The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts.

ABSTRACT

Cancer is characterized by uncontrolled growth, invasion, and metastasis. In addition to solid cancer cells, cancer-associated fibroblasts (CAFs) play important roles in cancer pathophysiology. They arise from "healthy" cells but get manipulated by solid cancer cells to supply them and develop a tumor microenvironment (TME) that protects the cancer cells from the immune defense. A wide variety of cell types can differentiate into CAFs, including fibroblasts, endothelial cells, and epithelial cells. Precise Ca2+ regulation is essential for each cell including CAFs. The electrogenic Na+/Ca2+ exchanger (NCX) is one of the ubiquitously expressed regulatory Ca2+ transport proteins that rapidly responds to changes of the intracellular ion concentrations. Its transport function is also influenced by the membrane potential and thereby indirectly by the activity of ion channels. NCX transports Ca2+ out of the cell (forward mode) or allows its influx (reverse mode), always in exchange for 3 Na+ ions that are moved into the opposite direction. In this review, we discuss the functional roles NCX has in CAFs and how these depend on the properties of the TME. NCX activity modifies migration and leads to a reduced proliferation and apoptosis. The effect of the NCX in fibrosis is still largely unknown.