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The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications—a review

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Abstract

An increasing number of studies emphasize the role of inflammation and metabolic changes in the induction of cancer-related symptoms, which can affect cancer evolution and prognosis. These changes result from the interactions between the tumor and the host. To date, however, markers of this peculiar condition, which can help clinicians to manage patients better, have still not been identified with certainty. Epithelial ovarian cancer (EOC) appears to be particularly appropriate to study these interactions because of its biological characteristics, its peculiar evolution, and the relevant scientific evidence available. Immunosuppression, anemia, depression, and weight loss affect the evolution of EOC and appear to be directly related to the immune-metabolic changes. In light of the aforementioned evidence, our review will focus on interleukin-6 (IL-6) and its role as potential marker of the patients’ immune-metabolic status, to better monitor disease outcome and identify the most appropriate therapeutic strategy in EOC. Furthermore, leptin will be discussed as a sensor of the changes of energy metabolism induced by IL-6.

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References

  1. Macciò A, Madeddu C, Massa D, Astara G, Farci D, Melis GB, Mantovani G (2009) Interleukin-6 and leptin as markers of energy metabolic changes in advanced ovarian cancer patients. J Cell Mol Med 13:3951–3959

    PubMed  Google Scholar 

  2. Gadducci A, Cosio S, Fanucchi A, Genazzani AR (2001) Malnutrition and cachexia in ovarian cancer patients: pathophysiology and management. Anticancer Res 21:2941–2497

    CAS  PubMed  Google Scholar 

  3. Goff B (2012) Symptoms associated with ovarian cancer. Clin Obstet Gynecol 55:36–42

    PubMed  Google Scholar 

  4. Cravo ML, Glória LM, Claro I (2000) Metabolic responses to tumour disease and progression: tumour-host interaction. Clin Nutr 19:459–465

    CAS  PubMed  Google Scholar 

  5. Morrison SD (1971) Partition of energy expenditure between host and tumor. Cancer Res 31:98–107

    CAS  PubMed  Google Scholar 

  6. Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 267:543–560

    CAS  PubMed  Google Scholar 

  7. Warburg O, Wind F, Negelein E (1926) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    Google Scholar 

  8. Fabian C, Koetz L, Favaro E, Indraccolo S, Mueller-Klieser W, Sattler UG (2012) Protein profiles in human ovarian cancer cell lines correspond to their metabolic activity and to metabolic profiles of respective tumor xenografts. FEBS J 279:882–891

    CAS  PubMed  Google Scholar 

  9. Maciver NJ, Jacobs SR, Wieman HL, Wofford JA, Coloff JL, Rathmell JC (2008) Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol 84:949–957

    PubMed  Google Scholar 

  10. Halliwell B (2012) Free radicals and antioxidants: updating a personal view. Nutr Rev 70:257–265

    PubMed  Google Scholar 

  11. Kirsch M, De Groot H (2001) NAD(P)H, a directly operating antioxidant? FASEB J 15:1569–1574

    CAS  PubMed  Google Scholar 

  12. Scott BC, Aruoma OI, Evans PJ, O’Neill C, Van der Vliet A, Cross CE, Tritschler H, Halliwell B (1994) Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic Res 20:119–133

    CAS  PubMed  Google Scholar 

  13. Bennani-Baiti N, Davis MP (2008) Cytokines and cancer anorexia cachexia syndrome. Am J Hosp Palliat Care 25:407–411

    PubMed  Google Scholar 

  14. Macciò A, Lai P, Santona MC, Pagliara L, Melis GB, Mantovani G (1998) High serum levels of soluble IL-2 receptor, cytokines, and C reactive protein correlate with impairment of T cell response in patients with advanced epithelial ovarian cancer. Gynecol Oncol 69:248–252

    PubMed  Google Scholar 

  15. Scambia G, Testa U, Benedetti Panici P, Foti E, Martucci R, Gadducci A, Perillo A, Facchini V, Peschle C, Mancuso S (1995) Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 71:354–356

    CAS  PubMed  Google Scholar 

  16. Scambia G, Testa U, Panici PB, Martucci R, Foti E, Petrini M, Amoroso M, Masciullo V, Peschle C, Mancuso S (1994) Interleukin-6 serum levels in patients with gynecological tumors. Int J Cancer 57:318–323

    CAS  PubMed  Google Scholar 

  17. Plante M, Rubin SC, Wong GY, Federici MG, Finstad CL, Gastl GA (1994) Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer 73:1882–1888

    CAS  PubMed  Google Scholar 

  18. Lane D, Matte I, Rancourt C, Piché A (2011) Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients. BMC Cancer 11:210

    CAS  PubMed  Google Scholar 

  19. Van der Zee AG, de Cuyper EM, Limburg PC, de Bruijn HW, Hollema H, Bijzet J, Krans M, de Vries EG (1995) Higher levels of interleukin-6 in cystic fluids from patients with malignant versus benign ovarian tumors correlate with decreased hemoglobin levels and increased platelet counts. Cancer 75:1004–1009

    PubMed  Google Scholar 

  20. Nowak M, Glowacka E, Szpakowski M, Szyllo K, Malinowski A, Kulig A, Tchorzewski H, Wilczynski J (2010) Proinflammatory and immunosuppressive serum, ascites and cyst fluid cytokines in patients with early and advanced ovarian cancer and benign ovarian tumors. Neuro Endocrinol Lett 31:375–383

    CAS  PubMed  Google Scholar 

  21. Coward JI, Kulbe H (2012) The role of interleukin-6 in gynaecological malignancies. Cytokine Growth Factor Rev 23:333–342

    CAS  PubMed  Google Scholar 

  22. Guo Y, Xu F, Lu T, Duan Z, Zhang Z (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 38:904–910

    CAS  PubMed  Google Scholar 

  23. Dijkgraaf EM, Welters MJ, Nortier JW, van der Burg SH, Kroep JR (2012) Interleukin-6/interleukin-6 receptor pathway as a new therapy target in epithelial ovarian cancer. Curr Pharm Des 18:3816–3827

    CAS  PubMed  Google Scholar 

  24. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20

    CAS  PubMed  Google Scholar 

  25. Alberti C, Pinciroli P, Valeri B, Ferri R, Ditto A, Umezawa K, Sensi M, Canevari S, Tomassetti A (2012) Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer. Oncogene 31:4139–4149

    CAS  PubMed  Google Scholar 

  26. Liu J, Yang G, Thompson-Lanza JA, Glassman A, Hayes K, Patterson A, Marquez RT, Auersperg N, Yu Y, Hahn WC et al (2004) A genetically defined model for human ovarian cancer. Cancer Res 64:1655–1663

    CAS  PubMed  Google Scholar 

  27. Wang Y, Li L, Guo X, Jin X, Sun W, Zhang X, Xu RC (2012) Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine 59:228–236

    CAS  PubMed  Google Scholar 

  28. Rabinovich A, Medina L, Piura B, Segal S, Huleihel M (2007) Regulation of ovarian carcinoma SKOV-3 cell proliferation and secretion of MMPs by autocrine IL-6. Anticancer Res 27:267–272

    CAS  PubMed  Google Scholar 

  29. Nilsson MB, Langley RR, Fidler IJ (2005) Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res 65:10794–10800

    CAS  PubMed  Google Scholar 

  30. Coward J, Kulbe H, Chakravarty P, Leader D, Vassileva V, Leinster DA, Thompson R, Schioppa T, Nemeth J, Vermeulen J et al (2011) Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res 17:6083–6096

    CAS  PubMed  Google Scholar 

  31. Hagemann T, Robinson SC, Thompson RG, Charles K, Kulbe H, Balkwill FR (2007) Ovarian cancer cell-derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis. Mol Cancer Ther 6:1993–2002

    CAS  PubMed  Google Scholar 

  32. Berek JS, Chung C, Kaldi K, Watson JM, Knox RM, Martínez-Maza O (1991) Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer. Am J Obstet Gynecol 164:1038–1042

    CAS  PubMed  Google Scholar 

  33. Wang Y, Niu XL, Qu Y, Wu J, Zhu YQ, Sun WJ, Li LZ (2010) Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett 295:110–123

    CAS  PubMed  Google Scholar 

  34. Tempfer C, Zeisler H, Sliutz G, Haeusler G, Hanzal E, Kainz C (1997) Serum evaluation of interleukin-6 in ovarian cancer patients. Gynecol Oncol 66:27–30

    CAS  PubMed  Google Scholar 

  35. Yigit R, Figdor CG, Zusterzeel PL, Pots JM, Torensma R, Massuger LF (2011) Cytokine analysis as a tool to understand tumour–host interaction in ovarian cancer. Eur J Cancer 47:1883–1889

    CAS  PubMed  Google Scholar 

  36. Mantovani G, Macciò A, Madeddu C, Mura L, Gramignano G, Lusso MR, Mulas C, Mudu MC, Murgia V, Camboni P et al (2002) Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status. Int J Cancer 98:84–91

    CAS  PubMed  Google Scholar 

  37. Macciò A, Madeddu C, Massa D, Mudu MC, Lusso MR, Gramignano G, Serpe R, Melis GB, Mantovani G (2005) Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood 106:362–367

    PubMed  Google Scholar 

  38. Procaccini C, Jirillo E, Matarese G (2012) Leptin as an immunomodulator. Mol Aspects Med 33:35–45

    CAS  PubMed  Google Scholar 

  39. Mantovani G, Macciò A, Mura L, Massa E, Mudu MC, Mulas C, Lusso MR, Madeddu C, Dessì A (2000) Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J Mol Med 78:554–561

    CAS  PubMed  Google Scholar 

  40. Mantovani G, Macciò A, Madeddu C, Mura L, Massa E, Mudu MC, Mulas C, Lusso MR, Gramignano G, Piras MB (2001) Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. J Mol Med 79:406–414

    CAS  PubMed  Google Scholar 

  41. Aleman MR, Santolaria F, Batista N, de La Vega M, Gonzalez-Reimers E, Milena A, Llanos M, Gómez-Sirvent JL (2002) Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the status of nutrition? Cytokine 19:21–26

    CAS  PubMed  Google Scholar 

  42. Macciò A, Madeddu C (2012) Inflammation and ovarian cancer. Cytokine 58:133–147

    PubMed  Google Scholar 

  43. Bode JG, Albrecht U, Häussinger D, Heinrich PC, Schaper F (2012) Hepatic acute phase proteins—regulation by IL-6- and IL-1-type cytokines involving STAT3 and its crosstalk with NF-κB-dependent signaling. Eur J Cell Biol 91:496–505

    CAS  PubMed  Google Scholar 

  44. Heinrich PC, Castell JV, Andus T (1990) Interleukin-6 and the acute phase response. Biochem J 265:621–636

    CAS  PubMed  Google Scholar 

  45. Stone RL, Nick AM, McNeish IA, Balkwill F, Han HD, Bottsford-Miller J, Rupairmoole R, Armaiz-Pena GN, Pecot CV, Coward J et al (2012) Paraneoplastic thrombocytosis in ovarian cancer. N Engl J Med 366:610–618

    CAS  PubMed  Google Scholar 

  46. Macciò A, Madeddu C, Gramignano G, Mulas C, Sanna E, Mantovani G (2010) Efficacy and safety of oral lactoferrin supplementation in combination with rHuEPO-beta for the treatment of anemia in advanced cancer patients undergoing chemotherapy: open-label, randomized controlled study. Oncologist 15:894–902

    PubMed  Google Scholar 

  47. Macciò A, Madeddu C, Gramignano G, Mulas C, Floris C, Sanna E, Cau MC, Panzone F, Mantovani G (2012) A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecol Oncol 124:417–425

    PubMed  Google Scholar 

  48. Jehn CF, Kühnhardt D, Bartholomae A, Pfeiffer S, Schmid P, Possinger K, Flath BC, Lüftner D (2010) Association of IL-6, hypothalamus–pituitary–adrenal axis function, and depression in patients with cancer. Integr Cancer Ther 9:270–275

    CAS  PubMed  Google Scholar 

  49. Arden-Close E, Gidron Y, Moss-Morris R (2008) Psychological distress and its correlates in ovarian cancer: a systematic review. Psychooncology 17:1061–1072

    PubMed  Google Scholar 

  50. Norton TR, Manne SL, Rubin S, Carlson J, Hernandez E, Edelson MI, Rosenblum N, Warshal D, Bergman C (2004) Prevalence and predictors of psychological distress among women with ovarian cancer. J Clin Oncol 22:919–926

    PubMed  Google Scholar 

  51. Costanzo ES, Lutgendorf SK, Sood AK, Anderson B, Sorosky J, Lubaroff DM (2005) Psychosocial factors and interleukin-6 among women with advanced ovarian cancer. Cancer 104:305–313

    PubMed  Google Scholar 

  52. Lutgendorf SK, Weinrib AZ, Penedo F, Russell D, DeGeest K, Costanzo ES, Henderson PJ, Sephton SE, Rohleder N, Lucci JA 3rd et al (2008) Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients. J Clin Oncol 26:4820–4827

    CAS  PubMed  Google Scholar 

  53. Schrepf A, Clevenger L, Christensen D, Degeest K, Bender D, Ahmed A, Goodheart MJ, Dahmoush L, Penedo F, Lucci JA 3rd et al (2012) Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability. Brain Behav Immun. doi:10.1016/j.bbi.2012.07.022

    Google Scholar 

  54. Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89:381–410

    CAS  PubMed  Google Scholar 

  55. Semaan A, Munkarah AR, Arabi H, Bandyopadhyay S, Seward S, Kumar S, Qazi A, Hussein Y, Morris RT, Ali-Fehmi R (2011) Expression of GLUT-1 in epithelial ovarian carcinoma: correlation with tumor cell proliferation, angiogenesis, survival and ability to predict optimal cytoreduction. Gynecol Oncol 121:181–186

    CAS  PubMed  Google Scholar 

  56. Gerriets VA, Rathmell JC (2012) Metabolic pathways in T cell fate and function. Trends Immunol 33:168–173

    CAS  PubMed  Google Scholar 

  57. Mazurek S (2011) Pyruvate kinase type M2: a key regulator of the metaolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980

    CAS  PubMed  Google Scholar 

  58. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51–56

    CAS  PubMed  Google Scholar 

  59. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    CAS  PubMed  Google Scholar 

  60. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–989

    CAS  PubMed  Google Scholar 

  61. Bongaerts GP, van Halteren HK, Verhagen CA, Wagener DJ (2006) Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism. Med Hypotheses 67:1213–1222

    CAS  PubMed  Google Scholar 

  62. Lundholm K, Edström S, Karlberg I, Ekman L, Scherstén T (1982) Glucose turnover, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients. Cancer 50:1142–1150

    CAS  PubMed  Google Scholar 

  63. Eden E, Edstrom S, Bennegard K, Schersten T, Lundholm K (1984) Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res 44:1718–1724

    CAS  PubMed  Google Scholar 

  64. Carson JA, Baltgalvis KA (2010) Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev 38:168–176

    PubMed  Google Scholar 

  65. Zhong Z, Wen Z, Darnell JE (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98

    CAS  PubMed  Google Scholar 

  66. Demaria M, Giorgi C, Lebiedzinska M, Esposito G, D’Angeli L, Bartoli A, Gough DJ, Turkson J, Levy DE, Watson CJ et al (2010) A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction. Aging 2:823–842

    CAS  PubMed  Google Scholar 

  67. Tomiyama A, Serizawa S, Tachibana K, Sakurada K, Samejima H, Kuchino Y, Kitanaka C (2006) Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors Bax and Bak. J Natl Cancer Inst 98:1462–1473

    CAS  PubMed  Google Scholar 

  68. Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402

    CAS  PubMed  Google Scholar 

  69. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994

    CAS  PubMed  Google Scholar 

  70. Feuerecker B, Pirsig S, Seidl C, Aichler M, Feuchtinger A, Bruchelt G, Senekowitsch-Schmidtke R (2012) Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol Ther 13:1425–1435

    CAS  PubMed  Google Scholar 

  71. Blumberg D, Hochwald S, Brennan MF, Burt M (1995) Interleukin-6 stimulates gluconeogenesis in primary cultures of rat hepatocytes. Metabolism 44:145–146

    CAS  PubMed  Google Scholar 

  72. Lundholm K, Edström S, Ekman L, Karlberg I, Scherstén T (1981) Metabolism in peripheral tissues in cancer patients. Cancer Treat Rep 65(Suppl 5):79–83

    PubMed  Google Scholar 

  73. Argilés JM, López-Soriano FJ (1999) The role of cytokines in cancer cachexia. Med Res Rev 19:223–248

    PubMed  Google Scholar 

  74. Kim TH, Choi SE, Ha ES, Jung JG, Han SJ, Kim HJ, Kim DJ, Kang Y, Lee KW (2011) IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle. Acta Diabetol. doi:10.1007/s00592-011-0259-z

    Google Scholar 

  75. Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, Koniaris LG, Zimmers TA (2012) JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 303:E410–E421

    CAS  PubMed  Google Scholar 

  76. Gercel-Taylor C, Doering DL, Kraemer FB, Taylor DD (1996) Aberrations in normal systemic lipid metabolism in ovarian cancer patients. Gynecol Oncol 60:35–41

    CAS  PubMed  Google Scholar 

  77. Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK (2004) Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 89:5577–5582

    CAS  PubMed  Google Scholar 

  78. Patra SK, Arora S (2012) Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome. Clin Chim Acta 413:1025–1034

    CAS  PubMed  Google Scholar 

  79. Inui A (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59:4493–4501

    CAS  PubMed  Google Scholar 

  80. Señarís RM, Trujillo ML, Navia B, Comes G, Ferrer B, Giralt M, Hidalgo J (2011) Interleukin-6 regulates the expression of hypothalamic neuropeptides involved in body weight in a gender-dependent way. J Neuroendocrinol 23:675–686

    PubMed  Google Scholar 

  81. Hoene M, Weigert C (2010) The stress response of the liver to physical exercise. Exerc Immunol Rev 16:163–183

    PubMed  Google Scholar 

  82. Das UN (2006) Is pyruvate an endogenous anti-inflammatory molecule? Nutrition 22:965–972

    CAS  PubMed  Google Scholar 

  83. Fink MP (2007) Ethyl pyruvate: a novel treatment for sepsis. Curr Drug Targets 8:515–518

    CAS  PubMed  Google Scholar 

  84. Wen H, Ting JP, O’Neill LA (2012) A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation? Nat Immunol 13:352–357

    CAS  PubMed  Google Scholar 

  85. Yoon S, Woo SU, Kang JH, Kim K, Kwon MH, Park S, Shin HJ, Gwak HS, Chwae YJ (2010) STAT3 transcriptional factor activated by reactive oxygen species induces IL-6 in starvation-induced autophagy of cancer cells. Autophagy 6:1125–1138

    CAS  PubMed  Google Scholar 

  86. Goossens GH, Blaak EE, Theunissen R, Duijvestijn AM, Clément K, Tervaert JW, Thewissen MM (2012) Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Mol Immunol 50:142–149

    CAS  PubMed  Google Scholar 

  87. Lee MJ, Fried SK (2009) Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296:E1230–E1238

    CAS  PubMed  Google Scholar 

  88. Morris DL, Rui L (2009) Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297:E1247–E1259

    CAS  PubMed  Google Scholar 

  89. Levy JR, Stevens W (2001) The effects of insulin, glucose, and pyruvate on the kinetics of leptin secretion. Endocrinology 142:3558–3562

    CAS  PubMed  Google Scholar 

  90. Cammisotto PG, Gélinas Y, Deshaies Y, Bukowiecki LJ (2005) Regulation of leptin secretion from white adipocytes by insulin, glycolytic substrates, and amino acids. Am J Physiol Endocrinol Metab 289:E166–E171

    CAS  PubMed  Google Scholar 

  91. Visintin I, Feng Z, Longton G, Ward DC, Alvero AB, Lai Y, Tenthorey J, Leiser A, Flores-Saaib R, Yu H et al (2008) Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res 14:1065–1072

    CAS  PubMed  Google Scholar 

  92. Mor G, Visintin I, Lai Y, Zhao H, Schwartz P, Rutherford T, Yue L, Bray-Ward P, Ward DC (2005) Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci U S A 102:7677–7682

    CAS  PubMed  Google Scholar 

  93. Matte I, Lane D, Laplante C, Rancourt C, Piché A (2012) Profiling of cytokines in human epithelial ovarian cancer ascites. Am J Cancer Res 2:566–580

    CAS  PubMed  Google Scholar 

  94. Hwang J, Na S, Lee H, Lee D (2009) Correlation between preoperative serum levels of five biomarkers and relationships between these biomarkers and cancer stage in epithelial ovarian cancer. J Gynecol Oncol 20:169–175

    CAS  PubMed  Google Scholar 

  95. Preston CC, Goode EL, Hartmann LC, Kalli KR, Knutson KL (2011) Immunity and immune suppression in human ovarian cancer. Immunotherapy 3:539–556

    PubMed  Google Scholar 

  96. Yigit R, Massuger LF, Figdor CG, Torensma R (2010) Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecol Oncol 117:366–372

    CAS  PubMed  Google Scholar 

  97. Gavalas NG, Karadimou A, Dimopoulos MA, Bamias A (2010) Immune response in ovarian cancer: how is the immune system involved in prognosis and therapy: potential for treatment utilization. Clin Dev Immunol 2010:791603

    PubMed  Google Scholar 

  98. Kusuda T, Shigemasa K, Arihiro K, Fujii T, Nagai N, Ohama K (2005) Relative expression levels of Th1 and Th2 cytokine mRNA are independent prognostic factors in patients with ovarian cancer. Oncol Rep 13:1153–1158

    CAS  PubMed  Google Scholar 

  99. Vermeij R, de Bock GH, Leffers N, Ten Hoor KA, Schulze U, Hollema H, van der Burg SH, van der Zee AG, Daemen T, Nijman HW (2011) Tumor-infiltrating cytotoxic T lymphocytes as independent prognostic factor in epithelial ovarian cancer with wilms tumor protein 1 overexpression. J Immunother 34:516–523

    CAS  PubMed  Google Scholar 

  100. Tomsová M, Melichar B, Sedláková I, Steiner I (2008) Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol 108:415–420

    PubMed  Google Scholar 

  101. Mantovani G, Macciò A, Pisano M, Versace R, Lai P, Esu S, Massa E, Ghiani M, Dessì D, Melis GB et al (1997) Tumor-associated lympho-monocytes from neoplastic effusions are immunologically defective in comparison with patient autologous PBMCs but are capable of releasing high amounts of various cytokines. Int J Cancer 71:724–731

    CAS  PubMed  Google Scholar 

  102. Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL (1996) Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res 2:161–173

    CAS  PubMed  Google Scholar 

  103. Giuntoli RL 2nd, Webb TJ, Zoso A, Rogers O, Diaz-Montes TP, Bristow RE, Oelke M (2009) Ovarian cancer-associated ascites demonstrates altered immune environment: implications for antitumor immunity. Anticancer Res 29:2875–2884

    CAS  PubMed  Google Scholar 

  104. Jeannin P, Duluc D, Delneste Y (2011) IL-6 and leukemia-inhibitory factor are involved in the generation of tumor-associated macrophage: regulation by IFN-c. Immunotherapy 3:23–26

    CAS  PubMed  Google Scholar 

  105. Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N et al (2007) Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood 110:4319–4330

    CAS  PubMed  Google Scholar 

  106. Robinson-Smith TM, Isaacsohn I, Mercer CA, Zhou M, Van Rooijen N, Husseinzadeh N (2007) Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. Cancer Res 67:5708–5716

    CAS  PubMed  Google Scholar 

  107. Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C, Balkwill FR (2005) Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol 175:1197–1205

    CAS  PubMed  Google Scholar 

  108. Nowak M, Klink M, Glowacka E, Sulowska Z, Kulig A, Szpakowski M, Szyllo K, Tchorzewski H (2010) Production of cytokines during interaction of peripheral blood mononuclear cells with autologous ovarian cancer cells or benign ovarian tumour cells. Scand J Immunol 71:91–98

    CAS  PubMed  Google Scholar 

  109. Wang H, Xie X, Lu WG, Ye DF, Chen HZ, Li X, Cheng Q (2004) Ovarian carcinoma cells inhibit T cell proliferation: suppression of IL-2 receptor beta and gamma expression and their JAK-STAT signaling pathway. Life Sci 74:1739–1749

    CAS  PubMed  Google Scholar 

  110. Tormo AJ, Letellier MC, Sharma M, Elson G, Crabé S, Gauchat JF (2012) IL-6 activates STAT5 in T cells. Cytokine 60:575–562

    CAS  PubMed  Google Scholar 

  111. Tanaka M, Suganami T, Kim-Saijo M, Toda C, Tsuiji M, Ochi K, Kamei Y, Minokoshi Y, Ogawa Y (2011) Role of central leptin signaling in the starvation-induced alteration of B-cell development. J Neurosci 31:8373–8380

    CAS  PubMed  Google Scholar 

  112. Matarese G, Sanna V, Fontana S, Zappacosta S (2002) Leptin as a novel therapeutic target for immune intervention. Curr Drug Targets Inflamm Allergy 1:13–22

    CAS  PubMed  Google Scholar 

  113. Tschöp J, Nogueiras R, Haas-Lockie S, Kasten KR, Castañeda TR, Huber N, Guanciale K, Perez-Tilve D, Habegger K, Ottaway N et al (2010) CNS leptin action modulates immune response and survival in sepsis. J Neurosci 30:6036–6047

    PubMed  Google Scholar 

  114. Obermair A, Handisurya A, Kaider A, Sevelda P, Kölbl H, Gitsch G (1998) The relationship of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients: a prospective review. Cancer 83:726–723

    CAS  PubMed  Google Scholar 

  115. Macciò A, Madeddu C (2012) Management of anemia of inflammation in the elderly. Anemia 2012:563251

    PubMed  Google Scholar 

  116. Kim JH, Lee JM, Ryu KS, Lee YS, Park YG, Hur SY, Lee KH, Lee SH (2011) The prognostic impact of duration of anemia during chemotherapy in advanced epithelial ovarian cancer. Oncologist 16:1154–1161

    CAS  PubMed  Google Scholar 

  117. Spivak JL (2000) The blood in systemic disorders. Lancet 355:1707–1712

    CAS  PubMed  Google Scholar 

  118. Morceau F, Dicato M, Diederich M (2009) Pro-inflammatory cytokine-mediated anemia: regarding molecular mechanisms of erythropoiesis. Mediat Inflamm 2009:405016

    CAS  Google Scholar 

  119. Andrews NC (2004) Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 113:1251–1253

    CAS  PubMed  Google Scholar 

  120. Wrighting DM, Andrews NC (2006) Interleukin-6 induces hepcidin expression through STAT3. Blood 108:3204–3209

    CAS  PubMed  Google Scholar 

  121. Neumcke I, Schneider B, Fandrey J, Pagel H (1999) Effects of pro- and antioxidative compounds on renal production of erythropoietin. Endocrinology 140:641–645

    CAS  PubMed  Google Scholar 

  122. Schrijvers D, De Samblanx H, Roila F; ESMO Guidelines Working Group (2010) Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use. Ann Oncol 21:v244–v247

    Google Scholar 

  123. Aapro M, Österborg A, Gascón P, Ludwig H, Beguin Y (2012) Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol 23:1954–1962

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors wish to thank Maria Leo for her assistance in preparing the illustrations of the paper. Work supported by the “Associazione Sarda per la ricerca nell’Oncologia Ginecologica-ONLUS.” Work in collaboration with TEVA Italia.

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Authors and Affiliations

  1. Department of Gynecologic Oncology, “A. Businco” Hospital, Regional Referral Center for Cancer Disease, via Edward Jenner, 09121, Cagliari, Italy

    Antonio Macciò

  2. Department of Medical Sciences “Mario Aresu”, University of Cagliari, Cagliari, Italy

    Clelia Madeddu

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  1. Antonio Macciò
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  2. Clelia Madeddu
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Correspondence to Antonio Macciò.

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Macciò, A., Madeddu, C. The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications—a review. J Mol Med 91, 1355–1368 (2013). https://doi.org/10.1007/s00109-013-1080-7

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  • DOI: https://doi.org/10.1007/s00109-013-1080-7

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