Giada Marroncini1,2, Benedetta Fibbi1,2, Alice Errico1,2, Cecilia Grappone3, Mario Maggi2, Alessandro Peri4,5. 1. Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139, Florence, Italy. 2. Endocrinology, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, AOU Careggi, 50139, Florence, Italy. 3. Gastroenterology, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, AOU Careggi, 50139, Florence, Italy. 4. Pituitary Diseases and Sodium Alterations Unit, AOU Careggi, 50139, Florence, Italy. alessandro.peri@unifi.it. 5. Endocrinology, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, AOU Careggi, 50139, Florence, Italy. alessandro.peri@unifi.it.
Abstract
PURPOSE: Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its etiopathogenesis is related to an underlying tumor in 14% of cases. Hyponatremia has been associated with a worse outcome in several pathologies, including cancer, in which the leading cause of this electrolyte alteration is the syndrome of inappropriate antidiuresis. The aim of this study was to analyze in vitro the effects of low extracellular [Na+] in cancer progression. MATERIALS AND METHODS: We used a previously validated experimental model of chronic hyponatremia to characterize the effects of low extracellular [Na+] in different human cancer cell lines: pancreatic adenocarcinoma (PANC-1), neuroblastoma (SK-N-AS, SH-SY5Y), colorectal adenocarcinoma (HCT-8), chronic myeloid leukemia (K562). RESULTS: Our results demonstrate a direct relationship between low [Na+], reduced cell adhesion and increased invasion and proliferation in all cell lines tested. Accordingly, the number of tumor colonies grown in soft agar and the expression of collagenases type IV (metalloproteinases 2 and 9) were markedly higher in cancer cells exposed to reduced extracellular [Na+]. Gene analysis showed an upregulation of molecular pathways involved in oxidative stress (heme oxygenase 1) and in proliferation and invasion (RhoA, ROCK-1, ROCK-2). The activation of RhoA/ROCK pathway was paralleled by a deregulation of the cytoskeleton-associated proteins, resulting in the promotion of actin cytoskeletal remodeling and cell invasion. CONCLUSIONS: Overall, our data demonstrate for the first time that low [Na+] promotes cancer progression in vitro, thus suggesting that hyponatremia is not a simple bystander of disease severity in cancer.
PURPOSE:Hyponatremia is the most common electrolyte disorder in hospitalized patients, and its etiopathogenesis is related to an underlying tumor in 14% of cases. Hyponatremia has been associated with a worse outcome in several pathologies, including cancer, in which the leading cause of this electrolyte alteration is the syndrome of inappropriate antidiuresis. The aim of this study was to analyze in vitro the effects of low extracellular [Na+] in cancer progression. MATERIALS AND METHODS: We used a previously validated experimental model of chronic hyponatremia to characterize the effects of low extracellular [Na+] in different humancancer cell lines: pancreatic adenocarcinoma (PANC-1), neuroblastoma (SK-N-AS, SH-SY5Y), colorectal adenocarcinoma (HCT-8), chronic myeloid leukemia (K562). RESULTS: Our results demonstrate a direct relationship between low [Na+], reduced cell adhesion and increased invasion and proliferation in all cell lines tested. Accordingly, the number of tumor colonies grown in soft agar and the expression of collagenases type IV (metalloproteinases 2 and 9) were markedly higher in cancer cells exposed to reduced extracellular [Na+]. Gene analysis showed an upregulation of molecular pathways involved in oxidative stress (heme oxygenase 1) and in proliferation and invasion (RhoA, ROCK-1, ROCK-2). The activation of RhoA/ROCK pathway was paralleled by a deregulation of the cytoskeleton-associated proteins, resulting in the promotion of actin cytoskeletal remodeling and cell invasion. CONCLUSIONS: Overall, our data demonstrate for the first time that low [Na+] promotes cancer progression in vitro, thus suggesting that hyponatremia is not a simple bystander of disease severity in cancer.
Entities:
Keywords:
Carcinogenesis; Gene expression; Human cancer cells; Low sodium [Na+]; Tumor invasion
Authors: Naveen S Vasudev; Janet E Brown; Sarah R Brown; Rumana Rafiq; Ruth Morgan; Poulam M Patel; Dearbhaile O'Donnell; Patricia Harnden; Mark Rogers; Kim Cocks; Kirsty Anderson; Alan Paul; Ian Eardley; Peter J Selby; Rosamonde E Banks Journal: Clin Cancer Res Date: 2008-03-15 Impact factor: 12.531