Cancer Stem Cells and Nitric Oxide

Abstract

Cancer stem cells (CSCs) forming the tumor heterogeneity are thought to be the main reason for ineffective and insufficient conventional cancer treatments including surgery, radiotherapy, and chemotherapy and, therefore, causing relapse, metastasis, and multidrug resistance in the long term. CSCs express specific biomarkers on their surface and, thus, differentiate from non-CSCs. The metabolic and signaling activities of CSCs have been shown to be different from those of non-CSCs, and there are still many unknown activities. CSCs share Wnt, Hedgehog, and Notch signaling pathways and many surface markers with embryonic and adult stem cells, indicating that CSCs are the starting point of tumor formation. Deregulation of intrinsic and extrinsic factors of cells induces altered metabolic activities, including the nitric oxide (NO) metabolism, that have a crucial role in the cell fate. CSCs produce high levels of NO and secrete it in the tumor microenvironment involving a wide range of components such as stromal cells, cancer-associated fibroblasts (CAFs), immune cells, nonimmune cells, and blood vessels. Studies have shown that cancer (stem) cell-derived NO promotes chronic inflammation in the tumor microenvironment, pro-tumorigenic activities of CAFs, drug resistance, invasion, and metastasis. These events are reversible by inhibiting cellular NO by NO-releasing drugs or NO donors in cancer therapy either alone or combined with other cytotoxic drugs. Thereby, NO is suggested to be a promising agent for cancer therapy, prevention of the metastatic cascade, and CSC transformation. Further research is needed to elucidate the highly sophisticated activities of NO and CSCs for the advancements of new therapeutic strategies targeting CSCs. © 2023 Elsevier Inc. All rights reserved.