Redox-Regulation in Cancer Stem Cells

Abstract

Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.

Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments

“…Consequently, the efficacy of radiation treatment is linked to a cell's ability to control ROS levels through various detoxification mechanisms. These include enzymes like manganese or copper-zinc superoxide dismutase, catalases, and glutathione peroxidase (GPX)/reductase that convert oxygen radicals to hydrogen peroxide and subsequently water, and nonenzymatic antioxidants, such as urate, glutathione, polyamines, vitamins E, A, and C. Tight regulation of ROS levels is also important for maintaining stemness; hence all pathways described above influence redox homeostasis 130 . GPX4 is one such regulator that protects cells from lipid oxidation and thereby protects from ferroptotic cell death 131 .…”

Regulation of iron metabolism and ferroptosis in cancer stem cells

“…In a previous study, we suggested that CSCs have a strong peroxidative lipid scavenging capacity and that the GPX4-GSH axis, a major mechanism of peroxidative lipid scavenging, is upregulated in CSCs and contributes to the acquisition and maintenance of stemness characteristics ( 15 ). A growing number of studies have shown that the GPX4-GSH axis plays an important antioxidant role in promoting or maintaining the stemness profile and drug resistance of colorectal, gastric, breast, pancreatic, liver, biliary, lung, and glioma CSCs ( 27 , 34 , 128 – 133 ).…”

“…Secondly, interactions between CSCs and their niche maintain self-renewal and promote drug resistance, metastasis, and relapse. Many studies have shown that CSCs visibly alter iron metabolism ( 9 ), lipid metabolism ( 10 ), multiple cell signaling ( 11 ), tumor microenvironment ( 12 , 13 ), redox regulation ( 14 , 15 ), epithelial-mesenchymal transformation (EMT) ( 7 , 16 ), and other aspects. In addition, due to their plasticity, quiescent CSCs can transform into cycling CSCs, leading to metastasis and relapse ( 17 ).…”

Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells

“…In the context of this study, the experimental oxygen levels were 7% for physoxia and 4% for hypoxia (mild). Typically, studies of CSC utilize cell culture conditions at room oxygen levels (21%) and control oxidative stress by adding antioxidants to the media 28 . However, no cells in internal organs, with the exception of cells lining the alveoli in the lungs, grow in 21% oxygen, and in the tumor microenvironment the oxygen levels can be very low.…”