title: The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma.
abstract: Endometrial cancer is the most common malignancy of the female genital tract, and the incidence and mortality rates from this disease are increasing. Although endometrial carcinoma has been regarded as a tissue-specific disease mediated by female sex steroid pathways, considerable evidence implicates a role for an inflammatory response in the development and propagation of endometrial cancer. We hypothesized that if specific patterns of cytokine expression were found to be predictive of adverse outcome, then selective receptor targeting may be a therapeutic option. This study was therefore undertaken to determine the relationship between cytokine production in primary cell culture and clinical outcome in endometrial adenocarcinoma. Fresh endometrial tissues were fractionated into epithelial and stromal fractions and cultured. After 6-7 days, supernatants were collected and cells enumerated. Batched aliquots were assayed using ELISA kits specific for CSF-1, GMCSF, G-CSF, TNF-α, IL-6, IL-8, and VEGF. Data were compared using ANOVA, Fisher's exact, and log rank tests. Increased epithelial VEGF production was observed more often in tumors with Type 2 variants (p = 0.039) and when GPR30 receptor expression was high (p = 0.038). Although increased stromal VEGF production was detected more often in grade 3 endometrioid tumors (p = 0.050), when EGFR expression was high (p = 0.003), and/or when ER/PR expression was low (p = 0.048), VEGF production did not correlated with overall survival (OS). Increased epithelial CSF-1 and TNF-α production, respectively, were observed more often in tumors with deep myometrial invasion (p = 0.014) and advanced stage (p = 0.018). Increased CSF-1 (89.5% vs. 42.9%, p = 0.032), TNF-α (88.9% vs. 42.9%, p = 0.032, and IL-6 (92.3% vs. 61.5%, p = 0.052) also correlated with low OS. In Cox multivariate models, CSF-1 was an independent predictor of low survival when stratified by grade (p = 0.046) and histology (p = 0.050), and TNF-α, when stratified by histology (p = 0.037). In this study, high CSF-1, TNF-α, and IL-6 production rates identified patients at greatest risk for death, and may signify patients likely to benefit from receptor-specific therapy.
authors.affiliation: Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Montefiore Medical Center, 3332 Rochambeau Avenue, Bronx, NY 10467, USA. hasmith@montefiore.org
authors.forename: Harriet O
authors.initials: HO
authors.lastname: Smith
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Stephens
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Qualls
authors.forename: Tal
authors.initials: T
authors.lastname: Fligelman
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Chang-Yun
authors.initials: CY
authors.lastname: Lin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Burton
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Griffith
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
mesh_terms: D000368:Aged; D016207:Cytokines / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008875:Middle Aged; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor