Cited by 18
“IL-6sr has also been shown to correlate with progression [27] and bone metastasis [26] and it was plausible that differential expression would have been measured in BPH versus CaP patients samples, however we noted no significant difference between these two patient populations.”
BackgroundResult
Soluble gp130 Regulates Prostate Cancer Invasion and Progression in an Interleukin-6 Dependent and Independent Manner
Shariat, S. F., Chromecki, T. F., Hoefer, J., Barbieri, C. E., Scherr, D. S., Karakiewicz, P. I., Roehrborn, C. G., Montorsi, F., Čulig, Z., & Cavarretta, I. T. R. (2011) · The Journal of Urology · doi:10.1016/j.juro.2011.06.048 · Cited by 17
The Role of Bisphosphonates in the Management of Advanced Cancer with a Focus on Non-Small-Cell Lung Cancer
Saba, N. F., & Khuri, F. R. (2005) · Oncology · doi:10.1159/000084518 · Cited by 17
“who reported that patients with prostate cancer and bone metastases exhibited a significant increase in bone resorption (p Cytokine Markers Elevated preoperative levels of the cytokine IL-6 and soluble IL-6 receptor may also be associated with bone relapse in men with prostate cancer [”
Background
Differential expression and effects of gp130 cytokines and receptors in prostate cancer cells
Palmer, J., Hertzog, P. J., & Hammacher, A. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.04.017 · Cited by 17
AT‐rich interaction domain 5A regulates the transcription of interleukin‐6 gene in prostate cancer cells
Ikeuchi, W., Wakita, Y., Zhang, G., Li, C., Itakura, K., & Yamakawa, T. (2021) · The Prostate · doi:10.1002/pros.24251 · Cited by 15
Impact of preoperative plasma levels of interleukin 6 and interleukin 6 soluble receptor on disease outcomes after radical cystectomy for bladder cancer
Schuettfort, V. M., Pradère, B., Trinh, Q., D’Andrea, D., Quhal, F., Mostafaei, H., Laukhtina, E., Mori, K., Motlagh, R. S., Rink, M., et al. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-021-02953-0 · Cited by 15
“Specimen collection and measurement have been described in detail previously [25].”
Cytokines and Janus kinase/signal transducer and activator of transcription signaling in prostate cancer: overview and therapeutic opportunities
Canesin, G., Krzyzanowska, A., Hellsten, R., & Bjartell, A. S. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.02.004 · Cited by 16
Significant Impact ofIL-6-174G/C but Inverse Relation with -634 C/G Polymorphism in Patients with Non-Small Cell Lung Cancer in Kashmiri Population
Bhat, I. A., Qasim, I., Masoodi, K. Z., Paul, S. A., Bhat, B. A., Rasool, R., Aziz, S. A., & Shah, Z. A. (2015) · Immunological Investigations · doi:10.3109/08820139.2015.1004336 · Cited by 14
“Many clinical reports have shown serum IL-6 level to be associated with stage and prognosis in different tumor types (Berek et al., 1991; Mouawad et al., 1996; Oka et al., 1996; Shariat et al., 2001; Wu et al., 1996; Zhang & Adachi, 1999).”
Background
Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer
Heath, E. I., Heilbrun, L. K., Mannuel, H. D., Liu, G., Lara, P. N., Monk, J. P., Flaig, T. W., Zurita, A. J., Mack, P. C., Vaishampayan, U. N., et al. (2019) · The Oncologist · doi:10.1634/theoncologist.2019-0331 · Cited by 14
Neutralization of interleukin (IL)-10 released by monocytes/macrophages enhances the up-regulatory effect of monocyte/macrophage-derived IL-6 on expressions of IL-6 and MUC1, and migration in HT-29 colon cancer cells
Li, Y., Chang, J. W. C., Hsieh, L., & Yeh, K. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.07.014 · Cited by 14
Molecular Biomarkers for Predicting Cancer Patient Radiosensitivity and Radiotoxicity in Clinical Practice
Gkikoudi, A., Kalospyros, S. A., Triantopoulou, S., Logotheti, S., Softa, V., Kappas, C., Theodorou, K., Laiakis, E. C., Manda, G., Terzoudi, G. I., et al. (2023) · Applied Sciences · doi:10.3390/app132312564 · Cited by 13
Antígeno prostático-específico, citoquinas pro-inflamatorias y patología prostática (Hiperplasia benigna y Cáncer): Relación con la malignidad
Alcaide, J. R. C., Martín, R. V. S., de Bethencourt, F. R., Bouraoui, Y., Berriguete, G. R., Oueslati, R., Pérez-Utrilla, M., Barthel, J. D. L. P., Paniagua, R., & García, M. R. (2009) · Archivos Españoles de Urología · doi:10.4321/s0004-06142009000500005 · Cited by 13
Evidence of the Link between Stroma Remodeling and Prostate Cancer Prognosis
Vecchiotti, D., Clementi, L., Cornacchia, E., Nolfi, M. D. V., Verzella, D., Capece, D., Zazzeroni, F., & Angelucci, A. (2024) · Cancers · doi:10.3390/cancers16183215 · Cited by 12
“Given its important role in tumor progression, as well as the established correlation between high levels of serum IL-6 and shorter survival [228], IL-6 could be a prognostic biomarker for PCa patients.”
Background
Gene Therapy Applications to Cancer Treatment
Scholl, S., Michaelis, S. A. M., & McDermott, R. (2003) · BioMed Research International · doi:10.1155/s1110724303209037 · Cited by 12
“A number of cytokines, such as IL-10 [102], IL-6 [103, 104], MCS-F (CSF-1) [105] VEGF [106, 107, 108], and soluble IL-2 receptor [109], have been associated with immunosuppression and/or poor patient survival.”
Background
The Role of Bisphosphonates in the Management of Advanced Cancer with a Focus on Non-Small-Cell Lung Cancer
Saba, N. F., & Khuri, F. R. (2005) · Oncology · doi:10.1159/000084517 · Cited by 12
IL-6/STAT3 signaling in prostate cancer: CAF-driven immune evasion and therapeutic opportunities
Zhou, T., Li, Y., Liu, Z., Zeng, Z., Li, T., Chen, L., Zhao, H., Wu, X., Shen, Y., Fan, H., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1736606 · Cited by 10
“A clinical study showed that metastatic castration-resistant prostate cancer (mCRPC) in patients with elevated levels of IL-6 usually indicates poor therapeutic effect (7).”
Resistance to prostate cancer treatments
Kŕause, W. (2022) · IUBMB Life · doi:10.1002/iub.2665 · Cited by 10
Serum receptor activator of nuclear factor κB ligand ( RANKL ) levels predict biochemical recurrence in patients undergoing radical prostatectomy
Todenhöfer, T., Hennenlotter, J., Leidenberger, P., Wald, A., Hohneder, A., Kühs, U., Mischinger, J., Aufderklamm, S., Gakis, G., Blumenstock, G., et al. (2013) · British Journal of Urology · doi:10.1111/j.1464-410x.2012.11759.x · Cited by 10
Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines
Sen, M., Johnston, P., Pollock, N. I., DeGrave, K. A., Joyce, S., Freilino, M. L., Hua, Y., Camarco, D. P., Close, D. A., Huryn, D., et al. (2017) · Journal of chemical biology · doi:10.1007/s12154-017-0169-9 · Cited by 12
“High serum IL6 levels have been detected in patients with lymphoma, lung [35], prostate [32, 40], breast [5], and colorectal cancer [48].”
Background
The Association between Neighborhood Disorder and Health: Exploring the Moderating Role of Genotype and Marriage
Lei, M., & Simons, R. L. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18030898 · Cited by 10
“Previous studies have indicated that it plays a role in the regulation of IL-6 and is associated with diabetes, chronic illness, certain cancers, and neurological disorders [43,44].”
Background
Osteoid cell-derived chemokines drive bone-metastatic prostate cancer
Johnson, C. S., & Cook, L. M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1100585 · Cited by 8
Redox Signaling Modulates Activity of Immune Checkpoint Inhibitors in Cancer Patients
Allegra, A., Murdaca, G., Mirabile, G., & Gangemi, S. (2023) · Biomedicines · doi:10.3390/biomedicines11051325 · Cited by 8
“Moreover, in the tumour microenvironment, high levels of intracellular ROS can stimulate the secretion of IL-6, a pro-inflammatory cytokine that facilitates proliferation, migration, and metastasis of several types of tumours [208,209], and the anti-tumour immune response to anti-PD-L1 treatment in solid tumours has b…”
Background
The Significance of Plasma C-reactive Protein in Patients With Elevated Serum Prostate-specific Antigen Levels
Chang, C.-C., Lin, A. T. L., Chen, K., Chung, H., & Chang, S.-C. (2010) · Urological Science · doi:10.1016/s1879-5226(10)60018-8 · Cited by 8
Effects of cell-cell crosstalk on gene expression patterns in a cell model of renal cell carcinoma lung metastasis
Kamińska, K., Czarnecka, A. M., Khan, M. I., Fendler, W. M., Klemba, A., Krasowski, P., Bartnik, E., & Szczylik, C. A. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.4234 · Cited by 8
“Moreover, in men with prostate cancer which has metastasized to the bone, plasma IL-6 levels and its soluble receptor (IL-6sR) levels are extremely high (44), what indicates their role in metastasis.”
The Role of Interleukin-6 Polymorphism (rs1800795) in Prostate Cancer Development and Progression
Jurečeková, J., Drobková, H., Šarlinová, M., Babušíková, E., Sivoňová, M. K., Matáková, T., Kliment, J., & Halášová, E. (2018) · Anticancer Research · doi:10.21873/anticanres.12643 · Cited by 8
Serum interleukin 6 and acute urinary retention in elderly men with benign prostatic hyperplasia in China: a cross-sectional study
Wu, D., Shi, Z.-E., Xu, D., Wu, Y. R., Qian, S., & Qi, J. (2021) · Translational Andrology and Urology · doi:10.21037/tau-20-914 · Cited by 8
“Similar to prostate-specific antigen (PSA), IL-6 has been used to evaluate prostatic inflammation and cancer (25-29), but no report exists concerning the use of serum IL-6 (sIL-6) to evaluate the risk of AUR in elderly men with BPH.”
Biomarkers for the Management of Castration-Resistant Prostate Cancer: We Are Not There Yet
Petrylak, D. P., & Crawford, E. D. (2017) · Targeted Oncology · doi:10.1007/s11523-017-0500-y · Cited by 7
Preoperative plasma level of endoglin as a predictor for disease outcomes after radical cystectomy for nonmetastatic urothelial carcinoma of the bladder
Laukhtina, E., Schuettfort, V. M., D’Andrea, D., Pradère, B., Mori, K., Quhal, F., Motlagh, R. S., Mostafaei, H., Katayama, S., Grossmann, N. C., et al. (2021) · Molecular Carcinogenesis · doi:10.1002/mc.23355 · Cited by 7
“Specimen collection and measurement have been described in detail elsewhere.(28) Briefly, blood was collected into Vacutainer CPT 8‐ml tubes containing 0.”
Method
Zoledronic acid effects interleukin-6 expression in hormone-independent prostate cancer cell lines
Asbagh, L. A., Uzunoğlu, S., & Çal, Ç. (2008) · International braz j urol · doi:10.1590/s1677-55382008000300013 · Cited by 7
Modulation of inflammatory mediators underlies the antitumor effect of the combination of morusin and docetaxel on prostate cancer cells
Fadil, S. A., Albadawi, D. A. I., Alshali, K. Z., Abdallah, H. M., & Saber, M. M. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117572 · Cited by 6
A Multigene-Panel Study Identifies Single Nucleotide Polymorphisms Associated with Prostate Cancer Risk
Manca, M. A., Scarpa, F., Cossu, D., Simula, E. R., Sanna, D., Ruberto, S., Noli, M., Ashraf, H., Solinas, T., Madonia, M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087594 · Cited by 6
“Interestingly, gene amplification of IL17 has been reported more frequently in CRPC and neuroendocrine prostate cancer than in hormone-naïve PCa [27].”
Background
TNF-blockade in patients with advanced hormone refractory prostate cancer
Diaz, L. A., Messersmith, W. A., Sokoll, L. J., Sinibaldi, V. J., Moore, S., Carducci, M. A., & Eisenberger, M. A. (2009) · Investigational New Drugs · doi:10.1007/s10637-009-9346-1 · Cited by 6
Soluble interleukin-6 receptor to interleukin-6 (sIL‑6R/IL-6) ratio in serum as a predictor of high Gleason sum at radical prostatectomy
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“This finding regarding the association between sIL‑6R circulating values and features of PCa aggressiveness and metastases is supported by the literature (9,10,18).”
Hepatocyte growth factor and interleukin-6 in combination with prostate volume are possible prostate cancer tumor markers in patients with gray-zone PSA levels
Nishimura, K., Arichi, N., Tokugawa, S., Yoshioka, I., Namba, Y., Kishikawa, H., Takahara, S., & Ichikawa, Y. (2007) · Prostate Cancer and Prostatic Diseases · doi:10.1038/sj.pcan.4501006 · Cited by 6
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PTEN in Prostate Cancer
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“One of the most prevalent infl ammatory mediators clearly implicated in prostate cancer is IL-6, a cytokine that has not only been associated with tumor growth, proliferation, and angiogenesis in many cancers [ 253 ], but whose high levels in the circulating plasma of prostate cancer patients have also been correlated…”
Background
Bone Metastasis Microenvironment Participates in the Development of Androgen Ablation Refractoriness and Chemotherapy Resistance of Prostate Cancer Cells Residing in the Skeleton: Clinical Implications
Koutsilieris, M., Τέντα, Ρ., Tiblalexi, D., Pitulis, N., Sotiriou, E., Lembessis, P., Bogdanos, J., Milathianakis, C., & Sourla, A. (2005) · Springer eBooks · doi:10.1007/1-4020-3414-8_19 · Cited by 5
Secondary Hormonal Manipulations in Prostate Cancer
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Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer
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The Ingredients for Prostate Cancer Nomograms: The Addition of Biomarkers Sets the Table for Future Recipes
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Authors: Shariat, S. F., Andrews, B., Kattan, M. W., Kim, J., Wheeler, T. M., & Slawin, K. M.
Affiliations: Houston Methodist (US)
Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Slawin, Kevin M.
ORCID: Shariat, Shahrokh F.
Kattan, Michael W.
Wheeler, Thomas M.
Venue: Urology
Publisher: Elsevier BV
Published: 2001-12
Volume: 58
Issue: 6
Pages: 1008-1015
ISSN: 0090-4295 (ISSN-L)
DOI: 10.1016/s0090-4295(01)01405-4
OpenAlex: W2009017218
Cited by: 261
References: 35
Citations by year: 2026: 6 · 2025: 1 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 17 · 2020: 5 · 2019: 5 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 19 · 2014: 10 · 2013: 12 · 2012: 8
FWCI: 9.37
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Urology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (1p20ca058203-01)
National Cancer Institute (CA58203)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Health Sciences › Medicine › Urology › Prostate Cancer Diagnosis and Treatment
Keywords: interleukin-6, soluble IL-6 receptor, prostate cancer, bone metastasis, biochemical recurrence, radical prostatectomy, prognostic factors, Gleason score, prostate-specific antigen, tumor progression, gp130 signaling
MeSH terms: Adult, Aged, Analysis of Variance, Biopsy, Bone Neoplasms, Follow-Up Studies, Humans, Male, Middle Aged, Prostate, Prostatectomy, Prostatic Neoplasms, Biomarkers, Tumor, Interleukin-6, Proportional Hazards Models, Disease Progression, Receptors, Interleukin-6

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Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis.

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