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Imunomarcação epitelial e estromal de citocinas em neoplasias de ovárioNeoplasia ovariana.Citocinas.Estroma.Epitélio.Imuno-histoquímica.Fatores prognósticos.Ovarian neoplasm.Cytokines.Stroma.Epithelium.Immunohistochemical.Prognostic factors.Ciências da SaúdeObjetivos: Os objetivos do nosso estudo foram verificar as diferenças entre a marcação tecidual estromal e epitelial por imuno-histoquímica das citocinas (IL2, IL8, TNF-R1, IL-5, IL-6 e IL-10) entre neoplasias benignas e malignas primárias de ovário, e avaliar a relação entre marcação estromal e epitelial do câncer ovariano com fatores prognósticos clínicos e patológicos. Materiais e Métodos: Nós avaliamos prospectivamente 56 pacientes que se submeteram a tratamento cirúrgico por cisto ovariano, de acordo com critérios pré-estabelecidos e com diagnóstico confirmado de neoplasia ovariana. Foi feito o estudo imuno-histoquímico das citocinas (IL2, IL8, TNF-R1, IL-5, IL-6 e IL-10). Os fatores prognósticos foram avaliados usando o Teste Exato de Fisher. O nível de significância foi inferior a 0,05. Resultados: Das 56 pacientes avaliadas, 28 tinham neoplasias maligna de ovário e 28 benignas. As marcações imuno-histoquímicas de TNF-R1 (estroma e epitélio), IL5 (estroma e epitélio), e IL10 (somente estroma) foram mais fortes nas neoplasias benignas. A marcação de IL2 foi mais forte nas neoplasias malignas comparado às benignas. IL8 teve marcação imuno-histoquímica mais fraca no estroma das neoplasias benignas comparado ao câncer ovariano. Em relação à imunomarcação de IL6, não houve significância estatística. Na avaliação imuno-histoquímica de IL2 no estroma, o grau histológico 3 foi significativamente relacionado com imuno-histoquímica de marcação 2/3 (p=0,003). As marcações 2/3 de TNF-R1 foram relacionadas à sobrevida livre de doença ≤ 30 meses, sugerindo um fator de mau prognóstico (p=0,017). Não houve diferença significativa em relação a outras citocinas estudadas, tanto na avaliação do estroma como do epitélio.Objectives: The aims of this study were to determine whether there are differences in tissue stromal and epithelial staining by immunohistochemistry of cytokines (IL2, IL8, TNF-R1, IL-5, IL-6 and IL-10) between benign tumors and malignant primary ovarian tumors, and to evaluate the relationship of stromal and epithelial staining in ovarian cancer with clinical and pathological prognostic factors. Material and Methods: We evaluated prospectively 56 patients underwent surgical treatment for ovarian cysts in accordance with pre-established criteria and with confirmed diagnosis of ovarian neoplasm. Immunohistochemistry study for cytokines (IL2, IL5, IL6, IL8, IL10, TNF-alpha) was performed. The prognostic factors were evaluated using the Fisher’s exact test. The significance level was less than 0.05. Results: We evaluated 56 patients with ovarian neoplasm (28 malignant and 28 benign neoplasms). The immunohistochemical staining by TNF (stroma and epithelium), IL5 (stroma and epithelium) and IL10 (only stroma) were stronger in benign neoplasms. IL2 immunostaining was stronger in malignant tumors compared with benign tumors. IL8 immunostaining was weaker in the stroma of benign neoplasms compared with ovarian cancer. Regarding IL-6 immunostaining, there was no statistical significance. In evaluating of stromal IL2, the histological grade 3 was significantly correlated with immunohistochemical of score 2/3 (p=0.003). TNF-alpha immunohistochemical staining scores 2 or 3 was related to disease-free survival ≤ to 30 months, suggesting that it is a factor of poor prognosis (p=0.017). There was no statistical significance in relation at other cytokines studied, both in the evaluation of the stroma as the epithelium.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESFundação de Ensino e Pesquisa de Uberaba - FUNEPUFundação de Amparo a Pesquisa do Estado de Minas Gerais - FAPEMIGUniversidade Federal do Triângulo Mineiro - UFTMUniversidade Federal do Triângulo MineiroInstituto de Ciências da Saúde - ICS::Programa de Pós-Graduação em Ciências da SaúdeBrasilUFTMPrograma de Pós-Graduação em Ciências da SaúdeNOMELINI, Rosekeila Simões03651235602http://lattes.cnpq.br/0564643325267326MURTA, Eddie Fernando Candido47665032649http://lattes.cnpq.br/5724192420139830JAMMAL, Millena Prata2022-07-25T17:32:24Z2015-05-262022-07-25T17:32:24Z2015-05-26info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttp://bdtd.uftm.edu.br/handle/123456789/1344porAGARWAL, R.; KAYE, S. B. Prognostic factors in ovarian cancer: how close are we to a complete picture? Ann Oncol, v. 16, n. 1, p. 4-6, 2005. AKAHANE, T. et al. The origin of stroma surrounding epithelial ovarian cancer cells. Int J Gynecol Pathol, v. 32, n. 1, p. 26-30, 2013. AKAHIRO, J. et al. Impact of serum interleukin-18 level as a prognostic indicator in patients with epithelial ovarian carcinoma. Int J Clin Oncol, v. 9, n. 1, p. 42-46, 2004. ALI-FEHMI, R. et al. Molecular typing of epithelial ovarian carcinomas using inflammatory markers. Cancer, v. 117, n. 2, p. 301-309, 2011. ANDERSON, G. M.; NAKADA, M. T.; DeWITTE, M. Tumor necrosis factoralpha in the pathogenesis and treatment of cancer. Curr Opin Pharmacol, v. 4, p. 314-320, 2004. ARANGO, E. G. Bioestatística teórica e computacional . Rio de Janeiro: Guanabara Koogan, 2001. cap. 3, p. 104-103. BAGGIOLINI, M.; DEWALD, B.; MOSER, B. Interleukin 8 and related chemotactic cytokines – CXC and CC chemokines. Adv Immunol, v. 55, p. 97-179, 1994. BALKWILL, F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev, v. 25, n. 3, p. 409-416, 2006. BALKWILL, F. Tumor necrosis factor or tumor promoting factor: Cytokine Growth Factor Rev, v. 13, n. 2, p. 135–141, 2002. BALKWILL, F. Tumour necrosis factor and cancer. Nat Rev Cancer, v. 9, n. 5, p. 361-371, 2009. BALKWILL, F.; CHARLES, K. A.; MANTOVANI, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell, v. 7, p. 211–217, 2005. BARON, V. T. et al. Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer. Br J Cancer, v. 112, n. 4, p. 755-64, 2015. BELLONE, S. et al. High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer. Gynecol Oncol, v. 98, p. 92-98, 2005. BENOY, I. H. et al. Real-time RT–PCR correlates with immunocytochemistry for the detection of disseminated epithelial cells in bone marrow aspirates of patients with breast cancer. Br J Cancer, v. 91, p. 1813–1820, 2004. BERGHELLA, A. M. et al. Peripheral blood immunological parameters for use as markers of pre-invasive to invasive colorectal cancer. Cancer Biother Radiopharm, v.17, n. 1, p. 43-50, 2002. BERTAZZA, L.; MOCELLIN, S. Tumor necrosis factor (TNF) biology and cell death. Front Biosci, v. 13, p. 2736-2743, 2008. CHARLES, K. A. et al. The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest, v. 119, n. 10, p. 3011–3023, 2009. CORINTI, S. et al. Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol, v. 166, n.7, p. 4312-4318, 2001. DESPHANDE, R. R. et al. Alterations of cytokine production in follicular cyclic ovaries induced in mice by neonatal estradiol injection. Am J Reprod Immunol, v. 44, p. 80–8, 2000. DOBRZYCKA, B. et al. Circulating levels of TNF-α and its soluble receptors in the plasma of patients with epithelial ovarian cancer. Eur Cytokine Netw, v. 20, n. 3, p. 131-134, 2009. DRANOFF, G. R. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer, v. 4, n. 1, p. 11-22, 2004. DUBEAU, L. The cell of origin of ovarian epithelial tumours. Lancet Oncol, v.9, p. 1191–1197, 2008. DUDLEY, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science, v. 298, p. 850-854, 2002. EREZ, N. et al. Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors. Biochem Biophys Res Commun, v. 437, n. 3, p. 397-402, 2013. FATHALLA, M. F. Incessant ovulation: a factor in ovarian neoplasia? Lancet, v. 2, m. 7716, p. 163, 1971. GARNER, E. I. Advances in the early detection of ovarian carcinoma. J Reprod Med, v. 50, p. 447-453, 2005. GAVALAS, N. G. et al. Immune Response in Ovarian Cancer: How Is the Immune System Involved in Prognosis and Therapy: Potential for Treatment Utilization. Clinical and Developmental Immunology, ID 791603, 15 pages, 2010. GHESQUIERE, B. et al. Metabolism of stromal and immune cells in health and disease. Nature, v. 511, p. 167–176, 2014. GILKS, C. B. et al. Tumor cell type can reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol, v. 39, p. 1239–1251, 2008. GOTO, N. 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, v. 77, n. 3, p. 217-225, 2006. GRIMM, E. A. et al. Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells. J Exp Med, v. 158, n. 4, p. 1356-61, 1983. HAGEMANN, A. R. et al. Tissue-based immune monitoring II: Multiple tumor sites reveal immunologic homogeneity in serous ovarian carcinoma. Cancer Biol Ther, v. 12, n. 4, p. 367-377, 2011. HANAHAN, D.; WEINBERG, R. A. Hallmarks of cancer: the next generation. Cell, v. 144, p. 646–674, 2011. HUANG, R. et al. CD117 Expression in Fibroblasts-Like Stromal Cells Indicates Unfavorable Clinical Outcomes in Ovarian Carcinoma Patients. PLoS ONE, v. 9, n. 11, e112209, 2014. HUANG, R. et al. CD117 Expression in Fibroblasts-Like Stromal Cells Indicates Unfavorable Clinical Outcomes in Ovarian Carcinoma Patients. PLoS ONE, v. 9, n. 11, 2014. INSTITUTO NACIONAL DE CÂNCER JOSÉ ALENCAR GOMES DA SILVA. Estimativa 2014: incidência de câncer no Brasil. Disponível em:< http:// http://www.inca.gov.br/estimativa/2014/sintese-de-resultados-comentarios.asp>. Acesso em: 6 fev. 2015. JEMAL, A. et al. Cancer statistics. CA Cancer J Clin, v. 60, n. 5, p. 277–300, 2010. JIA, L. et al. Inhibitory role of prohibitin in human ovarian epithelial cancer. Int J Clin Exp Pathol, v. 7, n. 5, p. 2247-2255, 2014. KANG, Y. Imaging signaling pathways and tumor-stromal interactions in cancer metastasis. J Nucl Med, v. 54, p. 32–32, 2013. KASSIM, S. K. et al. Vascular endothelial growth factor and interleukin-8 are associated with poor prognosis in epithelial ovarian cancer patients. Clin Biochem, v, 37, p. 363-369, 2004. KO, S. Y.; NAORA, H. Therapeutic strategies for targeting the ovarian tumor stroma. World J Clin Cases, v. 2, n. 6, p. 194-200, 2014. KÖBEL, M. et al. Ovarian Carcinoma Subtypes Are Different Diseases: Implications for Biomarker Studies. PLoS Med, v. 5, n. 12, p. 1749-60, 2008. KOUKLAKIS, G. et al. 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, v. 7, p. 195-199, 2013. KOZLOWSKI, L. et al. Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst, v. 48, p. 82-84, 2003. KROCKENBERGER, M. et al. Macrophage Migration Inhibitory Factor (MIF) Contributes to the Immune Escape of Ovarian Cancer by Downregulating NKG2D1. J Immunol, v. 180, p. 7338-7348, 2008. KRYCZEK, I. et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol, v. 178, n. 11, p. 6730-6733, 2007. KURMAN, R. J.; SHIH, Ie-Ming. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer - Shifting the paradigm. Human Pathology, v. 42, n. 7, p. 918–931, 2011. KURMAN, R. J.; SHIH, Ie-Ming. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol, v. 34, n. 3, p. 433-443, 2010. LEBREC, H. et al. Tumor Necrosis Factor Inhibition, and Cancer Risk. Curr Med Res Opin, v. 4, p. 1-76, 2015. LEE, S. J. et al. Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A. PLoS One, v. 7, n. 9, e40267, 2012. LIN, E.; CALVANO, S. E.; LOWRY, S. F. Inflammatory cytokines and cell response in surgery. Surgery, v. 127, p. 117-126, 2000. LIU, M. et al. Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression. Mod Pathol, v. 22, n. 3, p. 373-84, 2009. MACCALLI, C.; SCARAMUZZA, S.; PARMINANI, G. TNK cells (NKG2D+ CD8+ or CD4+T lymphocytes) in control of human tumors. Cancer Immunol Immunother, v. 58, n. 801-808, 2009. MANTOVANI, A. Cancer: inflammation by remote control. Nature, v. 435, v. 7043, p. 752–753, 2005. MARJONIEMI, V. M. Immunohistochemistry in gynaecological pathology: a review. Pathology, v. 36, 109Y19, 2004. MATZINGER, P. The danger model: a renewed sense of self. Science, v. 296, n. 5566, p. 301-305, 2002. MCCLUGGAGE, W. G. Immunohistochemical and Functional Biomarkers of Value in Female Genital Tract Lesions. Int J Gynecol Pathol, v. 25, n. 2, 2006. MCCLUGGAGE, W. G. Recent advances in immunohistochemistry in the diagnosis of ovarian neoplasms. J Clin Pathol, v. 53, p. 327Y34, 2000. 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, v. 8, n. 5, p. 848-853, 2012. MILBURN, M. V. et al. A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5. Nature, v. 363, n. 6425, p. 172-176, 1993. MINAMI, Y. et al. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol, v. 11, p. 245-268, 1993. MOCELLIN, S.; WANG, E.; MARINCOLA, F. M. Cytokines and immune response in the tumor microenvironment. J Immunother, v. 24, p. 392-407, 2001. MOSER, M.; MURPHY, K. M. Dendritic cell regulation of TH1-TH2 development. Nat Immunol, v. 1, n. 3, p. 199-205, 2000. MURTA, E. F. C. et al. Ultrasonographic criteria and tumor marker assay are good procedures for the diagnosis of ovarian neoplasia in preselected outpatients. Eur J Gynaecol Oncol, v. 25, p. 707-712, 2004. MURTA, E. F. C.; NOMELINI, R. S. Early diagnosis and predictors of malignancy in the evaluation of adnexal mass. Curr Opin Obstet Gynecol, v. 18, p. 14-19, 2006. NARASIMHAN, K.; CHANGQING, Z.; CHOOLANI, M. Ovarian cancer proteomics: Many technologies one goal. Proteomics Clin Appl, v. 2, n. 2, p. 195-218, 2008. NISIDA, A. C. T. Câncer de ovário: Importância, epidemiologia e fatores de risco. In: Halbe HW. Tratado de Ginecologia. São Paulo: Roca [2000]. p.2242-2245. OLIVIER, R. L. et al. Ca 125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. Gynecol Oncol, v. 100, p. 20-26, 2006. OTSMAN, A,; AUGESTEN, M. Cancer-associated fibroblasts and tumor growth-bystanders turning into key players. Curr Opin Genet Dev, v. 19, p. 67-73, 2009. ÖZEL, E. et al. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in ovarian surface epithelial carcinomas: is there any correlation with angiogenesis or clinicopathologic parameters? Int J Gynecol Cancer, v. 16, p. 549–555, 2006. PADILLA, L. A.; RADOSEVICH, D. M.; MILAD, M. P. Limitations on the pelvic examination for evaluation of the female pelvic organs. Int J Gynaecol Obstet, v. 88, p. 84-88, 2005. PARTRIDGE, E. et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol, v. 113, n. 4, p. 775-782, 2009. PIEK, J. M. et al. Tubal ligation and risk of ovarian cancer. Lancet, v. 358, n. 9284, p. 358:844, 2001. PLEWKA, D. et al. Immunohistochemical visualization of pro-inflammatory cytokines and enzymes in ovarian tumors. Folia histochemica et cytobiologica, v. 52, n. 2, p. 124–137, 2014. RABINOVICH, A. et al. Expression of IL-10 in human normal and cancerous ovarian tissues and cells. Eur Cytokine Netw, v. 21, n. 2, p. 122-128, 2010. RASPOLLINI, M. R.; TADDEI, G. L. Tumor markers in ovarian carcinoma. Int J Gynecol Obstet, v. 97, p. 175–181, 2007. RESTIFO, N. P.; WUNDERLICH, J. R. Molecular biology of cancer: cancer immunology. In: DeVITA, V. T.; HELLMAN, S.; ROSENBERG, S. A. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins, p. 139, 2005. RIVOIRE, W. A. et al. Neoplasias de ovário e de trompa de Falópio. In: FREITAS, F.; MENKE, C.; RIVOIRE, W. A. Passos e Rotinas em Ginecologia. 5. ed. Porto Alegre: Ed Artmed, 2006, 362-384. ROETT, M. A.; EVANS, P. Ovarian cancer: an overview. Am Fam Physician, v. 80, n. 6, p. 609-616, 2009. SCAMBIA, G. et al. Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer, v. 71, n. 2, p. 354-356, 1995. SETHI, G.; SUNG, B.; AGGARWAL, B. B. TNF: a master switch for inflammation to cancer. Front Biosci, v. 13, p. 5094-5107, 2008. SICA, A. et al. Macrophage polarization in tumour progression. Semin Cancer Biol, v. 5, p. 349-355, 2008. SMITH, H. Clinical Management of Ovarian Cancer [book review]. N Engl J Med, v. 345, n. 2, p. 152-153, 2001. SMYTH, M. J. et al. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer, v. 2, p. 850-861, 2002. SOMMER. C.; WHITE, F. Cytokines, Chemokines, and Pain. In: BEAULIEU, P. et al. Pharmacology of Pain. 1st Ed, Seattle, ASP Press, p. 279-302, 2010. SZLOSAREK, P. W. et al. Aberrant regulation of argininosuccinate synthetase by TNF-alpha in human epithelial ovarian cancer. Int J Cancer, v. 121, p. 6-11, 2007. TABIBZADEH, S. S. et al. Interleukin-6 immunoreactivity in human tumors. Am J Pathol, v. 135, n. 3, p. 427–433, 1989. TAKATSU, K. et al. T cell-replacing factor (TRF)/interleukin 5 (IL5) molecular and functional propeties. Immunol Rev, v. 102, p. 107-135, 1988. TAVASSOLI, F. A.; DEVILEE, P. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press: Lyon 2003. TORRES, M. P. et al. Immunopathogenesis of ovarian cancer. Minerva Med, v. 100, n. 5, p. 385-400, 2009. VICARI, A. P.; TRINCHIERI, G. Interleukin-10 in viral diseases and cancer: exiting the labyrinth? Immunol Rev, v. 202, p. 223-236, 2004. WANG, X. et al. Ovarian cancer, the coagulation pathway, and inflammation. J Transl Med, v. 3, p. 25, 2005. WATANABE, T. et al. Serum Levels of Rapid Turnover Proteins Are Decreased and Related to Systemic Inflammation in Patients with Ovarian Cancer. Oncology Letters, v. 7, n. 2, p. 373–377, 2014. XU, L.; FIDLER, I. J. Interleukin 8: an autocrine growth factor for human ovarian cancer. Oncol Res, v. 12, p. 97–106, 2000. YANG, Ji-Yeon. et al. Predicting time to ovarian carcinoma recurrence using protein markers. J Clin Invest, v. 123, n. 9, p. 3740–3750, 2013. ZAJICEK, J. Prevention of ovarian cystomas by inhibition of ovulation: a new concept. J Reprod Med, v. 20, n. 2, p. 114, 1978. ZEPPERNICK, F.; MEINHOLD-HEERLEIN, I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal câncer. Arch Gynecol Obstet, v. 290, p. 839–842, 2014. ZHANG, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med, v. 348, n. 3, p. 203-213, 2003. ZHU, J.; PAUL, W. E. CD4 T cells: fates, functions, and faults. Blood, v. 112, n. 5, p. 1557-1569, 2008.info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFTMinstname:Universidade Federal do Triangulo Mineiro (UFTM)instacron:UFTM2022-07-26T02:02:32Zoai:bdtd.uftm.edu.br:123456789/1344Biblioteca Digital de Teses e Dissertaçõeshttp://bdtd.uftm.edu.br/PUBhttp://bdtd.uftm.edu.br/oai/requestbdtd@uftm.edu.br||bdtd@uftm.edu.bropendoar:2024-04-24T09:59:34.220763Biblioteca Digital de Teses e Dissertações da UFTM - Universidade Federal do Triangulo Mineiro (UFTM)false
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