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.

HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs)

“…Further extending the current knowledge on the complex regulation of VEGF, our data suggest that GPER may contribute to the HIF-1α mediated transcriptional responses in hypoxic tumor microenvironment towards new blood vessel formation. Notably, an increased VEGF production was recently shown to parallel an elevated GPER expression in endometrial cancer patients with low survival rates [61]. These data in combination with our findings may suggest that in estrogen-dependent cancer cells diverse molecular mechanisms could converge on the production of cytokines and growth factors, promoting an enhancement of malignant epithelial growth and invasion through autocrine and/or paracrine pathways.…”

Tumor-Associated Macrophages: From Mechanisms to Therapy

“…High CSF1 concentrations in tumors are associated with poor prognosis and expression is often found at the leading edge of tumors (Laoui et al, 2011; Qian and Pollard, 2010). In endometrial cancer its synthesis by tumor cells is an independent predictor of poor overall survival (Smith et al, 2013). Consistent with these clinical observations, deletion of CSF1 genetically from several models of cancer results in delayed initiation (cervical), progression (breast, pancreas) and metastasis (breast) associated with the loss of TAMs.…”

GPER Mediates Activation of HIF1α/VEGF Signaling by Estrogens

“…Interestingly, our data may recall previous findings showing that the ER antagonist and GPER agonist OHT (4, 7) is able to upregulate VEGF in different tumor types, including breast cancer (40,41). In addition, it has been recently reported that low survival rates in patients with endometrial cancer are associated with both elevated GPER expression and VEGF levels (42), further providing a relationship between these 2 main players of tumor cells and the surrounding stroma.…”