Hyponatremia Promotes Cancer Growth in a Murine Xenograft Model of Neuroblastoma.

In cancer patients, hyponatremia is detected in about 40% of cases at hospital admission and has been associated to a worse outcome. We have previously observed that cancer cells from different tissues show a significantly increased proliferation rate and invasion potential, when cultured in low extracellular [Na+]. We have recently developed an animal model of hyponatremia using Foxn1nu/nu mice. The aim of the present study was to compare tumor growth and invasivity of the neuroblastoma cell line SK-N-AS in hyponatremic vs. normonatremic mice. Animals were subcutaneously implanted with luciferase-expressing SK-N-AS cells. When masses reached about 100 mm3, hyponatremia was induced in a subgroup of animals via desmopressin infusion. Tumor masses were significantly greater in hyponatremic mice, starting from day 14 and until the day of sacrifice (day 28). Immunohistochemical analysis showed a more intense vascularization and higher levels of expression of the proliferating cell nuclear antigen, chromogranin A and heme oxigenase-1 gene in hyponatremic mice. Finally, metalloproteases were also more abundantly expressed in hyponatremic animals compared to control ones. To our knowledge, this is the first demonstration in an experimental animal model that hyponatremia is associated to increased cancer growth by activating molecular mechanisms that promote proliferation, angiogenesis and invasivity.

Hyponatremia and Cancer: From Bedside to Benchside.

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na+] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na+] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer.

Effects of low extracellular sodium on proliferation and invasive activity of cancer cells in vitro.

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.