# Nicotinamide Adenine Dinucleotide (NAD) Metabolism as a Relevant Target in Cancer
## 7 **NAMPT in Cancer**  
To meet NAD+ demands, tumour cells must maintain high NAD+ levels, enhancing their synthesis mainly through the salvage pathway. The rate-limiting enzyme of this pathway, NAMPT, has been identified as an oncogene in some cancer types. In fact, increased NAMPT levels have been found in both haematologic malignancies [62; 63] and various solid tumours, including colon [40], prostate [64], breast [65], thyroid [66], gastric [67] and glioblastoma tumours [41; 42]. NAMPT is capable of increasing the tumorigenic properties of cells, such as cell proliferation, clone formation and resistance to apoptosis, thus allowing tumour initiation and progression [40; 41]. The expression of NAMPT also correlates with the clinical data of cancer patients in some tumours. For example, in stomach, colon and glioblastoma cancer, high levels of NAMPT correlate with aggressive tumour stages, metastasis, treatment resistance and worse prognosis [40; 41; 64; 67]. It also activates the secretion of interleukin 6 (IL-6), which induces the STAT3 signalling pathway, which favours the process of new blood vessel formation [62; 68; 69].  
Visfatin (or extracellular NAMPT) is also implicated in cancer and its role is currently being studied. Although the exact molecular mechanism of visfatin remains unknown, its role is currently being studied. In fact, high levels of serum visfatin have been detected in patients with variant types of cancer, including postmenopausal breast cancer, endometrial cancer, gastric cancer and hepatocellular carcinoma. Visfatin has been proposed as a diagnostic marker in cancer and it is associated with poor patient survival [46; 70; 71; 72]. Visfatin acts as a tumour cytokine promoting proliferation, neovascularization and metastasis in cancer. It has been described to regulate the function of adhesion molecules such as ICAM-1 and VCAM-1 through the activation of NF-\(\kappa\)B in human endothelial cells [46]. It also upregulates matrix metalloproteinase, such as MMP-2 and MMP-9, and vascular endothelial growth factors, promoting angiogenesis via the STAT3/IL-6 signaling pathway [68; 73]. Recently, it has been described that Visfatin can be secreted from cells via exosomes, which can promote the inflammatory and tumor microenvironment [74; 75]. Similar to other adipocytes (e.g., leptin, adiponectin and resistin), visfatin contributes to autocrine, paracrine and endocrine interactions between tumour cells and the microenvironment [46; 76]. In breast cancer, it has been reported that visfatin induces THP-1 differentiation into M2 macrophages suppressing the immune response promoting tumor progression. Moreover, M2 macrophages secrete CXCL1 which elevated visfatin via a positive feedback loop. Visfatin/M2/CXCL1 contribute to tumor migration and invasion [77].  
On the other hand, the exact molecular mechanism of visfatin remains unclear and its cellular receptor has been not found. However, visfatin presents insulin-mimetic effects, and it has been described that visfatin binds to and activates the insulin receptor of hepatocytes, myocytes and adipocytes [52]. There is controversy regarding if visfatin has the enzymatic activity as its intracellular form. Although the dimeric conformation of visfatin has been elucidated, it has been difficult to detect all of its substrates (PRPP, NAM and ATP) in serum [47; 75]. Moreover, the effects of visfatin do not depend on the presence of NAM, nor are they reproducible by NMN addition or blocked by NAMPT inhibitors [67; 78]. Lastly, the effects of visfatin are independent of the intracellular enzymatic activity of NAMPT.