Endocrine Abstracts

The intraperitoneal environment of the ovarian surface epithelium (OSE) has an oxygen (O₂) tension of 5–12%. This could impact cellular events leading to ovulation. Furthermore, ovarian cancers arising from the OSE (∼80–90% of ovarian malignancies) are likely to experience increased hypoxia due to the relatively poor vascularisation of solid tumours.

Using 1%, 5% or 20% O₂, we measured the expression of HSD11B1, COX-2, VEGF and Thrombospondin-1 (TSP-1) mRNA by Taqman qRT PCR in response to inflammatory (0.5 ng/ml Il-1α) and anti-inflammatory (1 μM cortisol (F) challenge in cultured sheep (s) OSE over 48 h at these 3 O₂ tensions.

In human (h) OSE, IL-1 up regulates HSD11B1 mRNAα and this effect is enhanced by addition of F. In our sheep model we found IL-1α to have a similar stimulatory effect and the stimulatory effect was dose-dependently increased by decreasing O₂. In contrast to hOSE, addition of F reversed the effect of IL-1α in sOSE. COX-2 mRNA followed a similar pattern to HSD11B1 in sOSE, with hypoxia again enhancing the stimulatory effect of IL-1α.

In sOSE, F limits its own production in a negative feedback effect on HSD11B1, even under severely hypoxic conditions in which the inflammatory response to IL-1α is augmented. Despite the increased inflammatory response to hypoxia, the addition of F was able to reduce the COX-2 response to IL-1α.

VEGF mRNA increased 6-fold under 1% O₂ confirming the hypoxic response of the cells. There was an additional stimulatory effect of IL-1α (6-fold) and inhibitory effect of F (60% of IL-1α) at all O₂ levels. TSP-1 mRNA was demonstrated for the first time in OSE and was increased 2-fold in response to hypoxia. This gene also responded to an inflammatory IL-1α challenge (2- to 3-fold) but only at reduced O₂, and F completely reversed this effect.

These results confirm that the hypoxic environment of the peritoneum alters gene expression in the OSE in response to inflammatory stimuli, which may impact ovulation and tumourogenesis. F is able to counteract the effects of IL-α even under severe hypoxia. Both angiogenic and anti-angiogenic factors are similarly affected by hypoxia, IL-1 and F suggesting a potential mechanism for inflammation and hypoxia to promote, and glucocorticoids to inhibit, tumour development. Further studies of OSE and ovarian cancer cells under hypoxic conditions will permit a better understanding of the mechanisms regulating these cells and may give insight into more effective treatment of ovarian cancer.