Authors:
Bahar Salimian, Christine Caneba, Aleksandra Nowicka, Ahmad Walid Nabiyar, Xinran Liu, Kevin Chen, Ann Klopp, and Deepak Nagrath
Summary:
Omental adipose stromal cells (O-ASCs) are multipotent population of mesenchymal stem cells contained in the omentum tissue which promote endometrial and ovarian tumor proliferation, migration and drug resistance. The mechanistic underpinnings of O-ASCs role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO) mediated metabolic coupling between O-ASCs and gynecological cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using L-NAME, we demonstrate that patient derived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells utilize O-ASCs-secreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells which led to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASC mediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment secreted factors induced increased NO synthesis in cancer cells using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers.
Source:
Cancer Research; (10/24/14)