# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 1 Introduction
### Stemness in Normal and Cancer Cells  
Stem cells are a rare population of cells with the innate capacity to self-renew and give rise to a lineage of progenitor cells that can mature and propagate into a variety of cell types. Residing in specific tissues, stem cells provide functions critical to the needs of their location while mediating homeostasis, maintenance and repair [69; 70; 71; 72]. Three major stem cell classes include embryonic stem (ES) cells, adult (somatic, postnatal) stem cells and cancer stem-like cells (CSCs), and their states are generally described in increasing levels of differentiation: totipotent, pluripotent, multipotent and unipotent. Totipotent stem cells possess an unlimited capacity with the potential to develop into virtually any cell found in the body, while pluripotent stem cells have limited potential to differentiate into three embryonic lineages (ectoderm, mesoderm and endoderm). Further differentiated are lineage-restricted multipotent stem cells (lineage-directed progenitor cells) with limited ability to differentiate or to give rise to other cell types, whereas unipotent stem cells can only give rise to one type of cell. ESCs originate from mammalian embryos preimplantation, while adult stem cells or somatic cells represent the self-renewing cells in skin, hair, intestine, liver and hematopoietic tissues. CSCs or tumor-initiating cells (TICs), are a rare population of cells with the ability to initiate the growth and maintenance of a heterogeneous tumor. They have been identified in a variety of hematopoietic cancers, solid tumors and tissues, including those of the bladder, breast, brain, lung, cervix and prostate [73; 74; 75; 76; 77]. Recent studies have demonstrated CSC frequencies to be not as scarce (0.0001% to 0.1%) as once believed, but that CSC numbers may be more dependent on cell type, stage of malignant progression, tumor cell phenotypic switching and even environmental factors, including foreign environments, such as those used in xenotransplantation assays [78; 79; 80; 81; 82; 83; 84]. In the case of xenotransplantation, [PERSON] et al. (2008) [85] demonstrated that NOD/SCID mice are prone to an underestimation of the frequency of tumorigenic human cancers. Using modified xenotransplantation assay conditions and highly immunocompromised (lacking mature T and B cells and functional NK cells) NOD/SCID interleukin-2 receptor gamma chain null (ll2 rg\({}^{-/-}\)) mice, an increase in the detection of tumorigenic melanoma cells by several orders of magnitude was observed. Limiting dilution assays using unselected patient primary and metastatic melanoma cells from 12 patients revealed that 25% resulted in tumor formation, while tumors formed from 27% using unselected cells from four patients. [PERSON] et al. (2007) [80] suggested that the low frequency of tumor-sustaining cells could be associated with the inability of human tumor cells to adapt to the mouse microenvironment. The origins of CSCs have not been completely revealed. However, it has been proposed that CSCs are long-lived adult stem cells or progenitors with accumulated neoplastic transformations that have enabled them to sustain cancer growth, progression and metastasis [86; 87; 88]. In lung cancer, for example, epithelial stem cells undergo malignant transformation [89]. A dysfunctional environment niche may also transform normal stem cells into CSCs. [PERSON] et al. (2014) [90; 91] demonstrated that bone marrow-derived cells recruited into gastric glands, upon chronic injury, develop into gastric adenocarcinoma. It has also been suggested that CSCs, or even recurrent CSCs (rCSCs), can arise through cell fusion between mutated stem cells and differentiated cells [92; 93; 94; 95; 87; 96; 97; 98; 99; 88; 99; 95]. Besides tumor initiation and cancer relapse, CSCs have been purported to be a cause of metastasis. Due to the variety of CSC properties, subpopulations have been proposed to include primary CSCs (pCSCs) that induce tumor formation and metastatic CSC (mCSCs) that induce metastases [79].