Clinical and Experimental Medicine

, Volume 18, Issue 4, pp 547–554 | Cite as

TNF-R2 in tumor microenvironment as prognostic factor in epithelial ovarian cancer

  • Rosekeila Simões NomeliniEmail author
  • Luciano Eliziário Borges Júnior
  • Cid Almeida de Lima
  • Ana Flávia Carrijo Chiovato
  • Douglas Côbo Micheli
  • Beatriz Martins Tavares-Murta
  • Eddie Fernando Candido Murta
Original Article


The aims of the study were to compare the levels of tumor necrosis factor alpha (TNF-α) and its soluble type I (sTNF-R1) and type II (sTNF-R2) receptors detected in intracystic liquid and serum from benign and malignant ovarian neoplasms and to relate them to prognostic factors in epithelial ovarian cancer. The patients were divided into benign ovarian neoplasms (n = 46) and malignant ovarian neoplasms (n = 17). The serum and intracystic samples were collected before and during surgery for ovarian cyst, respectively. The levels of TNF-α, sTNF-R1, and sTNF-R2 were measured using ELISA. Results were compared with the Mann–Whitney test. Concentration of sTNF-R2 in the intracystic samples collected from the malignant neoplasia was significantly higher than that of the benign neoplasias (p = 0.02). Higher intracystic levels of sTNF-R2 exhibited a significant association with tumor differentiation grades 2 and 3 (p = 0.0087). There was no statistical significance in relation to serum levels. Tumor microenvironment levels of sTNF-R2 may represent a factor of poor prognosis in epithelial ovarian cancer.


Tumor necrosis factor alpha Tumor necrosis factor receptor 1 Tumor necrosis factor receptor 2 Intracystic fluid Ovarian neoplasm Prognostic factor 



The authors wish to acknowledge the funding received from the CNPq, FUNEPU, and the FAPEMIG.

Funding source

The funding sources financed the purchase of the ELISA kits and the necessary equipment for the storage of the samples and the realization of the experiments in the laboratory.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest.

Ethical approval

The study was approved by the Research Ethics Committee (CEP) of UFTM, CAAE 30507414.5.0000.5154.

Informed consent

Consent was obtained from all patients involved in the study.


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Murta EF, Nomelini RS. Early diagnosis and predictors of malignancy of adnexal masses. Curr Opin Obstet Gynecol. 2006;18(1):14–9.CrossRefGoogle Scholar
  3. 3.
    Zhang F, Zhang ZL. The diagnostic value of transvaginal sonograph (TVS), color doppler, and serum tumor marker CA125, CEA, and AFP in ovarian cancer. Cell Biochem Biophys. 2015;72(2):353–7.CrossRefGoogle Scholar
  4. 4.
    Moyer VA. US Preventive, Services Task Force: screening for ovarian cancer: U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med. 2012;157(12):900–4.CrossRefGoogle Scholar
  5. 5.
    Zhu CS, Pinsky PF, Kramer BS, et al. The prostate, lung, colorectal, and ovarian cancer screening trial and its associated research resource. J Natl Cancer Inst. 2013;105(22):1684–93.CrossRefGoogle Scholar
  6. 6.
    Gupta M, Babic A, Beck AH, et al. TNF-α expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis? Hum Pathol. 2016;54:82–91.CrossRefGoogle Scholar
  7. 7.
    Murta BMT, Cunha Fde Q, Miranda R, et al. Differential tumor microenvironment in human ovarian cystic tumors. Tumori. 2004;90(5):491–7.CrossRefGoogle Scholar
  8. 8.
    Szlosarek PW, Grimshaw MJ, Kulbe H, et al. Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol Cancer Ther. 2006;5(2):382–90.CrossRefGoogle Scholar
  9. 9.
    Kulbe H, Thompson R, Wilson JL, et al. The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 2007;67(2):585–92.CrossRefGoogle Scholar
  10. 10.
    Sethi G, Sung B, Aggarwal BB. TNF: a master switch for inflammation to cancer. Front Biosci. 2008;13:5094–107.CrossRefGoogle Scholar
  11. 11.
    Charles KA, Kulbe H, Soper R, et al. The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest. 2009;119(10):3011–23.CrossRefGoogle Scholar
  12. 12.
    Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006;25(3):409–16.CrossRefGoogle Scholar
  13. 13.
    Dobrzycka B, Terlikowski SJ, Kowalczuk O, et al. Circulating levels of TNF-alpha and its soluble receptors in the plasma of patients with epithelial ovarian cancer. Eur Cytokine Netw. 2009;20(3):131–4.PubMedGoogle Scholar
  14. 14.
    Dobrzycka B, Terlikowski SJ, Garbowicz M, et al. Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer. Folia Histochem Cytobiol. 2009;47(4):609–13.PubMedGoogle Scholar
  15. 15.
    Murta EFC, Silva CS, Gomes RAS, et al. Ultrasonographic criteria and tumor marker assay are good procedures for the diagnosis of ovarian neoplasia in preselected outpatients. Eur J Gynaecol Oncol. 2004;25:707–12.PubMedGoogle Scholar
  16. 16.
    Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34(3):433–43.CrossRefGoogle Scholar
  17. 17.
    Ali-Fehmi R, Semaan A, Sethi S, et al. Molecular typing of epithelial ovarian carcinomas using inflammatory markers. Cancer. 2011;117(2):301.CrossRefGoogle Scholar
  18. 18.
    Kurman RJ, Shih IM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol. 2011;42(7):918–31.CrossRefGoogle Scholar
  19. 19.
    Giuntoli RL 2nd, Webb TJ, Zoso A, et al. Ovarian cancer-associated ascites demonstrates altered immune environment: implications for antitumor immunity. Anticancer Res. 2009;29:2875–84.PubMedGoogle Scholar
  20. 20.
    Mhawech-Fauceglia P, Wang D, Ali L, et al. Intraepithelial T cells and tumor-associated macrophages in ovarian cancer patients. Cancer Immun. 2013;13:1.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Aggarwal BB. Comparative analysis of the structure and function of TNF-a and TNF-j3. Immunol Ser. 1992;56:61–78.PubMedGoogle Scholar
  22. 22.
    Turetskaya RL, Fashena SJ, Paul NL, et al. Genomic structure, induction, and production of TNF-a. Immunol Ser. 1992;56:35–60.PubMedGoogle Scholar
  23. 23.
    Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today. 1992;13:151–3.CrossRefGoogle Scholar
  24. 24.
    Rothe J, Gehr G, Loetscher H, et al. Tumor necrosis factor receptors structure and function. Immunol Res. 1992;11:81–90.CrossRefGoogle Scholar
  25. 25.
    Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation and death. Cell. 1994;76:959–62.CrossRefGoogle Scholar
  26. 26.
    Sasi SP, Yan X, Enderling H, et al. Breaking the ‘harmony’ of TNF-α signaling for cancer treatment. Oncogene. 2012;31(37):4117–27.CrossRefGoogle Scholar
  27. 27.
    Anderson GM, Nakada MT, DeWitte M. Tumor necrosis factor alpha in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4:314–20.CrossRefGoogle Scholar
  28. 28.
    Gadducci A, Ferdeghini M, Castellani C, et al. Serum levels of tumor necrosis factor (TNF), soluble receptors for TNF (55- and 75-kDa sTNFr), and soluble CD14 (sCD14) in epithelial ovarian cancer. Gynecol Oncol. 1995;58:184–8.CrossRefGoogle Scholar
  29. 29.
    Radke J, Schmidt D, Böhme M, et al. Cytokine level in malignant ascites and peripheral blood of patients with advanced ovarian carcinoma. Geburtshilfe Frauenheilkd. 1996;56(2):83–7.CrossRefGoogle Scholar
  30. 30.
    Nowak M, Klink M, Glowacka E, et al. Production of cytokines during interaction of peripheral blood mononuclear cells with autologous ovarian cancer cells or benign ovarian tumour cells. Scand J Immunol. 2010;71(2):91–8.CrossRefGoogle Scholar
  31. 31.
    Mielczarek-Palacz A, Kondera-Anasz Z, Sikora J. Higher serum levels of tumour necrosis factor and its soluble receptors are associated with ovarian tumours. Arch Med Sci. 2012;8(5):848–53.CrossRefGoogle Scholar
  32. 32.
    Goto N, Tsurumi H, Takemura M, et al. Serum-soluble tumor necrosis factor receptor 2 (sTNF-R2) level determines clinical outcome in patients with aggressive non-Hodgkin’s lymphoma. Eur J Haematol. 2006;77(3):217–25.CrossRefGoogle Scholar
  33. 33.
    Kouklakis G, Efremidou EI, Pitiakoudis M, et al. Polychronidis, Development of primary malignant melanoma during treatment with a TNF-α antagonist for severe Crohn’s disease: a case report and review of the hypothetical association between TNF-α blockers and cancer. Drug Des Devel Ther. 2013;7:195–9.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Govindaraj C, Scalzo-Inguanti K, Madondo M, et al. Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2 + Tregs within the tumor microenvironment. Clin Immunol. 2014;149(1):97–110.CrossRefGoogle Scholar
  35. 35.
    Martins Filho A, Jammal MP, Côbo EC, et al. Correlation of cytokines and inducible nitric oxide synthase expression with prognostic factors in ovarian cancer. Immunol Lett. 2014;158(1–2):195–9.CrossRefGoogle Scholar
  36. 36.
    Jammal MP, Martins-Filho A, Silveira TP, et al. Cytokines and prognostic factors in epithelial ovarian cancer. Clin Med Insights Oncol. 2006;10:71–6.Google Scholar
  37. 37.
    Piura B, Medina L, Rabinovich A, et al. Distinct expression and localization of TNF system in ovarian carcinoma tissues: possible involvement of TNF-α in morphological changes of ovarian cancerous cells. Anticancer Res. 2014;34(2):745–52.PubMedGoogle Scholar
  38. 38.
    Kampan NC, Madondo MT, McNally OM, et al. Interleukin 6 present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells. Front Immunol. 2017;8:1482.CrossRefGoogle Scholar
  39. 39.
    Sasi SP, Bae S, Song J, et al. Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants. PLoS ONE. 2014;9(3):e92373.CrossRefGoogle Scholar
  40. 40.
    Chen X, Subleski JJ, Kopf H, et al. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4 + CD25 + FoxP3 + T regulatory cells: applicability to tumor-infiltrating T regulatory cells. J Immunol. 2008;180(10):6467–71.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Rosekeila Simões Nomelini
    • 1
    Email author
  • Luciano Eliziário Borges Júnior
    • 1
  • Cid Almeida de Lima
    • 1
  • Ana Flávia Carrijo Chiovato
    • 1
  • Douglas Côbo Micheli
    • 2
  • Beatriz Martins Tavares-Murta
    • 2
  • Eddie Fernando Candido Murta
    • 1
  1. 1.Research Institute of Oncology (IPON)/Discipline of Gynecology and ObstetricsFederal University of Triângulo MineiroUberabaBrazil
  2. 2.Discipline of PharmacologyFederal University of Triângulo MineiroUberabaBrazil

Personalised recommendations