Increased Levels of Stress Induces a More Metastatic Phenotype in Human Melanoma Cells

Abstract

Growing evidence suggests that stress plays a vital role in metastasis and tumor development by activating the sympathetic nervous system. The catecholamines released into the tumor microenvironment (TME), specifically norepinephrine (NE), results in a cascade effect leading to a variety of pro‐metastatic activities that sustain tumor growth and increase melanoma aggressiveness. Most notable are the secretion of cytokines and the stimulation of tumor‐associated macrophages (TAMs). Using a co‐culture system of several human melanoma cancer cells and macrophages, we found that sustained exposure of NE in the TME induced the release of tumor‐growth and progression‐associated cytokines from TAMs. Several of the upregulated cytokines found, including IL‐11, IL‐24, GRO‐a, MIF, DKK‐1, and angiopoietin‐2, are known to induce growth, migration, invasion, and tumor development in human melanoma. An ELISA assay of human‐MIF was used to validate the cytokine array in which upregulation of MIF was noted in co‐culture with NE present. At a molecular level, these findings suggest how physiological stress in cancer patients can further lead to cancer progression. These preliminary findings may lead to supportive therapies that emphasize mental health and the treatment of the psychological state of the patient. Our next steps include continuing the validation of the cytokine arrays using different ELISA assays to quantify protein levels of stress‐secreted cytokines in the TME that augment the metastatic phenotype of human melanoma cells.