title: Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells.
abstract: Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that 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 gynecologic 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 N(G)-nitro-l-arginine methyl ester (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 use O-ASC-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, leading 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 using l-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas.
authors.forename: Bahar
authors.initials: B
authors.lastname: Salimian Rizi
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Christine
authors.initials: C
authors.lastname: Caneba
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nowicka
authors.affiliation: GE Power & Water, Boulder, Colorado.
authors.forename: Ahmad W
authors.initials: AW
authors.lastname: Nabiyar
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas.
authors.forename: Xinran
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Bioengineering, Rice University, Houston, Texas.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ann
authors.initials: A
authors.lastname: Klopp
authors.affiliation: Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas. Department of Bioengineering, Rice University, Houston, Texas. deepak.nagrath@rice.edu.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D009852:Omentum / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D009569:Nitric Oxide