# Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemess
## 1 Introduction
### Tumor Microenvironment and the CSC Niche  
Stem cell processes are controlled by intrinsic factors that are cell-autonomous transcription factors and genes and a network of extrinsic factors that include soluble factors and adhesion molecules from ECM and niche cells [115]. Stem cells reside in niches or specialized microenvironments consisting of a symphony of interactive cells, including fibroblasts, endothelial and perivascular cells, adipose cells, cytokines, immune cells, macrophages, extracellular matrix (ECM) and soluble factors excreted from cells [116; 117; 118]. The interactions between stem cells and the niche play an important role in stem cell maintenance with CSCs driving niche formation and the niche controlling CSC self-renewal, proliferation, differentiation, invasion and metastasis [119; 120; 121; 122; 123; 124; 125]. The stem cell niche is regulated by extrinsic stimulation by Notch, Wnt, Hedgehog or BMP. The niche is specialized in preventing differentiation, maintaining CSC stemness and environments suitable for tumor survival and progression [126]. The niche is also an interactive network that is capable of metabolic sensing and mechanical inputs. Through adhesion molecules and paracrine factors, stem cells within the niche interact with supporting cells forming a complex network. Cell contact signals and exchanges in molecular signals help maintain the niche and support the unique characteristics of stem cells (pluripotency and self-renewal). Hypoxic sites in tumors can produce CSC niches and induce stemness in tumor cells through hypoxia inducible factor 1 (HIF-1) and activation of transcription factors involved in reprogramming of iPSCs: Oct4, Sox2, Nanog and KLF4 [127]. Hypoxic microenvironments also lead to increased VEGF and E-cadherin levels [128]. The tissue microenvironment is a powerful line of defense against tumorigenesis. Embryonic skin in the uterus can inhibit tumor formation of implanted murine B16 malignant melanoma cells. Likewise, chick and zebrafish embryonic microenvironments have been observed to inhibit tumor formation of implanted cancer cells [129; 130; 131; 132]. The normal tissue microenvironment can be influenced and transformed into a malignant niche by cancer cells and the supporting stroma or necessary cells. In melanoma, endothelial cells and fibroblasts secrete factors that facilitate melanocyte cell movement from the basement membrane while accelerating the tumorigenic transformation of melanocytes [133; 128; 134]. Cancer-associated fibroblasts (CAFs) secrete hepatocyte growth factor and TGF-\(\beta\), which mediate mutant p53-dependent invasion and metastasis. _mut_p53, through prolonging of NF-\(\kappa\)B activation and cell survival, can promote the inflammatory environment needed for the development of colorectal tumors. [PERSON] et al. (2015) [135] reported a novel _mut_p53 GOF in promoting inflammatory signals by the repression of the secreted interleukin-1 receptor antagonist (sIL-1 Ra). The findings demonstrate that _mut_p53 tumorigenesis requires sIL-1 Ra suppression, resulting in a chronic pro-inflammatory tumor microenvironment. _mut_p53 influences tumor and microenvironment interactions and may induce pro-oncogenic GOF changes in tumors and stromal cells alike. As demonstrated by [PERSON] et al. (2010) [136], _mut_p53-expressing fibroblasts could promote tumor growth better than p53 null fibroblasts. _Mut_p53 GOF activities have been identified in cell reprogramming, expansion, maintenance and interaction with the tumor stroma. It is well known that _wt_p53 is a suppressor of somatic stem cell reprogramming, preventing differentiated somatic cells from being reprogrammed into pluripotent stem cells with unlimited expansion ability. _Mut_p53 can initiate tumor formation by promoting the generation and expansion of pluripotent cells. For example, loss of p53 results in the de-differentiation of somatic cells, while _mut_p53 enhances reprogramming [137; 138; 139; 20]. [PERSON] et al.