Dual influence of TNFα on diverse in vitro models of ovarian cancer subtypes.

Ovarian cancer is the most lethal gynecological cancer. Numerous subtypes exist, each with distinct risk factors and prognosis. What underlies these subtypes and their progression is not clear, although inflammation through NFκB may play a key role. We performed a study on a series of well-characterized in vitro ovarian cancer models including TOV21G, TOV112D and OV90 originally derived from clear cell, endometrioid and high grade serous carcinoma respectively. Cells were treated with 0-100 ng/ml TNFα over 6-72 h. The NFκB pathway was inhibited by a series of NFκB pathway inhibitors, 100µM PDTC, 1µM PS-1145 and 200nM TPCA and the influence on cellular viability and inflammation was measured via an MTS assay and qPCR respectively. TNFα stimulation of NFκB was confirmed via Western blot. We found TNFα facilitated continued growth of TOV21G and TOV112D cells in an NFκB independent method. In contrast, TNFα inhibited OV90 cell growth in an NFκB dependent manner. TNFα stimulated production of IL-6, IL-8, MCP-1 and RANTES on all three cells lines, but only IL-6 and IL-8 were via NFκB mediated mechanisms. These results indicate TNFα may have diverse effects mediated through both NFκB and non-NFκB pathways on ovarian cancer cells. Understanding the role for TNFα in each subtype may have significant implications for charting disease progression and designing personalized treatments.

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

BACKGROUND: Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS: To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS: The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKß/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS: Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.