The successful treatment of EOC remains a major challenge. Most (> 85%) EOC patients presenting with advanced disease will relapse. Recurrence defines incurable disease in most cases. The main obstacle to effective treatment is the failure of initial therapy to eradicate a sufficient number of tumor cells to prevent disease recurrence. One emerging model for the persistence of tumor cells after chemotherapy invokes ascites as a tumor microenvironment that promotes
de novo drug resistance. Acellular fractions of EOC ascites have been shown to have anti-apoptotic activities [
3,
4] and ascites with pro-survival activities against cytotoxic agents were recently shown to significantly correlate with shorter progression-free survival in ovarian cancer patients [
6]. These findings suggest that EOC ascites contain factors that affect progression-free survival by promoting tumor cell survival. EOC ascites contain a variety of soluble factors, including cytokines, which may contribute to
de novo resistance of tumor cells. Because of the high levels of IL-6 and IL-8 found in ascites and the prosurvival activity of ascites, we hypothesized that IL6 and IL-8 could impact on progression-free survival. The identification of biomarkers that predict tumor progression would contribute to stratify patients for the selection of initial therapy.
We measured IL-6 and IL-8 levels in ascites samples obtained at the time of the initial surgery in a group of 39 patients with previously untreated EOC. Mean ascites levels of IL-6 and Il-8 found in our cohort were comparable to those previously reported by Giuntoli
et al. in 22 ascites samples from women with EOC [
12]. Our results show that elevated IL-6, but not IL-8, levels in ascites of patients with EOC correlated with shorter progression-free survival. We found low IL-6 levels to correlate significantly with prior chemotherapy (
P = 0.037). However, these data should be considered with caution given the small number of patients in the group that received chemotherapy prior to their surgery. No significant correlation was found between IL-6 and IL-8 levels in ascites and the other clinicopathological parameters such as stage, grade, histologic type and size of residual tumor left after initial debulking. These data are consistent with those of Tempfer
et al. [
26] and Scambia
et al. [
27] which showed that elevated IL-6 concentration in serum of ovarian cancer patients correlated with poor overall survival. They are also consistent with the observation that IL-6 promoter polymorphism, which may affect IL-6 levels, impacts on survival of women with ovarian cancer [
30]. However, measuring IL-6 in ascites might actually be more relevant than measuring it in serum. IL-6 is released by the peritoneal mesothelial cells and concentrates in ascites [
12,
15] where it could affect tumor cell behaviour. IL-6 may be cleared rapidly from the circulation and consequently serum levels may not correlate with ascites levels.
Although, our data suggest that IL-6 levels in ascites are associated with shorter progression-free survival, the precise underlying molecular mechanisms responsible for these findings remain to be established. One possibility is that elevated ascites IL-6 levels promote
de novo tumor cells resistance to chemotherapy contributing to earlier disease recurrence [
31]. This is supported by the observation that IL-6 inhibited death receptor-induced cell death in long term cell viability assays (Lane, unpublished data). IL-6 signaling cascade in ovarian cancer cells has been associated with the development of Taxol resistance [
32,
33]. Alternatively, IL-6 could stimulate the proliferation of tumor cells leading to a shorter progression-free survival [
18]. IL-6-mediated angiogenesis could also play a role [
23]. Tumor angiogenesis plays an important role in cancer progression and metastasis. The angiogenesis and the disruption of vascular barrier both contribute to ascites formation [
34]. Because IL-6 has been shown to be involved in tumor angiogenesis in ovarian cancer, IL-6 may be important in promoting the formation of ascites as well as the progression of ovarian cancer. IL-6 signalling prevents chemotherapy-induced endothelial cells apoptosis and the blockage of its signalling cascade was therapeutically beneficial in xenograft mouse model [
35]. Thus, interference with IL-6 pathway may offer opportunities for ovarian cancer therapy. However, using a monoclonal antibody that specifically blocks IL-6 signaling, siltuximab, Guo
et al. demonstrated that although the combination of siltuximab with paclitaxel increased the sensitivity of ovarian tumor cells to paclitaxel
in vitro, the combination was ineffective
in vivo in xenogrft mouse model [
36]. Although clinical trials of monoclonal antibodies to IL-6 for the treatment of other types of cancer have shown encouraging results [
37,
38], a clear benefit for patients with ovarian cancer remains to be demonstrated. Finally, the high levels of IL-6 could enhance the immune suppressive status of the tumor microenvironment by inducing B7-H4 expression on tumor associated macrophages and promote apoptosis in these cells [
39]. IL-6 may divert the immune response from Th1 towards a suppressive Th2 response although controversial data have been reported [
11,
40,
41]. IL-6 may also contribute to reprogram the tumor adjacent stromal microenvironment which may facilitate dissemination to the peritoneal cavity. The contribution of this reactive stromal is being recognized as an important element for tumor progression [
42].