IL-6 is known as a pleotropic cytokine implicated in EOC carcinogenesis. It influences EOC growth and development through direct and indirect effects on tumor cells or their microenvironment, respectively [
4,
5]. As such, IL-6 has been indicated to promote EOC cell proliferation, migration, invasion, survival and resistance to chemotherapeutic agents [
9,
10,
16]. Reports show that IL-6 contributes to the development of EOC-induced malignant ascites [
8]. Here, we demonstrated that IL-6 was expressed at higher levels in human EOC tissues than in normal ovarian tissues. In agreement, increased tumoral expression [
17] and high serum [
18,
19] or ascetic [
20] levels of IL-6 have been reported in patients with EOC. Accordingly, clinicopathological relevance of intratumoral, serum or ascitic IL-6 in EOC has been investigated [
18‐
25]. Plewka et al. [
26] observed that malignant serous tumors had higher expression levels of IL-6 as compared with serous borderline and benign lesions. Guo et al. [
27] reported a significant difference in immunohistochemical expressions of IL-6 among the metastatic, drug-resistant recurrent tumors, and matched primary tumors, with more staining density and positivity observed in the drug-resistant and metastatic tumors. In another study by Coward et al. [
28], intensity of IL-6 staining in malignant cells was found to be significantly associated with poor prognosis. Similarly, a link between high levels of serum or ascitic IL-6 and unfavorable clinical outcome has been reported. In this regard, serum IL-6 has shown significant association with tumor burden, clinical disease status, and survival [
21,
22], as well as prognostic value [
25], in EOC. In a study by Scambia et al. [
29], higher levels of serum IL-6 was found in patients unresponsive to chemotherapy. In line with these findings, Cohen et al. [
30] found that cisplatin treatment of EOC cells upregulated IL-6, and IL-6 inhibition, on the other hand, resulted in significant sensitization to cisplatin, suggesting that IL-6 could contribute to the induction of platinum resistance in EOC. In agreement, Wang et al. found that both exogenous and endogenous IL-6 could induce cisplatin and paclitaxel resistance in vitro via increased expression of both multidrug resistance-related genes and apoptosis inhibitory proteins, as well as activation of extracellular signal-regulated kinases (ERK) and Akt signaling [
9]. They also demonstrated that IL-6 might contribute to the refractoriness of EOC to tamoxifen [
31]. In our study, however, intratumoral IL-6 showed neither dependent nor independent predicting value for OS, DFS or response to the platinum-based chemotherapy. In line with our results, Plante el al [
20] indicated that serum and ascites IL-6 levels did not correlate statistically with OS. In contrast to our observation, where almost equal intratumoral IL-6 levels were detected in platinum-based resistant and sensitive cases, they reported lower ascitic IL-6 in patients who responded to chemotherapy, although the difference was not found to be statistically significant.
In EOC, ascites is present in at least one third of patients and is believed to contribute to the spread of cancer to secondary sites [
32], as well as to peritoneal dissemination [
33]. Interestingly, the predictive value of IL-6 for the development of post-treatment ascites was observed in the present study. In line with our findings, Plante el al [
20] reported a direct association between ascitic IL-6 and ascites volume. In agreement, Lo et al. [
8] described an IL-6 trans-signaling pathway in formation and progression of ascites in EOC wherein IL-6 and its soluble IL-6 receptor (IL-6Rα) serve as an important regulator of endothelial cell survival, migration, and integrity, and IL-6 trans-signaling on endothelial cells prevents chemotherapy-induced apoptosis, induces endothelial hyperpermeability, and increases transendothelial migration of ovarian cancer cells, contributing to ascites formation and tumor progression.