# Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer
## 9 NAMPT in Cancer Stem Cells (CSCs)  
Tumours are highly heterogeneous entities that are organised hierarchically into different subgroups of tumour cells. Cancer stem cells (CSCs) are at the top of this hierarchy. CSCs are a small subpopulation of cells with the ability to self-renew and differentiate into the different types of cells that form the bulk of the tumour. Similar to normal stem cells, these CSCs can self-renew and differentiate, but they do so in an uncontrolled manner. CSCs are responsible for tumour initiation and progression and for metastasis and resistance to therapies. CSCs can originate from normal stem cells or from differentiated tumour cells that are capable of acquiring stem cell capabilities through dedifferentiation mechanisms [110; 111; 112; 113]. (Figure 4) The dedifferentiation process is similar to the process of reprogramming somatic cells into pluripotent cells (iPSCs), which is induced through the activation of some pluripotency transcription factors, such as OCT3/4, SOX2, KLF4 and c-MYC [114; 115]. The interconversion capacity between both phenotypes, different cells and stem/pluripotent cells is known as cell plasticity. The cellular microenvironment and some signalling pathways activate and regulate this cellular plasticity. Some of the main pathways that regulate CSCs are Notch, Hippo, SHH, PI3K, WNT and NF-kB [110; 113; 116]. Both CsCs and iPSCs can show an active Warburg metabolic effect, which induces the hypoxic state necessary for the maintenance of the stem cell phenotype. Thus, the stem cell phenotype or pluripotency can be highly glycolytic when the cells are actively dividing [110; 117; 118]. However, much controversy exists regarding the typical metabolic profile of CSCs. In general, CSCs are in the G0 phase, or quiescence, a state in which they consume oxygen and depend mainly on OXPHOS metabolism, by which they obtain a greater antioxidant response to compensate for the high levels of ROS. This slow metabolism allows them to survive conventional therapies that mainly attack cells with high rates of proliferation. As sole survivors, CSCs change from their quiescent state to a more proliferative and glycolytic state, thus regenerating the tumour again [111; 117; 119]. In recent years, research has focused on searching for surface markers and transcriptional signatures specific to the CSC phenotype. CSCs express specific antigens on their surface, similar to normal stem cells. These surface markers that characterise CSCs depend largely on the type of cancer, and the best known are CD44+CD24\(-\) and ALDH in breast cancer, CD44+ and CD133+ in colon and gastric cancer, CD34+CD38\(-\) in leukaemia, CD133+ in glioblastoma and sarcoma and CD13/CD45/CD90 in liver cancer [120; 121]. However, the CSC population presents a high degree of heterogeneity, with different subgroups or categories even in the same tumour [110; 113; 116]. Finding new markers and genes that help us to identify CSC popula  
Figure 4: Brief scheme of CSC contribution to recurrence and metastasis. tions is vital to developing new and more specific therapeutic strategies. NAMPT enriches the CSC population of the tumour mainly through the salvage route, thus allowing an adequate supply of NAD+ [42; 43]. NAMPT and NAD+ are involved in the processes of pluripotency and dedifferentiation to CSCs. It has been observed that media supplementation with NAM can prevent senescence and apoptosis and promote reprogramming and iPSC generation. Furthermore, reduced NAD+ levels in human stem cells can cause spontaneous differentiation and apoptosis [116; 122]. The autofluorescence emitted by the NADH reduced form can be quantified by cytometry, and a subpopulation with high NADH has been related to the CD133+ subpopulation of CSCs in glioblastoma [123; 124]. NAMPT not only increases tumorigenic properties but also allows the acquisition of the properties and phenotype of CSCs through the activation of OSKM factors, including SOX2, OCT4, KLF4 and NANOG [40; 41].