The Role of High-Salt Diet on Melanoma Growth

Abstract

Cutaneous melanoma is one of the most aggressive cancer types in Western countries with a rising incidence over the last decades. Treatment of early-diagnosed melanoma constitutes a good survival rate and recovery. However, melanoma is a multifaceted disease with high mutational burden that hinders novel therapeutic strategies. Another risk factor in developed countries is the excessive consumption of processed food, the so-called Western diet. This diet is characterized by high content of fat, sugar, proteins, and salt. It is widely believed that a high-salt diet (HSD) leads to sodium accumulation in the skin and modulates the immune system towards a pro-inflammatory state. <br /> The main goal of the thesis was to investigate the influence of a HSD on cutaneous cancer growth and to identify cellular and molecular mechanisms for potential therapeutic strategies. Mice fed with HSD showed significantly less tumor volume compared to mice under a control diet. Furthermore, metastasis formation in the lung tissue was also reduced in mice under HSD. Analysis of the tumor microenvironment revealed a similar abundance of immune cells in both investigated groups. Furthermore, the distribution of immune cells in the tumor-draining lymph nodes was not altered by the increased salt intake so the role of the immune system was excluded in the HSD-mediated tumor reduction <br /> Instead, HSD tremendously affects tumor metabolism by reducing glycolysis and oxidative phosphorylation activity. Transcriptomic analysis revealed downregulation of cell cycle and metabolism-associated pathways, and metabolomic profiling of tumor tissue confirmed downregulation of glycolysis and fatty acid metabolism. Analyzing glycolytic enzymes showed downregulation of mRNA levels in melanoma cells under HSD, strengthening the theory that excessive salt intake impairs glycolysis. <br /> Furthermore, melanoma cells after HSD showed significant upregulation of modulators involved in the melanogenesis pathway. This activity may rather promote melanoma toward cell differentiation and result in the inhibition of cell proliferation. <br /> In conclusion, the thesis revealed new insights into how HSD influences melanoma growth. The direct effect of HSD affects tumor metabolism and could be considered in future therapeutic approaches. Furthermore, the presented data indicate changes in melanogenesis activity in melanoma cells exposed to HSD and may explain the salt-mediated tumor reduction.