Abstract 1433: Omental derived adipose stromal cells regulate nitric oxide homeostasis to maintain tumorigenicity in ovarian cancer cells

Abstract

Abstract The rate of obesity is increasing dramatically in the United States, resulting in a rising incidence of obesity associated diseases including colorectal, gallbladder, esophageal, renal, breast, endometrial and ovarian cancer. The location of excess adipose tissue is reportedly an important factor which influences the effect of obesity on cancer incidence. The tumor promoting effects of regional adipose may be attributed, at least in part, to the presence of mesenchymal stem cell (MSC) population in adipose tissue. Adipose derived stromal cells (ASCs) are a multi-potent population of MSCs, which support cancer progression in many models. These cells are uniquely tumor tropic, migrating into tumor stroma from regional sources where they support formation of tumor stroma elements and promote tumor progression. Thus, we hypothesize that the omentum provides a particularly hospitable microenvironment for OVCA metastasis due to the presence of omental ASCs (O-ASCs). One critically important, yet often overlooked contributor to ovarian tumor growth, progression and metastasis in obese individuals is nitric oxide (NO). Cancer cells' high affinity for NO and NO's characteristic high solubility in lipids could explain the proximity of many carcinomas to fatty tissue, and thus the high positive correlation between obesity and cancer. Here we report a novel NO mediated reciprocal coupling between O-ASCs and ovarian cancer which promotes cancer cell growth and energy metabolism. Our results show that O-ASCs supports viability of cancer cells by secreting arginine and cancer cells in turn induce adipogenesis in O-ASCs by secreting citrulline. We found that OASCs promote tumor growth and increase resistance to chemotherapy by modulating NO homeostasis. The inhibition of NO synthesis or scavenging of NO enhanced chemo-sensitivity. Using metabolic profiling we found that OASCs rewire metabolic pathways related to nitrogenous amino acids and reprogram energy metabolism. In summary, our data indicate that modulation of intrinsic NO substantially affects tumor growth and drug toxicity in ovarian cancer cells. Our study will lead to significant advances in the understanding of the omentum in altering cancer metabolism and lead to novel therapeutics. Citation Format: Bahar Salimian Rizi, Ann H. Klopp, Deepak Nagrath. Omental derived adipose stromal cells regulate nitric oxide homeostasis to maintain tumorigenicity in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1433. doi:10.1158/1538-7445.AM2014-1433