CC BY 4.0 · Rev Bras Ginecol Obstet 2023; 45(12): e780-e789
DOI: 10.1055/s-0043-1772590
Original Article
Oncology

Systemic Inflammatory Patterns in Ovarian Cancer Patients: Analysis of Cytokines, Chemokines, and Microparticles

Padrões inflamatórios sistêmicos em pacientes com câncer de ovário: Análise de citocinas, quimiocinas e micropartículas
1   Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Botucatu, SP, Brasil
,
1   Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Botucatu, SP, Brasil
,
2   Instituto René Rachou – Fiocruz Minas, Belo Horizonte, MG, Brasil
,
3   Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
,
3   Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
,
1   Department of Gynecology and Obstetrics, Faculty of Medicine, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Botucatu, SP, Brasil
› Author Affiliations

Abstract

Objective To compare the patterns of systemic inflammatory response in women with epithelial ovarian cancer (EOC) or no evidence of malignant disease, as well as to evaluate the profile of systemic inflammatory responses in type-1 and type-2 tumors. This is a non-invasive and indirect way to assess both tumor activity and the role of the inflammatory pattern during pro- and antitumor responses.

Materials and Methods We performed a prospective evaluation of 56 patients: 30 women without evidence of malignant disease and 26 women with EOC. The plasma quantification of cytokines, chemokines, and microparticles (MPs) was performed using flow cytometry.

Results Plasma levels of proinflammatory cytokines interleukin-12 (IL12), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) interleukin-1 beta (IL-1β), and interleukin-10 (IL-10), and C-X-C motif chemokine ligand 9 (CXCL-9) and C-X-C motif chemokine ligand 10 (CXCL-10) were significantly higher in patients with EOC than in those in the control group. Plasma levels of cytokine interleukin-17A (IL-17A) and MPs derived from endothelial cells were lower in patients with EOC than in the control group. The frequency of leukocytes and MPs derived from endothelial cells was higher in type-2 tumors than in those without malignancy. We observed an expressive number of inflammatory/regulatory cytokines and chemokines in the cases of EOC, as well as negative and positive correlations involving them, which leads to a higher complexity of these networks.

Conclusion The present study showed that, through the development of networks consisting of cytokines, chemokines, and MPs, there is a greater systemic inflammatory response in patients with EOC and a more complex correlation of these biomarkers in type-2 tumors.

Resumo

Objetivo Comparar os padrões de resposta inflamatória sistêmica em mulheres com câncer epitelial de ovário (CEO) ou sem evidência de doença maligna, bem como avaliar o perfil de respostas inflamatórias sistêmicas em tumores dos tipos 1 e 2. Esta é uma forma não invasiva e indireta de avaliar tanto a atividade tumoral quanto o papel do padrão inflamatório durante as respostas pró- e antitumorais.

Métodos Ao todo, 56 pacientes foram avaliados prospectivamente: 30 mulheres sem evidência de doença maligna e 26 mulheres com CEO. A quantificação plasmática de citocinas, quimiocinas e micropartículas (MPs) foi realizada por citometria de fluxo.

Resultados Os níveis plasmáticos das citocinas pró-inflamatórias interleucina-12 (IL12), interleucina-6 (IL-6), fator de necrose tumoral alfa (tumor necrosis factor alpha, TNF-α, em inglês), interleucina-1 beta (IL-1β), e interleucina-10 (IL-10), e da quimiocina de motivo C-X-C 9 (CXCL-9) e da quimiocina de motivo C-X-C 10 (CXCL-10) foram significativamente maiores em pacientes com EOC do que nos controles. Os níveis plasmáticos da citocina interleucina-17A (IL17A) e MPs derivados de células endoteliais foram menores em pacientes com CEO do que no grupo de controle. A frequência de leucócitos e de MPs derivadas de células endoteliais foi maior nos tumores de tipo 2 do que naqueles sem malignidade. Observou-se um número expressivo de citocinas e quimiocinas inflamatórias/regulatórias nos casos de CEO, além de correlações negativas e positivas entre elas, o que leva a uma maior complexidade dessas redes.

Conclusão Este estudo mostrou que, por meio da construção de redes compostas por citocinas, quimiocinas e MPs, há maior resposta inflamatória sistêmica em pacientes com CEO e correlação mais complexa desses biomarcadores em tumores de tipo 2.

Contributions

All of the authors contributed with the project and data interpretation, the writing of the article, the critical review of the intellectual content, and with the final approval of the version to be published.




Publication History

Received: 14 March 2023

Accepted: 14 July 2023

Article published online:
23 December 2023

© 2023. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Pavlik EJ, Smith C, Dennis TS, Harvey E, Huang B, Chen Q. et al. Disease-Specific Survival of Type I and Type II Epithelial Ovarian Cancers-Stage Challenges Categorical Assignments of Indolence & Aggressiveness. Diagnostics (Basel) 2020; 10 (02) 56
  • 2 Chang CM, Chuang CM, Wang ML, Yang YP, Chuang JH, Yang MJ. et al. Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer. Int J Mol Sci 2016; 17 (08) 1272
  • 3 National Cancer Institute [internet]. SEER Stat Fact Sheets: Ovarian Cancer. [access in 2022 Nov 7]. Available from: https://seer.cancer.gov/statfacts/html/ovary.html
  • 4 Van Aalderen MC, Trappenburg MC, Van Schilfgaarde M, Molenaar PJ, Cate HT, Terpstra WE, Leyte A. Procoagulant myeloblast-derived microparticles in AML patients: changes in numbers and thrombin generation potential during chemotherapy. J Thromb Haemost 2011; 9 (01) 223-226
  • 5 Kurman RJ, Shih IeM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol 2011; 42 (07) 918-931
  • 6 Macciò A, Madeddu C. Inflammation and ovarian cancer. Cytokine 2012; 58 (02) 133-147
  • 7 Browning L, Patel MR, Horvath EB, Tawara K, Jorcyk CL. IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis. Cancer Manag Res 2018; 10: 6685-6693
  • 8 Zhang H, Wang Z, Wang F, Wang C, Zhang H. IL-6 and IL-8 are involved in JMJD2A-regulated malignancy of ovarian cancer cells. Arch Biochem Biophys 2020; 684: 108334
  • 9 Gong J, Jaiswal R, Dalla P, Luk F, Bebawy M. Microparticles in cancer: A review of recent developments and the potential for clinical application. Semin Cell Dev Biol 2015; 40: 35-40
  • 10 Shantsila E, Montoro-García S, Gallego P, Lip GYH. Circulating microparticles: challenges and perspectives of flow cytometric assessment. Thromb Haemost 2014; 111 (06) 1009-1014
  • 11 Liubomirski Y, Lerrer S, Meshel T, Rubinstein-Achiasaf L, Morein D, Wiemann S. et al. Tumor-Stroma-Inflammation Networks Promote Pro-metastatic Chemokines and Aggressiveness Characteristics in Triple-Negative Breast Cancer. Front Immunol 2019; 10: 757
  • 12 Pagés F, Kroemer G. Prognostic impact of anticancer immune responses: an introduction. Semin Immunopathol 2011; 33 (04) 317-319
  • 13 Jaiswal R, Sedger LM. Intercellular Vesicular Transfer by Exosomes, Microparticles and Oncosomes - Implications for Cancer Biology and Treatments. Front Oncol 2019; 9: 125
  • 14 Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rébé C. et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol 2011; 224 (03) 389-400
  • 15 Tárnok A, Hambsch J, Chen R, Varro R. Cytometric bead array to measure six cytokines in twenty-five microliters of serum. Clin Chem 2003; 49 (6 Pt 1): 1000-1002
  • 16 Pelissier Vatter FA, Cioffi M, Hanna SJ, Castarede I, Caielli S, Pascual V. et al. Extracellular vesicle- and particle-mediated communication shapes innate and adaptive immune responses. J Exp Med 2021; 218 (08) e20202579
  • 17 Hollander M, Wolfe DA, Chicken E. Nonparametric statistical methods. John Wiley & Sons; 2013
  • 18 Trinidad CV, Tetlow AL, Bantis LE, Godwin AK. Reducing Ovarian Cancer Mortality Through Early Detection: Approaches Using Circulating Biomarkers. Cancer Prev Res (Phila) 2020; 13 (03) 241-252
  • 19 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13 (11) 2498-2504
  • 20 Burke F, Relf M, Negus R, Balkwill F. A cytokine profile of normal and malignant ovary. Cytokine 1996; 8 (07) 578-585
  • 21 Cândido EB, Silva LM, Carvalho AT, Lamaita RM, Porto RM Filho, Cota BDCV, Silva-Filho AL. Immune response evaluation through determination of type 1, type 2, and type 17 patterns in patients with epithelial ovarian cancer. Reprod Sci 2013; 20 (07) 828-837
  • 22 Cheng L, Wu S, Zhang K, Qing Y, Xu T. A comprehensive overview of exosomes in ovarian cancer: emerging biomarkers and therapeutic strategies. J Ovarian Res 2017; 10 (01) 73
  • 23 Tian W, Lei N, Zhou J, Chen M, Guo R, Qin B. et al. Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion. Cell Death Dis 2022; 13 (01) 64
  • 24 Chen Q, Xu B, Lan L, Yang D, Yang M, Jiang J. et al. High mRNA expression level of IL-6R was associated with better prognosis for patients with ovarian cancer: a pooled meta-analysis. Sci Rep 2017; 7 (01) 8769-8778
  • 25 Rodrigues IS, Martins-Filho A, Micheli DC, Lima CA, Tavares-Murta BM, Murta EFC, Nomelini RS. IL-6 and IL-8 as Prognostic Factors in Peritoneal Fluid of Ovarian Cancer. Immunol Invest 2020; 49 (05) 510-521
  • 26 Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol 2022; 19 (04) 237-253
  • 27 Misra AK, Levy MM, Ward NS. Biomarkers of Immunosuppression. Crit Care Clin 2020; 36 (01) 167-176
  • 28 Zheng Z, Huang G, Gao T, Huang T, Zou M, Zou Y, Duan S. Epigenetic Changes Associated With Interleukin-10. Front Immunol 2020; 11: 1105
  • 29 Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014; 13 (03) 272-280
  • 30 Kisielewski R, Tołwińska A, Mazurek A, Laudański P. Inflammation and ovarian cancer–current views. Ginekol Pol 2013; 84 (04) 293-297
  • 31 Savant SS, Sriramkumar S, O'Hagan HM. The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer. Cancers (Basel) 2018; 10 (08) 251