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.

The context-dependent role of the Na+/Ca2+-exchanger (NCX) in pancreatic stellate cell migration

“…Tumor cells secrete various growth factors that stimulate and activate PSCs [ 27 ]. Here, we tested whether the stimulation of stellate cell migration with PDGF is regulated by NCX1 when cells are kept at pH e 7.4 (see Fig.…”

“…It provides as direct link between Ca 2+ signaling and the cellular Na + homeostasis which is stressed by the properties of the TME. So far, the function of the NCX in cancer-associated fibroblasts is not well understood [ 27 ]. Therefore, we undertook a systematic characterization of the NCX1 in PSCs.…”

“…Eventually, tissue pressure rises to up to 100 mmHg which in turn leads to reduced O 2 supply, resulting in hypoxic areas [ 31 ]. In addition, the modified metabolism of tumor cells creates an acidic environment [ 27 , 30 ].…”

“…The modified tumor microenvironment (TME) triggers Ca 2+ signaling through the activation of mechanosensitive ion channels and growth factors. Moreover, the activation of mechanosensitive ion channels as well as the necessity to defend the intracellular pH in the acidic TME in a Na + -dependent manner (e.g., by NHE1 or NBCe1 activation) leads to increased [Na + ] i loading [ 27 ]. Na + loading is augmented because the Na + /K + -ATPase is inhibited in a hypoxic and acidic environment [ 35 ].…”

Dysregulation of calcium homeostasis in cancer and its role in chemoresistance

“…In the forward mode, it transfers three Na + ions inside and two Ca 2+ ions outside the cells and thus acts as an anti-apoptotic channel. In the reverse mode, it transfers three Na + ions outside and two Ca 2+ ions inside and thus acts as a pro-apoptotic channel by increasing the Ca 2+ accumulation in the cells [ 31 ] . PMCA is an ATP-based Ca 2+ pump, helping to maintain low [Ca 2+ ] cyt .…”