Mitochondrial and energy metabolism‐related properties as novel indicators of lung cancer stem cells

Abstract

Energy metabolism is the foundation of survival for all organisms, and mitochondria are the most important energy-supplying organelles in eukaryotic cells. However, the mitochondrial and energy/metabolism-related properties of cancer stem cells (CSCs), the stem cell-like subpopulation in tumor masses, remain unknown. In our study, we compared the masses of mitochondria and mitochondrial DNA (mtDNA), the mitochondrial membrane potential (Dwm), oxygen/glucose consumption, and the concentration of reactive oxygen species (ROS) and ATP between lung CSCs (LCSCs) and non-LCSCs. In addition, the change in features during differentiation was examined. Some mitochondrial and energy metabolism-related properties, such as perinuclear mitochondrial distribution, a lower quantity of mtDNA, higher Dwm, lower oxygen/glucose consumption, and lower intracellular concentrations of ROS and ATP, can be used as indicators of LCSCs.Increasing evidence indicates that cancer stem cells (CSCs) are initiators of the occurrence, development and recurrence of malignant tumors. 1 Thus, it is important to understand the biological characteristics of this subpopulation in the tumor mass. Due to the great efforts of many researchers, more and more specific features of CSCs have been revealed, such as cytotoxic resistance, invasiveness, proliferation/division, immunogenicity, hypoxic tolerance and the capacity of neovessels induction. 1,2 These findings aid in understanding the underlying mechanisms of growth, recurrence after therapy, immune escape and invasion/metastasis of malignant tumors.Energy metabolism is the foundation of survival for all organisms. As for mitochondria are the most important organelles that provide energy for sustaining the metabolic needs of eukaryotic cells. They are also known, vital components in many cell processes, including differentiation and apoptosis. 3 In recent years, mitochondrial and energy/metabolism-related features of normal adult/embryonic stem (ES) cells have been studied by an increasing number of researchers. 3,4 It has been suggested that the function and integrity of mitochondria may influence the viability, the proliferative and differentiation potential and the lifespan of normal stem cells. 3,5 Some features, including perinuclear mitochondrial arrangement, low ATP content, high rate of oxygen consumption, and low quantity of mitochondrial DNA (mtDNA), have been thought to be indicators of ''stemness'' of these undifferentiated cells. A departure from this profile suggests that cells are differentiating or perhaps becoming senescent. [3][4][5][6] In addition, it has been observed that much lower levels of reactive oxygen species (ROS), which are thought to be the by-products of mitochondrial biogenesis, are required for adult haemopoietic stem cells (HSCs) to remain quiescent and retain their stem features, such as self-renewal potential and multipotency. 7 At the same time, mitochondrialrelated abnormalities have also been considered to have an important role in the origin and development of ...

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

“…In fact, although it is generally accepted that mtDNA replication is enhanced during SC differentiation, a transitory decrease in mtDNA content was observed during the first days of differentiation. 22 Thus, although mitochondria-related gene expression revealed dissimilar expression signatures during P19SCs differentiation, our data seem to confirm equivalent mitochondrial mass in P19SCs and P19dCs. Similarly, no significant differences in mitochondrial mass were detected between lung CSCs and non-stem cancer cells.…”

“…Nevertheless, lung CSCs presented low mtDNA copy number. 22 One way or the other, the number of mitochondria seems to be tightly controlled in pluripotent cells because excessive mitochondrial biogenesis can result in defective maintenance of the SC pool as described for hematopoietic SCs.…”

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

“…31,32 This difference may be ascribed to the peculiar oxidative state of CSCs, which have been reported to have low levels of ROS and increased expression of free radical-scavenging systems. 9,33 ABT-737 targets quiescent lung cancer stem cells A Zeuner et al…”

“…3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. [4][5][6][7][8][9] Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies. 10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-X L and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance.…”

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

“…Some cancer stem cells (CSCs), for example breast and lung CSCs, maintain low ROS levels due to several factors, including increased expression of free radicals scavengers, lower quantity of mtDNA and higher ∆Ψ m [8,9]. In contrast, LSCs from BCR-ABL1 -positive CML-CP and IDH1/2 mutation -positive AML accumulate high levels of ROS [5,10].…”