Abstract 2931: Synergy between secreted factors promotes a hyper-secretory phenotype which may fuel ovarian cancer progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.2931-2931
• Main Authors: Davalos, Albert R., Schaum, Nicholas, Campisi, Judith
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-2931

The challenge in ovarian cancer research is twofold: 1) identification of early biomarkers of the disease and 2) uncovering targetable molecules to treat malignancy while minimizing toxicity. Mutations in the BRCA1/BRCA2 gene locus account for approximately 15% of patients with ovarian cancer, but several other risk factors are known, including increasing age and obesity. We recently uncovered that a nuclear protein (HMGB1) becomes secreted when cells undergo cellular senescence and we detect increased levels in plasma from elderly compared to young individuals. Significantly, we detect abundant extranuclear HMGB1 staining in tissue from patients with serous ovarian carcinoma, suggesting the presence of senescence cells in the tumor. We find elevated levels of circulating HMGB1 in patients diagnosed with serous carcinoma. Tissue microarray data analysis correlates with reduced survival in ovarian cancer patients staining with higher levels of HMGB1. Like aging, obesity is a risk factor for ovarian cancer but how remains poorly understood. We found that plasma from mice on high fat diets contained higher levels of HMGB1 compared to mice on normal diets. To extend this observation, we found that culturing ovarian cancer derived cells with saturated fatty acids promoted significantly increased secretion of HMGB1, IL-6 and MMP-3. Moreover, senescent cells which exhibit a secretory phenotype became “hyper-secretory” when cultured with saturated fatty acids. Recent data revealed that the redox state of HMGB1 establishes the protein's function. Secreted HMGB1 synergizes with other secreted factors to stimulate secretion of inflammatory molecules. Indeed we found cells cultured with fatty acid released cf DNA (cell free DNA) which can complex with secreted HMGB1 to promote cytokine secretion. Immunocytochemsitry revealed that tissue from serous ovarian cancer patients exhibited strong FABP-4 expression, a marker for adipoctyes but also shown to be secreted in obese individuals. Taken together these results lead to the possibility that multiple cells types synergize to create a permissive microenvironment to foster ovarian cancer development and progression. Citation Format: Albert R. Davalos, Nicholas Schaum, Judith Campisi. Synergy between secreted factors promotes a hyper-secretory phenotype which may fuel ovarian cancer progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington