TY - JOUR
T1 - The clinical significance of inflammatory cytokines in primary cell culture in endometrial carcinoma
AU - Smith, Harriet O.
AU - Stephens, Nicole D.
AU - Qualls, Clifford R.
AU - Fligelman, Tal
AU - Wang, Tao
AU - Lin, Chang Yun
AU - Burton, Elizabeth
AU - Griffith, Jeffrey K.
AU - Pollard, Jeffrey W.
N1 - Funding Information:
This work was supported by National Institutes of Health grant PAR-96-012 (HOS, NDS) , University of New Mexico School of Medicine Research Allocations Committee grant 4-12320 (HOS) , University of New Mexico School of Medicine Women's Health Research Center grant 2-35647 (HOS) , NIH Clinical and Translational Science Award (CSTA) #1UL1RR031977-01 (CRQ) , and Albert Einstein Cancer Center Pilot Project FRP 5-28-08 (HOS, JWP) .
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - CSF-1
KW - Endometrial carcinoma
KW - Inflammatory cytokines
KW - Macrophages
KW - Tumor microenvironment
KW - VEGF
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U2 - 10.1016/j.molonc.2012.07.002
DO - 10.1016/j.molonc.2012.07.002
M3 - Article
C2 - 22944067
AN - SCOPUS:84872501133
SN - 1574-7891
VL - 7
SP - 41
EP - 54
JO - Molecular Oncology
JF - Molecular Oncology
IS - 1
ER -